DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org; Henderson, Randal; Pham, Dat

Purpose: Proton therapy has been shown to reduce radiation dose to organs at risk (OAR) and could be used to safely escalate the radiation dose. We analyzed outcomes in a group of phase 2 study patients treated with dose-escalated proton therapy with concurrent chemotherapy for stage 3 non-small cell lung cancer (NSCLC). Methods and Materials: From 2009 through 2013, LU02, a phase 2 trial of proton therapy delivering 74 to 80 Gy at 2 Gy/fraction with concurrent chemotherapy for stage 3 NSCLC, was opened to accrual at our institution. Due to slow accrual and competing trials, the study was closed after justmore » 14 patients (stage IIIA, 9 patients; stage IIIB, 5 patients) were accrued over 4 years. During that same time period, 55 additional stage III patients were treated with high-dose proton therapy, including 7 in multi-institutional proton clinical trials, 4 not enrolled due to physician preference, and 44 who were ineligible based on strict entry criteria. An unknown number of patients were ineligible for enrollment due to insurance coverage issues and thus were treated with photon radiation. Median follow-up of surviving patients was 52 months. Results: Two-year overall survival and progression-free survival rates were 57% and 25%, respectively. Median lengths of overall survival and progression-free survival were 33 months and 14 months, respectively. There were no acute grade 3 toxicities related to proton therapy. Late grade 3 gastrointestinal toxicity and pulmonary toxicity each occurred in 1 patient. Conclusions: Dose-escalated proton therapy with concurrent chemotherapy was well tolerated with encouraging results among a small cohort of patients. Unfortunately, single-institution proton studies may be difficult to accrue and consideration for pragmatic and/or multicenter trial design should be considered when developing future proton clinical trials.« less

Escalation to High Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease

PubMed Central

Triplett, Brandon M.; Kuttab, Hani I.; Kang, Guolian; Leung, Wing

2015-01-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10–100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. PMID:26278046

Selection of the initial design for the two-stage continual reassessment method.

PubMed

Jia, Xiaoyu; Ivanova, Anastasia; Lee, Shing M

2017-01-01

In the two-stage continual reassessment method (CRM), model-based dose escalation is preceded by a pre-specified escalating sequence starting from the lowest dose level. This is appealing to clinicians because it allows a sufficient number of patients to be assigned to each of the lower dose levels before escalating to higher dose levels. While a theoretical framework to build the two-stage CRM has been proposed, the selection of the initial dose-escalating sequence, generally referred to as the initial design, remains arbitrary, either by specifying cohorts of three patients or by trial and error through extensive simulations. Motivated by a currently ongoing oncology dose-finding study for which clinicians explicitly stated their desire to assign at least one patient to each of the lower dose levels, we proposed a systematic approach for selecting the initial design for the two-stage CRM. The initial design obtained using the proposed algorithm yields better operating characteristics compared to using a cohort of three initial design with a calibrated CRM. The proposed algorithm simplifies the selection of initial design for the two-stage CRM. Moreover, initial designs to be used as reference for planning a two-stage CRM are provided.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

PubMed

Alistar, Angela; Morris, Bonny B; Desnoyer, Rodwige; Klepin, Heidi D; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W; Boteju, Asela R; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J; Pardee, Timothy S; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris

2017-06-01

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center. Copyright © 2017 Elsevier Ltd. All rights reserved.

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PubMed

Belderbos, José S A; De Jaeger, Katrien; Heemsbergen, Wilma D; Seppenwoolde, Yvette; Baas, Paul; Boersma, Liesbeth J; Lebesque, Joos V

2003-02-01

To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma1

PubMed Central

Quinn, Jennifer A.; Reardon, David A.; Friedman, Allan H.; Rich, Jeremy N.; Sampson, John H.; Vredenburgh, James; Gururangan, Sridharan; Provenzale, James M.; Walker, Amy; Schweitzer, Holly; Bigner, Darell D.; Tourt-Uhlig, Sandra; Herndon, James E.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah; Ziegler, Karen; Bohlin, Cindy; Lentz, Christy; Friedman, Henry S.

2004-01-01

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs. PMID:15134629

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer.

PubMed

Wang, Kyle; Pearlstein, Kevin A; Patchett, Nicholas D; Deal, Allison M; Mavroidis, Panayiotis; Jensen, Brian C; Lipner, Matthew B; Zagar, Timothy M; Wang, Yue; Lee, Carrie B; Eblan, Michael J; Rosenman, Julian G; Socinski, Mark A; Stinchcombe, Thomas E; Marks, Lawrence B

2017-11-01

To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of PET and Other Functional Imaging to Guide Target Delineation in Radiation Oncology.

PubMed

Verma, Vivek; Choi, J Isabelle; Sawant, Amit; Gullapalli, Rao P; Chen, Wengen; Alavi, Abass; Simone, Charles B

2018-06-01

Molecular and functional imaging is increasingly being used to guide radiotherapy (RT) management and target delineation. This review summarizes existing data in several disease sites of various functional imaging modalities, chiefly positron emission tomography/computed tomography (PET/CT), with respect to RT target definition and management. For gliomas, differentiation between postoperative changes and viable tumor is discussed, as well as focal dose escalation and reirradiation. Head and neck neoplasms may also benefit from precise PET/CT-based target delineation, especially for cancers of unknown primary; focal dose escalation is also described. In lung cancer, PET/CT can influence coverage of tumor volumes, dose escalation, and adaptive management. For cervical cancer, PET/CT as an adjunct to magnetic resonance imaging planning is discussed, as are dose escalation and delineation of avoidance targets such as the bone marrow. The emerging role of choline-based PET for prostate cancer and its impact on dose escalation is also described. Lastly, given the essential role of PET/CT for target definition in lymphoma, phase III trials of PET-directed management are reviewed, along with novel imaging modalities. Taken together, molecular and functional imaging approaches offer a major step to individualize radiotherapeutic care going forward. Copyright © 2018 Elsevier Inc. All rights reserved.

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer☆

PubMed Central

Warren, Samantha; Partridge, Mike; Carrington, Rhys; Hurt, Chris; Crosby, Thomas; Hawkins, Maria A.

2014-01-01

Purpose This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm3. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001. Conclusions Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials. PMID:25304796

Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

PubMed

Huang, Alison J; Cummings, Steven R; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2016-03-01

To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

Continuous Transdermal Nitroglycerin Therapy for Menopausal Hot Flashes: A Single-Arm Dose-Escalation Trial

PubMed Central

Huang, Alison J.; Cummings, Steven R.; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

2015-01-01

Objective To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Methods Peri- and postmenopausal women reporting at least 7 hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hr nitroglycerin patch applied daily without patch-free periods. Over four weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hr as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t-tests examined change in outcomes between baseline and maximal-dose therapy as well as after discontinuation of nitroglycerin. Results Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hr, three to 0.4 mg/hr, two to 0.2 mg/hr, and one remained on 0.1 mg/hr nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P=0.041) and 96% increase in moderate-to-severe hot flashes (P<0.001). Conclusions Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel non-hormonal hot flash treatment. PMID:26263283

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

PubMed

Triplett, Brandon M; Kuttab, Hani I; Kang, Guolian; Leung, Wing

2015-12-01

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than the 3 + 3 Design for Practical Phase I Trials

PubMed Central

Ji, Yuan; Wang, Sue-Jane

2013-01-01

The 3 + 3 design is the most common choice among clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 95% of phase I trials have been based on the 3 + 3 design. Given that it is intuitive and its implementation does not require a computer program, clinicians can conduct 3 + 3 dose escalations in practice with virtually no logistic cost, and trial protocols based on the 3 + 3 design pass institutional review board and biostatistics reviews quickly. However, the performance of the 3 + 3 design has rarely been compared with model-based designs in simulation studies with matched sample sizes. In the vast majority of statistical literature, the 3 + 3 design has been shown to be inferior in identifying true maximum-tolerated doses (MTDs), although the sample size required by the 3 + 3 design is often orders-of-magnitude smaller than model-based designs. In this article, through comparative simulation studies with matched sample sizes, we demonstrate that the 3 + 3 design has higher risks of exposing patients to toxic doses above the MTD than the modified toxicity probability interval (mTPI) design, a newly developed adaptive method. In addition, compared with the mTPI design, the 3 + 3 design does not yield higher probabilities in identifying the correct MTD, even when the sample size is matched. Given that the mTPI design is equally transparent, costless to implement with free software, and more flexible in practical situations, we highly encourage its adoption in early dose-escalation studies whenever the 3 + 3 design is also considered. We provide free software to allow direct comparisons of the 3 + 3 design with other model-based designs in simulation studies with matched sample sizes. PMID:23569307

[A comparative study of the effectiveness and tolerability of a procedure involving slow dose-escalation of rivastigmine in patients with mild or moderate Alzheimer-type dementia: the SCALEX study].

PubMed

Agüera-Ortiz, L F; Ramos-García, M; Gobartt, A L

To determine and to compare the tolerability and effectiveness of a slow escalation of the dose of rivastigmine in patients with Alzheimer's disease with respect to using it with a faster escalation. We conducted a multi-centre, naturalistic, open-label, randomised trial with 429 hospital outpatients diagnosed with Alzheimer-type dementia (according to DSM-IV and NINCDS-ADRA criteria) and in whom treatment with rivastigmine was clinically indicated. Two study groups were established: slow escalation and fast escalation (in accordance with usual clinical practice); effectiveness and tolerability variables were analysed in the two groups, as was the proportion of patients who reached therapeutic doses (> 6 mg/day). The scores obtained on the CGI, MMSE, NPI and Barthel index scales were analysed, together with adverse events and reactions concerning spontaneous communication, and scores on the UKU scale. The slow escalation group displayed slightly higher percentages of sub-therapeutic anticipated interruptions than the fast escalation group (chi-square test; p < 0.05). On comparing the two treatment groups, no statistically significant differences were observed for the evolution of the scores on the different scales of effectiveness; no statistically significant differences were found between the two groups in the safety and tolerability analyses (chi-square test, exact test; p > 0.05) for most of the parameters that were studied (adverse reactions in spontaneous communication and the modified UKU scale). Slow escalation of the dose of rivastigmine did not display greater effectiveness or tolerability in comparison to an escalation applied in accordance with usual clinical practice.

Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Syndikus, Isabel; Morgan, Rachel C.; Sydes, Matthew R., E-mail: ms@ctu.mrc.ac.u

2010-07-01

Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Managementmore » (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade {>=}2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade {>=}2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade {>=}2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.« less

75 FR 73104 - Clinical Development Programs for Sedation Products; Request for Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-29

... sedation claims? Would dose-escalation comparative trial designs be useful in studying sedation products? 5... understanding the physiology of sedation and clinical trial design issues related to the development of sedation... to procedural and intensive care unit (ICU) sedation, as well as associated clinical trial design...

Learning From Trials on Radiation Dose in Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, Jeffrey, E-mail: jbradley@wustl.edu; Hu, Chen

2016-11-15

In this issue of the International Journal of Radiation Oncology • Biology • Physics, Taylor et al present a meta-analysis of published data supporting 2 findings: (1) radiation dose escalation seems to benefit patients who receive radiation alone for non-small cell lung cancer; and (2) radiation dose escalation has a detrimental effect on overall survival in the setting of concurrent chemotherapy. The latter finding is supported by data but has perplexed the oncology community. Perhaps these findings are not perplexing at all. Perhaps it is simply another lesson in the major principle in radiation oncology, to minimize radiation dose to normalmore » tissues.« less

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

ERIC Educational Resources Information Center

Malow, Beth; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2012-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures…

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

PubMed

Saber, Haleh; Del Valle, Pedro; Ricks, Tiffany K; Leighton, John K

2017-11-01

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe. Published by Elsevier Inc.

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morris, W. James, E-mail: jmorris@bccancer.bc.ca; BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398more » trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.« less

Phase I/II prospective trial of cancer-specific imaging using ultrasound spectrum analysis tissue-type imaging to guide dose-painting prostate brachytherapy.

PubMed

Ennis, Ronald D; Quinn, S Aidan; Trichter, Frieda; Ryemon, Shannon; Jain, Anudh; Saigal, Kunal; Chandrashekhar, Sarayu; Romas, Nicholas A; Feleppa, Ernest J

2015-01-01

To assess the technical feasibility, toxicity, dosimetry, and preliminary efficacy of dose-painting brachytherapy guided by ultrasound spectrum analysis tissue-type imaging (TTI) in low-risk, localized prostate cancer. Fourteen men with prostate cancer who were candidates for brachytherapy as sole treatment were prospectively enrolled. Treatment planning goal was to escalate the tumor dose to 200% with a modest de-escalation of dose to remaining prostate compared with our standard. Primary end points included technical feasibility of TTI-guided brachytherapy and equivalent or better toxicity compared with standard brachytherapy. Secondary end points included dose escalation to tumor regions and de-escalated dose to nontumor regions on the preimplant plan, negative prostate biopsy at 2 years, and freedom from biochemical failure. Thirteen of fourteen men successfully completed the TTI-guided brachytherapy procedure for a feasibility rate of 93%. A software malfunction resulted in switching one patient from TTI-guided to standard brachytherapy. An average of 2.7 foci per patient was demonstrated and treated with an escalated dose. Dosimetric goals on preplan were achieved. One patient expired from unrelated causes 65 days after brachytherapy. Toxicity was at least as low as standard brachytherapy. Two-year prostate biopsies were obtained from six men; five (83%) were definitively negative, one showed evidence of disease with treatment effect, and none were positive. No patients experienced biochemical recurrence after a median followup of 31.5 (24-52) months. We have demonstrated that TTI-guided dose-painting prostate brachytherapy is technically feasible and results in clinical outcomes that are encouraging in terms of low toxicity and successful biochemical disease control. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk; Partridge, Mike; Carrington, Rhys

2014-10-01

Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5more » Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.« less

Randomized Double-Blinded Dose Escalation Trial of Triptorelin for Ovary Protection in Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Brunner, Hermine I.; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C.; Imundo, Lisa; Williams, Calvin B.; Wallace, Carol A; Aikawa, Nadia E.; Nelson, Shannen; Klein-Gitelman, Marisa S.; Rose, Susan R.

2015-01-01

Objectives To determine for females with childhood-onset systemic lupus erythematosus (cSLE) who require cyclophosphamide the dose of triptorelin that suffices to maintain complete ovarian suppression (COS); measure the time needed to achieve ovarian suppression after triptorelin initiation, and explore the safety of triptorelin. Methods In this randomized double-blind placebo-controlled dose-escalation study females (< 21 years) were randomized 4:1 to receive triptorelin or placebo (25 triptorelin, 6 placebo). Starting doses of triptorelin between 25 and 100 microgram/kg/dose were used. Triptorelin dosage was escalated until COS was maintained. The primary outcome was the weight-adjusted dose of triptorelin that for at least 90% of the patients provides COS based on Gonadotropin-releasing-hormone Agonist Stimulation Testing. Secondary outcomes were time to ovarian suppression measured by unstimulated FSH and LH levels after study drug initiation. Results Triptorelin dosed at 120 microgram/kg bodyweight led to sustained COS in 90% of the patients. After the initial dose of triptorelin 22 days were needed for achieve COS. Rates of adverse events (AE) and serious adverse events (SAE) per 100 patient-month of follow-up were not higher in the triptorelin group as compared to the placebo group (triptorelin vs. placebo; AE: 189 vs. 362; SAE: 2.05 vs. 8.48). Conclusions For achieving and maintaining COS high doses of triptorelin are needed but appear to be well tolerated in adolescent females with cSLE. Our data suggest that a lag time of 22 days after triptorelin initiation is required before starting or continuing cyclophosphamide-therapy. Trial Registration Number clinicaltrials.gov identifier: NCT00124514 PMID:25676588

Communicating and understanding the purpose of pediatric phase I cancer trials.

PubMed

Cousino, Melissa K; Zyzanski, Stephen J; Yamokoski, Amy D; Hazen, Rebecca A; Baker, Justin N; Noll, Robert B; Rheingold, Susan R; Geyer, J Russell; Alexander, Stewart C; Drotar, Dennis; Kodish, Eric D

2012-12-10

Quality informed consent should provide a clear understanding of the purpose of the research. Given the ethical challenges of pediatric phase I cancer trials, it is important to investigate physician-parent communication during informed consent conferences (ICCs) and parental understanding of the purpose of these studies. In the multisite Informed Consent in Pediatric Phase I Cancer Trials study, 85 ICCs for phase I research between June 2008 and May 2011 were directly observed, and 60 parents were subsequently interviewed. The scientific purpose was defined as composite understanding of drug safety, dose finding, and dose escalation. We determined the frequency with which physicians explained these and other phase I-related concepts during the ICC. Parent interviews were analyzed to determine understanding. The child was present at 83 of 85 ICCs. Only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I cancer trials; 35% demonstrated little or no understanding. Parents of higher socioeconomic status and racial majority status were more likely to understand the scientific purpose. Factors associated with understanding included physician explanation of the goal of the applicable phase I protocol offered (explained in 85% of ICCs) and explanation of the dose cohorts (explained in 43% of ICCs). Physicians explained drug safety in 23% of ICCs, dose finding in 52% of ICCs, and dose escalation in 53% of ICCs. Many parents of children participating in phase I trials do not understand the purpose of these trials. Physician-parent communication about the purpose of phase I research is lacking during ICCs.

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012.

PubMed

Brower, Jeffrey V; Chen, Shuai; Bassetti, Michael F; Yu, Menggang; Harari, Paul M; Ritter, Mark A; Baschnagel, Andrew M

2016-12-01

To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Biological PET-guided adaptive radiotherapy for dose escalation in head and neck cancer: a systematic review.

PubMed

Hamming-Vrieze, Olga; Navran, Arash; Al-Mamgani, Abrahim; Vogel, Wouter V

2018-06-04

In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor. A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by i) delineation of sub-volumes suitable for adaptive re-planning, ii) in silico adaptive treatment planning or iii) treatment of patients with PET based dose escalated adaptive radiotherapy. Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT). In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.

Dose escalation in permanent brachytherapy for prostate cancer: dosimetric and biological considerations

NASA Astrophysics Data System (ADS)

Li, X. Allen; Wang, Jian Z.; Stewart, Robert D.; Di Biase, Steven J.

2003-09-01

No prospective dose escalation study for prostate brachytherapy (PB) with permanent implants has been reported. In this work, we have performed a dosimetric and biological analysis to explore the implications of dose escalation in PB using 125I and 103Pd implants. The concept of equivalent uniform dose (EUD), proposed originally for external-beam radiotherapy (EBRT), is applied to low dose rate brachytherapy. For a given 125I or 103Pd PB, the EUD for tumour that corresponds to a dose distribution delivered by EBRT is calculated based on the linear quadratic model. The EUD calculation is based on the dose volume histogram (DVH) obtained retrospectively from representative actual patient data. Tumour control probabilities (TCPs) are also determined in order to compare the relative effectiveness of different dose levels. The EUD for normal tissue is computed using the Lyman model. A commercial inverse treatment planning algorithm is used to investigate the feasibility of escalating the dose to prostate with acceptable dose increases in the rectum and urethra. The dosimetric calculation is performed for five representative patients with different prostate sizes. A series of PB dose levels are considered for each patient using 125I and 103Pd seeds. It is found that the PB prescribed doses (minimum peripheral dose) that give an equivalent EBRT dose of 64.8, 70.2, 75.6 and 81 Gy with a fraction size of 1.8 Gy are 129, 139, 150 and 161 Gy for 125I and 103, 112, 122 and 132 Gy for 103Pd implants, respectively. Estimates of the EUD and TCP for a series of possible prescribed dose levels (e.g., 145, 160, 170 and 180 Gy for 125I and 125, 135, 145 and 155 for 103Pd implants) are tabulated. The EUD calculation was found to depend strongly on DVHs and radiobiological parameters. The dosimetric calculations suggest that the dose to prostate can be escalated without a substantial increase in both rectal and urethral dose. For example, increasing the PB prescribed dose from 145 to 180 Gy increases EUD for the rectum by only 3%. Our studies indicate that the dose to urethra can be kept within 100-120% of the prescription dose for all the dose levels studied. In conclusion, dose escalation in permanent implant for localized prostate cancer may be advantageous. It is dosimetrically possible to increase dose to prostate without a substantial increase in the dose to the rectum and urethra. Based on the results of our studies, a prospective dose escalation trial for prostate permanent implants has been initiated at our institution.

SU-D-202-01: Functional Lung Avoidance and Response-Adaptive Escalation (FLARE) RT: Feasibility of a Precision Radiation Oncology Strategy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, S; Lee, E; Miyaoka, R

Purpose: NSCLC patient RT is planned without consideration of spatial heterogeneity in lung function or tumor response, which may have contributed to failed uniform dose escalation in a randomized trial. The feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [{sup 99m}Tc]MAA-SPECT/CT perfused lung while redistributing 74Gy within [{sup 18}F]FDG-PET/CT biological target volumes was assessed. Methods: Eight Stage IIB–IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain <20Gy mean lung dose (MLD). Prescriptions included 60Gy to PTV and concomitantmore » boost of 74Gy mean to biological target volumes (BTV=GTV+PET margin) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial TPS via previously reported ROI discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with VMAT, proton pencil beam scanning (PBS) with 3%-3mm robust optimization, and combination PBS (avoidance) plus VMAT (escalation). Dosimetric differences were evaluated by Friedman non-parametric paired test with multiple sampling correction. Results: PTV and normal tissue objectives were not violated in 24 FLARE RT plans. Population median of mean BTV dose was 73.7Gy (68.5–75.5Gy), mean FDG-PET peak dose was 89.7Gy (73.5–103Gy), MLD was 12.3Gy (7.5–19.6Gy), and perfused MLD was 4.8Gy (0.9–12.1Gy). VMAT achieved higher dose to the FDG-PET peak subvolume (p=0.01), while PBS delivered lower dose to lung (p<0.001). Voxelwise linear correlation between BTV dose and FDG-PET uptake was higher for VMAT (R=0.93) and PBS+VMAT (R=0.94) compared to PBS alone (R=0.89). Conclusion: FLARE RT is feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG-PET dose escalation balances target/normal tissue objective tradeoffs. These results support future testing of FLARE RT safety and efficacy within a precision radiation oncology trial. This work was supported by a Research Scholar grant from the Radiological Society of North American Research & Education Foundation.« less

Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd.

PubMed

Hughes, Timothy P; Munhoz, Eduardo; Aurelio Salvino, Marco; Ong, Tee Chuan; Elhaddad, Alaa; Shortt, Jake; Quach, Hang; Pavlovsky, Carolina; Louw, Vernon J; Shih, Lee-Yung; Turkina, Anna G; Meillon, Luis; Jin, Yu; Acharya, Sandip; Dalal, Darshan; Lipton, Jeffrey H

2017-10-01

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2-75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188). © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu; Ayala, Deandra; Jensen, Courtney

2012-02-01

Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patientsmore » experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.« less

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

PubMed Central

2010-01-01

Background YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. Methods This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. Results Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. Conclusions The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. Trial registration ClinicalTrials.gov unique identifier: NCT00633490 PMID:20923544

Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rahimi, Asal, E-mail: asal.rahimi@utsouthwestern.edu; Thomas, Kimberly; Spangler, Ann

Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohortmore » to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting.« less

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PubMed

Socinski, Mark A; Morris, David E; Halle, Jan S; Moore, Dominic T; Hensing, Thomas A; Limentani, Steven A; Fraser, Robert; Tynan, Maureen; Mears, Andrea; Rivera, M Patricia; Detterbeck, Frank C; Rosenman, Julian G

2004-11-01

Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brower, Jeffrey V.; Chen, Shuai; Bassetti, Michael F.

Purpose: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Methods and Materials: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. Results: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received dosesmore » >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). Conclusions: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.« less

PHP-HT (VitaResc Biotech).

PubMed

Baldwin, A; Wiley, E

2001-04-01

VitaResc (formerly Apex) is developing PHP-HT, pyridoxalated hemoglobin polyoxyethylene conjugate, for the potential treatment of nitric oxide-induced shock (characterized by hypotension), associated with various etiologies, initially in septic shock. A phase I safety study and an initial phase I/II patient trial for NO-induced shock have been completed, and VitaResc has enrolled patients in three of five planned cohorts in a continuation of these trials to include a protocol of continuous infusion and dose escalation [330680,349187,390918]. The results from the dose escalation trials are expected to provide the basis for a randomized, controlled phase II/III pivotal trial of PHP-HT [390918]. VitaResc has licensed PHP-HT exclusively from Ajinomoto for all indications, worldwide, except Japan [275263]. Ajinomoto originally developed the human derived and chemically modified hemoglobin preparation as a blood substitute, but no development has been reported by the company since 1997 [275277,303577]. The other potential indications of PHP-HT include shock associated with burns, pancreatitis, hemodialysis and cytokine therapies [275277]. VitaResc expects the annual market potential of PHP-HT to exceed 1 billion dollars [330680].

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

PubMed

Chisholm, Julia C; Suvada, Jozef; Dunkel, Ira J; Casanova, Michela; Zhang, Weijiang; Ritchie, Natasha; Choi, YounJeong; Park, Jane; Das Thakur, Meghna; Simko, Stephen; Wan Rachel Tam, Nga; Ferrari, Andrea

2018-05-01

Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials. © 2018 Wiley Periodicals, Inc.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Landau, David B., E-mail: david.landau@kcl.ac.uk; Hughes, Laura; Baker, Angela

2016-08-01

Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumormore » doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.« less

Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers.

PubMed

Zhou, Yinghui; Whitehead, John; Korhonen, Pasi; Mustonen, Mika

2008-03-01

Bayesian decision procedures have recently been developed for dose escalation in phase I clinical trials concerning pharmacokinetic responses observed in healthy volunteers. This article describes how that general methodology was extended and evaluated for implementation in a specific phase I trial of a novel compound. At the time of writing, the study is ongoing, and it will be some time before the sponsor will wish to put the results into the public domain. This article is an account of how the study was designed in a way that should prove to be safe, accurate, and efficient whatever the true nature of the compound. The study involves the observation of two pharmacokinetic endpoints relating to the plasma concentration of the compound itself and of a metabolite as well as a safety endpoint relating to the occurrence of adverse events. Construction of the design and its evaluation via simulation are presented.

Twelve Months of Nightly Zolpidem Does Not Lead to Dose Escalation: A Prospective Placebo-Controlled Study

PubMed Central

Roehrs, Timothy A.; Randall, Surilla; Harris, Erica; Maan, Renee; Roth, Thomas

2011-01-01

Study Objectives: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Design: Randomized, double-blind, placebo-controlled, clinical trial. Setting: Outpatient with tri-monthly one-week, sleep laboratory assessments. Participants: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32–64 yrs old, 14 men and 19 women. Interventions: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Results: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Conclusions: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. Clinical Trial Registration: Safety and Efficacy of Chronic Hypnotic Use; # NCT01006525; http://www.clinicaltrials.gov/ Citation: Roehrs TA; Randall S; Harris E; Maan R; Roth T. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study. SLEEP 2011;34(2):207–212. PMID:21286241

Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen.

PubMed

Henke, Lauren; Kashani, Rojano; Robinson, Clifford; Curcuru, Austen; DeWees, Todd; Bradley, Jeffrey; Green, Olga; Michalski, Jeff; Mutic, Sasa; Parikh, Parag; Olsen, Jeffrey

2018-03-01

SBRT is used to treat oligometastatic or unresectable primary abdominal malignancies, although ablative dose delivery is limited by proximity of organs-at-risk (OAR). Stereotactic, magnetic resonance (MR)-guided online-adaptive radiotherapy (SMART) may improve SBRT's therapeutic ratio. This prospective Phase I trial assessed feasibility and potential advantages of SMART to treat abdominal malignancies. Twenty patients with oligometastatic or unresectable primary liver (n = 10) and non-liver (n = 10) abdominal malignancies underwent SMART. Initial plans prescribed 50 Gy/5 fractions (BED 100 Gy) with goal 95% PTV coverage by 95% of prescription, subject to hard OAR constraints. Daily real-time online-adaptive plans were created as needed, based on daily setup MR-image-set tumor/OAR "anatomy-of-the-day" to preserve hard OAR constraints, escalate PTV dose, or both. Treatment times, patient outcomes, and dosimetric comparisons between initial and adaptive plans were prospectively recorded. Online adaptive plans were created at time of treatment for 81/97 fractions, due to initial plan violation of OAR constraints (61/97) or observed opportunity for PTV dose escalation (20/97). Plan adaptation increased PTV coverage in 64/97 fractions. Zero Grade ≥ 3 acute (<6 months) treatment-related toxicities were observed. SMART is clinically deliverable and safe, allowing PTV dose escalation and/or simultaneous OAR sparing compared to non-adaptive abdominal SBRT. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talleur, Aimee C.; Navid, Fariba; Spunt, Sheri L.

Purpose: To determine the rate of local failure using focal conformal, limited margin radiation therapy (RT) and dose escalation for tumors ≥8 cm (greatest dimension at diagnosis) in children and young adults with Ewing sarcoma (EWS). Methods and Materials: Eligible patients with EWS were treated on a phase 2 institutional trial of focal conformal, limited margin RT using conformal or intensity modulated techniques. The treatment volume incorporated a 1-cm constrained margin around the gross tumor. Unresected tumors, <8 cm at diagnosis, received a standard dose of 55.8 Gy and tumors ≥8 cm, an escalated dose to 64.8 Gy. Patients with microscopic residual disease after resectionmore » received adjuvant RT to 50.4 Gy. Adjuvant brachytherapy was permitted in selected patients. Results: Forty-five patients were enrolled: 26 with localized and 19 with metastatic disease. Median (range) age, tumor size, and follow-up were 13.0 years (2.9-24.7 years), 9.0 cm (2.4-17.0 cm), and 54.5 months (1.9-122.2 months), respectively. All patients received systemic chemotherapy. The median (range) RT dose for all patients was 56.1 Gy (45-65.5 Gy). Seventeen patients received adjuvant, 16 standard-dose, and 12 escalated-dose RT. Failures included 1 local, 10 distant, and 1 local/distant. The estimated 10-year cumulative incidence of local failure was 4.4% ± 3.1%, with no statistical difference seen between RT treatment groups and no local failures in the escalated-dose RT treatment group. Conclusions: Treatment with focal conformal, limited margin RT, including dose escalation for larger tumors, provides favorable local tumor control in EWS.« less

Clonidine Extended-Release Tablets for Pediatric Patients with Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Jain, Rakesh; Segal, Scott; Kollins, Scott H.; Khayrallah, Moise

2011-01-01

Objective: This study examined the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Method: This 8-week, placebo-controlled, fixed-dose trial, including 3 weeks of dose escalation, of patients 6 to 17 years old with ADHD evaluated the…

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

PubMed Central

2013-01-01

Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. Trial registration ClinicalTrials.gov number:NCT00978211 PMID:23320604

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Thaker, Premal H.; Brady, William E.; Lankes, Heather A.; Odunsi, Kunle; Bradley, William H.; Moore, Kathleen N.; Muller, Carolyn Y.; Anwer, Khursheed; Schilder, Russell J.; Alvarez, Ronald D.; Fracasso, Paula M.

2017-01-01

Objective The study’s purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID:28802766

Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brade, Anthony M., E-mail: anthony.brade@rmp.uhn.on.ca; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario; Ng, Sylvia

Purpose: To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). Methods and Materials: Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated.more » Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. Results: Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level −1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. Conclusions: Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.« less

Positron Emission Tomography-Guided, Focal-Dose Escalation Using Intensity-Modulated Radiotherapy for Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madani, Indira; Duthoy, Wim; Derie, Cristina R.N.

2007-05-01

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [{sup 18}-F]fluoro-2-deoxy-D-glucose positron emission tomography ({sup 18}F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was appliedmore » for the remaining 22 fractions of 2.16 Gy. Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted {sup 18}F-FDG-PET-delineated region. Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.« less

Randomized Clinical Trials of Gene Transfer for Heart Failure with Reduced Ejection Fraction.

PubMed

Penny, William F; Hammond, H Kirk

2017-05-01

Despite improvements in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid. The initial CUPID trial randomized 14 subjects to placebo and 25 subjects to escalating doses of adeno-associated virus type 1 encoding sarcoplasmic reticulum calcium ATPase (AAV1.SERCA2a). AAV1.SERCA2a was well tolerated, and the high-dose group met a 6 month composite endpoint. In the subsequent CUPID-2 study, 243 subjects received either placebo or the high dose of AAV1.SERCA2a. AAV1.SERCA2a administration, while safe, failed to meet the primary or any secondary endpoints. STOP-HF used plasmid endocardial injection of stromal cell-derived factor-1 to promote stem-cell recruitment. In a 93-subject trial of patients with ischemic etiology heart failure, the primary endpoint (symptoms and 6 min walk distance) failed, but subgroup analyses showed improvements in subjects with the lowest ejection fractions. A fourth trial randomized 14 subjects to placebo and 42 subjects to escalating doses of adenovirus-5 encoding adenylyl cyclase 6 (Ad5.hAC6). There were no safety concerns, and patients in the two highest dose groups (combined) showed improvements in left ventricular function (left ventricular ejection fraction and -dP/dt). The safety data from four randomized clinical trials of gene transfer in patients with symptomatic HFrEF suggest that this approach can be conducted with acceptable risk, despite invasive delivery techniques in a high-risk population. Additional trials are necessary before the approach can be endorsed for clinical practice.

Stereotactic Injection of DTI-015 into Recurrent Malignant Gliomas: Phase I/II Trial

PubMed Central

Hassenbusch, Samuel J; Nardone, Emilio M; Levin, Victor A; Leeds, Norman; Pietronigro, Dennis

2003-01-01

Abstract DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the intratumoral treatment of gliomas. The ethanol solvent vehicle facilitates a rapid and thorough saturation of the tumor with the dissolved anticancer agent BCNU. We conducted a phase I/II dose escalation study of DTI-015 in 40 heavily pretreated patients with inoperable recurrent malignant glioma. The study goals were to establish a maximally tolerated dose (MTD) for DTI-015 and assess its safety and activity. Patients received stereotactic intratumoral injection of DTI-015 under magnetic resonance imaging guidance. Dose escalation was performed in two phases. First, DTI-015 volume was escalated at a set BCNU concentration of 12.5 mg/ml; second, BCNU mg dose was escalated by increasing BCNU concentration to 30, 45, 60, and 75 mg/ml. A MTD of 5 ml and 240 mg was established. Twenty-five of 28 DTI-015 treatments (89%) using ≤MTD were administered safely without producing high-grade drug-related adverse events. Median survival for GBM patients administered DTI-015 at ≤MTD was 55 weeks. Magnetic resonance imaging demonstrated stable disease in 72% of evaluable patients with a median of 10.5 weeks. The results suggest that DTI-015 administered at ≤MTD is well tolerated and active in patients with inoperable recurrent GBM. PMID:12659665

Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy.

PubMed

Kumar, Sameera S; Higgins, Kristin A; McGarry, Ronald C

2017-01-01

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

PubMed

Battelino, Tadej; Rasmussen, Michael Højby; De Schepper, Jean; Zuckerman-Levin, Nehama; Gucev, Zoran; Sävendahl, Lars

2017-10-01

To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin ® SimpleXx ® (0.03 mg/kg; n=2 each) for 7 days. Pharmacokinetic and pharmacodynamic profiles were assessed. Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

PubMed

Pappas, Dimitrios A; John, Ani; Curtis, Jeffrey R; Reed, George W; Karki, Chitra; Magner, Robert; Kremer, Joel M; Shewade, Ashwini; Greenberg, Jeffrey D

2016-06-01

In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. ClinicalTrials.gov identifier, NCT01625650.

Increasing Use of Dose-Escalated External Beam Radiation Therapy for Men With Nonmetastatic Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swisher-McClure, Samuel, E-mail: Swisher-Mcclure@uphs.upenn.edu; Leonard Davis Institute of Health Economics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Mitra, Nandita

Purpose: To examine recent practice patterns, using a large national cancer registry, to understand the extent to which dose-escalated external beam radiation therapy (EBRT) has been incorporated into routine clinical practice for men with prostate cancer. Methods and Materials: We conducted a retrospective observational cohort study using the National Cancer Data Base, a nationwide oncology outcomes database in the United States. We identified 98,755 men diagnosed with nonmetastatic prostate cancer between 2006 and 2011 who received definitive EBRT and classified patients into National Comprehensive Cancer Network (NCCN) risk groups. We defined dose-escalated EBRT as total prescribed dose of ≥75.6 Gy. Usingmore » multivariable logistic regression, we examined the association of patient, clinical, and demographic characteristics with the use of dose-escalated EBRT. Results: Overall, 81.6% of men received dose-escalated EBRT during the study period. The use of dose-escalated EBRT did not vary substantially by NCCN risk group. Use of dose-escalated EBRT increased from 70.7% of patients receiving treatment in 2006 to 89.8% of patients receiving treatment in 2011. On multivariable analysis, year of diagnosis and use of intensity modulated radiation therapy were significantly associated with receipt of dose-escalated EBRT. Conclusions: Our study results indicate that dose-escalated EBRT has been widely adopted by radiation oncologists treating prostate cancer in the United States. The proportion of patients receiving dose-escalated EBRT increased nearly 20% between 2006 and 2011. We observed high utilization rates of dose-escalated EBRT within all disease risk groups. Adoption of intensity modulated radiation therapy was strongly associated with use of dose-escalated treatment.« less

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.

PubMed

Heery, Christopher R; O'Sullivan-Coyne, Geraldine; Madan, Ravi A; Cordes, Lisa; Rajan, Arun; Rauckhorst, Myrna; Lamping, Elizabeth; Oyelakin, Israel; Marté, Jennifer L; Lepone, Lauren M; Donahue, Renee N; Grenga, Italia; Cuillerot, Jean-Marie; Neuteboom, Berend; Heydebreck, Anja von; Chin, Kevin; Schlom, Jeffrey; Gulley, James L

2017-05-01

Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. National Cancer Institute and Merck KGaA. Copyright © 2017 Elsevier Ltd. All rights reserved.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.

PubMed

Clark, Richard E; Polydoros, Fotios; Apperley, Jane F; Milojkovic, Dragana; Pocock, Christopher; Smith, Graeme; Byrne, Jenny L; de Lavallade, Hugues; O'Brien, Stephen G; Coffey, Tony; Foroni, Letizia; Copland, Mhairi

2017-07-01

Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated. Studies of more ambitious de-escalation are warranted. Newcastle University and Bloodwise. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacology of 13-cis-retinoic acid in humans.

PubMed

Kerr, I G; Lippman, M E; Jenkins, J; Myers, C E

1982-05-01

Vitamin A and its analogs (retinoids) have shown great promise for the chemoprevention of cancer as well as being a possible new class of chemotherapeutic agents. A Phase I and II trial of 13-cis-retinoic acid in advanced cancers was initiated, and the clinical pharmacology of the drug was studied. All patients received p.o. 13-cis-retinoic acid starting at 0.5 mg/kg/day, escalating over 4 weeks to a maximum dose of 8 mg/kg/day in divided doses. Although there was a linear correlation of plasma concentration with dose escalation, large inter-individual variations in peak plasma concentrations were noted. At the maximum drug dose, the mean peak plasma concentration was 4 X 10(-6) M. There was little drug accumulation on this schedule, as trough concentrations between p.o. doses often dropped below 1 X 10(-6) M. The drug was metabolized extensively to a metabolite, the concentrations of which exceeding parent 13-cis-retinoic acid concentrations with chronic dosing. Retinol concentrations were below the normal range.

The Acute Effect of Methylphenidate in Brazilian Male Children and Adolescents with ADHD: A Randomized Clinical Trial

ERIC Educational Resources Information Center

Szobot, C. M.; Ketzer, C.; Parente, M. A.; Biederman, J.; Rohde, L. A.

2004-01-01

Objective: To evaluate the acute efficacy of methylphenidate (MPH) in Brazilian male children and adolescents with ADHD. Method: In a 4-day, double-blind, placebo-controlled, randomized, fix dose escalating, parallel-group trial, 36 ADHD children and adolescents were allocated to two groups: MPH (n = 19) and placebo (n = 17). Participants were…

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.

Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV,more » and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.« less

A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diez, Patricia; Vogelius, Ivan S.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

2010-07-15

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.more » Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.« less

Radiotherapy for Prostate Cancer: is it 'what you do' or 'the way that you do it'? A UK Perspective on Technique and Quality Assurance.

PubMed

Mason, M D; Moore, R; Jones, G; Lewis, G; Donovan, J L; Neal, D E; Hamdy, F C; Lane, J A; Staffurth, J N

2016-09-01

The treatment of prostate cancer has evolved markedly over the last 40 years, including radiotherapy, notably with escalated dose and targeting. However, the optimal treatment for localised disease has not been established in comparative randomised trials. The aim of this article is to describe the history of prostate radiotherapy trials, including their quality assurance processes, and to compare these with the ProtecT trial. The UK ProtecT randomised trial compares external beam conformal radiotherapy, surgery and active monitoring for clinically localised prostate cancer and will report on the primary outcome (disease-specific mortality) in 2016 following recruitment between 1999 and 2009. The embedded quality assurance programme consists of on-site machine dosimetry at the nine trial centres, a retrospective review of outlining and adherence to dose constraints based on the trial protocol in 54 participants (randomly selected, around 10% of the total randomised to radiotherapy, n = 545). These quality assurance processes and results were compared with prostate radiotherapy trials of a comparable era. There has been an increasingly sophisticated quality assurance programme in UK prostate radiotherapy trials over the last 15 years, reflecting dose escalation and treatment complexity. In ProtecT, machine dosimetry results were comparable between trial centres and with the UK RT01 trial. The outlining review showed that most deviations were clinically acceptable, although three (1.4%) may have been of clinical significance and were related to outlining of the prostate. Seminal vesicle outlining varied, possibly due to several prostate trials running concurrently with different protocols. Adherence to dose constraints in ProtecT was considered acceptable, with 80% of randomised participants having two or less deviations and planning target volume coverage was excellent. The ProtecT trial quality assurance results were satisfactory and comparable with trials of its era. Future trials should aim to standardise treatment protocols and quality assurance programmes where possible to reduce complexities for centres involved in multiple trials. Copyright © 2016. Published by Elsevier Ltd.

Dose-Volume Parameters of the Corpora Cavernosa Do Not Correlate With Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer: Results From a Dose-Escalation Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wielen, Gerard J. van der; Hoogeman, Mischa S.; Dohle, Gert R.

2008-07-01

Purpose: To analyze the correlation between dose-volume parameters of the corpora cavernosa and erectile dysfunction (ED) after external beam radiotherapy (EBRT) for prostate cancer. Methods and Materials: Between June 1997 and February 2003, a randomized dose-escalation trial comparing 68 Gy and 78 Gy was conducted. Patients at our institute were asked to participate in an additional part of the trial evaluating sexual function. After exclusion of patients with less than 2 years of follow-up, ED at baseline, or treatment with hormonal therapy, 96 patients were eligible. The proximal corpora cavernosa (crura), the superiormost 1-cm segment of the crura, and themore » penile bulb were contoured on the planning computed tomography scan and dose-volume parameters were calculated. Results: Two years after EBRT, 35 of the 96 patients had developed ED. No statistically significant correlations between ED 2 years after EBRT and dose-volume parameters of the crura, the superiormost 1-cm segment of the crura, or the penile bulb were found. The few patients using potency aids typically indicated to have ED. Conclusion: No correlation was found between ED after EBRT for prostate cancer and radiation dose to the crura or penile bulb. The present study is the largest study evaluating the correlation between ED and radiation dose to the corpora cavernosa after EBRT for prostate cancer. Until there is clear evidence that sparing the penile bulb or crura will reduce ED after EBRT, we advise to be careful in sparing these structures, especially when this involves reducing treatment margins.« less

Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making.

PubMed

Yap, Christina; Billingham, Lucinda J; Cheung, Ying Kuen; Craddock, Charlie; O'Quigley, John

2017-12-15

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR . ©2017 American Association for Cancer Research.

American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer.

PubMed

Spratt, Daniel E; Soni, Payal D; McLaughlin, Patrick W; Merrick, Gregory S; Stock, Richard G; Blasko, John C; Zelefsky, Michael J

To review outcomes for high-risk prostate cancer treated with combined modality radiation therapy (CMRT) utilizing external beam radiation therapy (EBRT) with a brachytherapy boost. The available literature for high-risk prostate cancer treated with combined modality radiation therapy was reviewed and summarized. At this time, the literature suggests that the majority of high-risk cancers are curable with multimodal treatment. Several large retrospective studies and three prospective randomized trials comparing CMRT to dose-escalated EBRT have demonstrated superior biochemical control with CMRT. Longer followup of the randomized trials will be required to determine if this will translate to a benefit in metastasis-free survival, disease-specific survival, and overall survival. Although greater toxicity has been associated with CMRT compared to EBRT, recent studies suggest that technological advances that allow better definition and sparing of critical adjacent structures as well as increasing experience with brachytherapy have improved implant quality and the toxicity profile of brachytherapy. The role of androgen deprivation therapy is well established in the external beam literature for high-risk disease, but there is controversy regarding the applicability of these data in the setting of dose escalation. At this time, there is not sufficient evidence for the omission of androgen deprivation therapy with dose escalation in this population. Comparisons with surgery remain limited by differences in patient selection, but the evidence would suggest better disease control with CMRT compared to surgery alone. Due to a series of technological advances, modern combination series have demonstrated unparalleled rates of disease control in the high-risk population. Given the evidence from recent randomized trials, combination therapy may become the standard of care for high-risk cancers. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Radiation Therapy for Locally Advanced Esophageal Cancer.

PubMed

Chun, Stephen G; Skinner, Heath D; Minsky, Bruce D

2017-04-01

The treatment of locally advanced esophageal cancer is controversial. For patients who are candidates for surgical resection, multiple prospective clinical trials have demonstrated the advantages of neoadjuvant chemoradiation. For patients who are medically inoperable, definitive chemoradiation is an alternative approach with survival rates comparable to trimodality therapy. Although trials of dose escalation are ongoing, the standard radiation dose remains 50.4 Gy. Modern radiotherapy techniques such as image-guided radiation therapy with motion management and intensity-modulated radiation therapy are strongly encouraged with a planning objective to maximize conformity to the intended target volume while reducing dose delivered to uninvolved normal tissues. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of ketotifen premedication on adverse reactions during peanut oral immunotherapy

PubMed Central

2014-01-01

Background Oral immunotherapy (OIT) has shown promise in inducing desensitization for food allergy. However, there are safety concerns regarding the frequency and severity of adverse events during food OIT. Objective To evaluate the effect of Ketotifen premedication on adverse reactions during peanut OIT. Methods A randomized single blind placebo controlled pilot study was performed. Peanut OIT was performed using a previously published protocol. Ketotifen was up-titrated to 2 mg twice daily over two weeks (week -2 to 0), followed by a peanut OIT initial escalation day (day 1). Ketotifen was administered from week 0–4 of peanut OIT; reactions to peanut OIT doses were recorded by clinic staff and subject diary. Results Six subjects (median age 10 years, peanut IgE >100kUA/L) were enrolled, 4 randomized to Ketotifen, 2 to placebo. The most common side effect of Ketotifen was fatigue (9% during up-titration). The rate of reaction per peanut OIT dose was lower for subjects on ketotifen (K) compared to placebo (P) during initial escalation on day 1 (K: 22% (8/36) vs. P: 67% (12/18)); week 0–4 build-up doses (K: 75% (3/4) vs. P: 100% (2/2)); and week 0–4 home doses (K: 50% (54/108) vs. P: 82% (27/33)). The rate of gastrointestinal symptoms per peanut OIT dose was also lower for subjects on ketotifen during initial escalation on day 1 (K: 17% (6/36) vs. P: 61% (11/18)); week 0–4 build-up doses (K: 75% (3/4) vs P: 100% (2/2)); and week 0–4 home doses (K: 46% (50/108) vs. P: 82% (27/33)). Conclusions Ketotifen premedication is well tolerated and reduces the rate of gastrointestinal symptoms during peanut OIT. These findings require confirmation in a larger study of Ketotifen premedication used throughout peanut OIT. Trial registration Clinical Trials number: NCT0162515 PMID:25031584

Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group.

PubMed

Borchmann, Peter; Haverkamp, Heinz; Lohri, Andreas; Mey, Ulrich; Kreissl, Stefanie; Greil, Richard; Markova, Jana; Feuring-Buske, Michaela; Meissner, Julia; Dührsen, Ulrich; Ostermann, Helmut; Keller, Ulrich; Maschmeyer, Georg; Kuhnert, Georg; Dietlein, Markus; Kobe, Carsten; Eich, Hans; Baues, Christian; Stein, Harald; Fuchs, Michael; Diehl, Volker; Engert, Andreas

2017-04-01

Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPP escalated group and 93·0% (89·4-96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPP escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor–Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study

PubMed Central

Albrecht, Mary; Mukherjee, A. Lisa; Tierney, Camlin; Morse, Gene D.; Dykes, Carrie; Klingman, Karin L.; Demeter, Lisa M.

2012-01-01

Background We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. Methods Eligible HIV-infected subjects with a screening viral load of ≥1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ≤1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. Results One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [P = .13, median (25th, 75th percentile log10 copies/mL change): −0.03 (−0.74, 0.62) with TDM and 0.11 (−2.3, 0.82) with SOC]. In subgroup analysis, patients with ≥0.69 active PIs benefited from TDM compared to those with <0.69 active PIs (P = .05). Conclusions While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity. PMID:22044856

A phase 1, randomized, controlled dose-escalation study of EP-1300 polyepitope DNA vaccine against Plasmodium falciparum malaria administered via electroporation.

PubMed

Spearman, Paul; Mulligan, Mark; Anderson, Evan J; Shane, Andi L; Stephens, Kathy; Gibson, Theda; Hartwell, Brooke; Hannaman, Drew; Watson, Nora L; Singh, Karnail

2016-11-04

Plasmodium falciparum malaria is one of the leading infectious causes of childhood mortality in Africa. EP-1300 is a polyepitope plasmid DNA vaccine expressing 38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens expressed predominantly in the liver phase of the parasite's life cycle. We performed a phase 1 randomized, placebo-controlled, dose escalation clinical trial of the EP-1300 DNA vaccine administered via electroporation using the TriGrid Delivery System device (Ichor Medical Systems). Although the delivery of the EP-1300 DNA vaccine via electroporation was safe, tolerability was less than that usually observed with standard needle and syringe intramuscular administration. This was primarily due to acute local discomfort at the administration site during electroporation. Despite the use of electroporation, the vaccine was poorly immunogenic. The reasons for the poor immunogenicity of this polyepitope DNA vaccine remain uncertain. ClinicalTrials.gov NCT01169077. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiation Therapy Intensification for Solid Tumors: A Systematic Review of Randomized Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamoah, Kosj; Showalter, Timothy N.; Ohri, Nitin, E-mail: ohri.nitin@gmail.com

Purpose: To systematically review the outcomes of randomized trials testing radiation therapy (RT) intensification, including both dose escalation and/or the use of altered fractionation, as a strategy to improve disease control for a number of malignancies. Methods and Materials: We performed a literature search to identify randomized trials testing RT intensification for cancers of the central nervous system, head and neck, breast, lung, esophagus, rectum, and prostate. Findings were described qualitatively. Where adequate data were available, pooled estimates for the effect of RT intensification on local control (LC) or overall survival (OS) were obtained using the inverse variance method. Results: Inmore » primary central nervous system tumors, esophageal cancer, and rectal cancer, randomized trials have not demonstrated that RT intensification improves clinical outcomes. In breast cancer and prostate cancer, dose escalation has been shown to improve LC or biochemical disease control but not OS. Radiation therapy intensification may improve LC and OS in head and neck and lung cancers, but these benefits have generally been limited to studies that did not incorporate concurrent chemotherapy. Conclusions: In randomized trials, the benefits of RT intensification have largely been restricted to trials in which concurrent chemotherapy was not used. Novel strategies to optimize the incorporation of RT in the multimodality treatment of solid tumors should be explored.« less

Assuring high quality treatment delivery in clinical trials - Results from the Trans-Tasman Radiation Oncology Group (TROG) study 03.04 "RADAR" set-up accuracy study.

PubMed

Haworth, Annette; Kearvell, Rachel; Greer, Peter B; Hooton, Ben; Denham, James W; Lamb, David; Duchesne, Gillian; Murray, Judy; Joseph, David

2009-03-01

A multi-centre clinical trial for prostate cancer patients provided an opportunity to introduce conformal radiotherapy with dose escalation. To verify adequate treatment accuracy prior to patient recruitment, centres submitted details of a set-up accuracy study (SUAS). We report the results of the SUAS, the variation in clinical practice and the strategies used to help centres improve treatment accuracy. The SUAS required each of the 24 participating centres to collect data on at least 10 pelvic patients imaged on a minimum of 20 occasions. Software was provided for data collection and analysis. Support to centres was provided through educational lectures, the trial quality assurance team and an information booklet. Only two centres had recently carried out a SUAS prior to the trial opening. Systematic errors were generally smaller than those previously reported in the literature. The questionnaire identified many differences in patient set-up protocols. As a result of participating in this QA activity more than 65% of centres improved their treatment delivery accuracy. Conducting a pre-trial SUAS has led to improvement in treatment delivery accuracy in many centres. Treatment techniques and set-up accuracy varied greatly, demonstrating a need to ensure an on-going awareness for such studies in future trials and with the introduction of dose escalation or new technologies.

Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

PubMed

Denham, James W; Steigler, Allison; Joseph, David; Lamb, David S; Spry, Nigel A; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett; Oldmeadow, Christopher; Holliday, Elizabeth G; Attia, John

2015-06-01

The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p<0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.

PubMed

Chiocca, E Antonio; Abbed, Khalid M; Tatter, Stephen; Louis, David N; Hochberg, Fred H; Barker, Fred; Kracher, Jean; Grossman, Stuart A; Fisher, Joy D; Carson, Kathryn; Rosenblum, Mark; Mikkelsen, Tom; Olson, Jeff; Markert, James; Rosenfeld, Steven; Nabors, L Burt; Brem, Steven; Phuphanich, Surasak; Freeman, Scott; Kaplan, Rick; Zwiebel, James

2004-11-01

ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial.

PubMed

Karpova, Darja; Bräuninger, Susanne; Wiercinska, Eliza; Krämer, Ariane; Stock, Belinda; Graff, Jochen; Martin, Hans; Wach, Achim; Escot, Christophe; Douglas, Garry; Romagnoli, Barbara; Chevalier, Eric; Dembowski, Klaus; Hooftman, Leon; Bonig, Halvard

2017-01-03

Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF. Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1-2 h infusion of 500-2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476).

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m 2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu; Das, Shiva; Gu, Lin

2015-12-01

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standardmore » 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.« less

Intrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage.

PubMed

Etminan, Nima; Macdonald, R Loch; Davis, Cara; Burton, Kevin; Steiger, Hans-Jakob; Hänggi, Daniel

2015-01-01

The effective reduction of delayed cerebral ischemia (DCI), a main contributor for poor outcome following aneurysmal subarachnoid hemorrhage (SAH), remains challenging. Previous clinical trials on systemic pharmaceutical treatment of SAH mostly failed to improve outcome, probably because of insensitive pharmaceutical targets and outcome measures, small sample size, insufficient subarachnoid drug concentrations and also detrimental, systemic effects of the experimental treatment per se. Interestingly, in studies that are more recent, intrathecal administration of nicardipine pellets following surgical aneurysm repair was suggested to have a beneficial effect on DCI and neurological outcome. However, this positive effect remained restricted to patients who were treated surgically for a ruptured aneurysm. Because of the favorable results of the preclinical data on DCI and neurological outcome in the absence of neurotoxicity or systemic side effects, we are initiating clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial is designed as an unblinded, nonrandomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients surgically treated for aSAH and will investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial is a phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH.

A phase I trial of a new antiemetic drug--clebopride malate--in cisplatin-treated patients.

PubMed

Bleiberg, H; Piccart, M; Lips, S; Panzer, J M; N'Koua Mbon, J B

1992-02-01

Clebopride, a new benzamide derivative, has, in common with the other members of this group, antidopaminergic activity. In animals, its therapeutic ratio is superior to that of metoclopramide at doses free of side effects associated with hyperprolactinemia and extrapyramidal symptoms. The present study was designed to define the maximum tolerated dose (MTD) in patients with advanced histologically-proven cancer, treated with cisplatin at a dose of greater than 50 mg/m2. Most of them were pretreated and refractory to standard antiemetics. Clebopride was started at a dosage of 0.10 mg/kg in a group of 6 patients and escalated by 0.2 mg at each dose level. A total of 30 patients were included. Side effects include somnolence, diarrhea and extrapyramidal-like symptoms. The latter occurred at almost all dose levels in 14% of the cycles and limited continuation of the study. Activity in this group of patients was encouraging but, considering the rate of extrapyramidal symptoms, further dose escalation is not indicated and activity at lower, nontoxic levels should be investigated.

Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer With Respect to the Outcome of Radical Radiotherapy Dose Escalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vergis, Roy; Corbishley, Catherine M.; Thomas, Karen

Purpose: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation. Methods and Materials: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect tomore » outcome. Results: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5-76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression. Conclusions: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients.« less

Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study.

PubMed

Ahn, Myung-Ju; Kim, Dong-Wan; Cho, Byoung Chul; Kim, Sang-We; Lee, Jong Seok; Ahn, Jin-Seok; Kim, Tae Min; Lin, Chia-Chi; Kim, Hye Ryun; John, Thomas; Kao, Steven; Goldman, Jonathan W; Su, Wu-Chou; Natale, Ronald; Rabbie, Sarit; Harrop, Bryony; Overend, Philip; Yang, Zhenfan; Yang, James Chih-Hsin

2017-11-01

CNS metastases-including brain and leptomeningeal metastases-from epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine kinase inhibitor with high capability to penetrate the blood-brain barrier. We aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal metastases. This open-label, multicentre, phase 1 study was undertaken at 11 centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible patients included those with histologically confirmed, advanced-stage, EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and dose-expansion phases. In the dose-escalation phase, patients who had progressed after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either brain or leptomeningeal metastases who had never received an EGFR tyrosine kinase inhibitor and patients with leptomeningeal metastases who had been pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was safety and tolerability, with severity of adverse events assessed with the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03. This trial is registered with ClinicalTrials.gov, number NCT02228369. Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were enrolled into the study, 29 to the dose-escalation phase and 38 to the dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the dose-escalation phase and 20 (53%) in the dose-expansion phase were still receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three patients who received 500 mg twice a day in the dose-escalation phase (grade 3 acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 200 mg and 300 mg twice a day were selected for further assessment in the dose-expansion phase. Drug-related skin and gastrointestinal disorders of any grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, respectively, and led to treatment discontinuation in one (4%) patient treated with 200 mg twice a day (grade 3 increase of alanine aminotransferase and aspartate aminotransferase) and two (13%) patients given 300 mg twice a day (grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and gastrointestinal disorders occurred in four (17%) and two (9%) patients, respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders arose. Other grade 3 disorders included hepatobiliary and renal disorders (three [13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), infections and infestations (one [7%] at 300 mg twice a day), and metabolism and nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice a day). AZD3759 at a dose of 200 mg twice daily showed a tolerable safety profile in patients with NSCLC and CNS metastases who had either never received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, and its promising clinical activity, support further assessment of this compound in studies. AstraZeneca. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vainshtein, Jeffrey M., E-mail: jvainsh@med.umich.edu; Schipper, Matthew; Zalupski, Mark M.

2013-05-01

Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factorsmore » on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.« less

Sexual Function After Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Results From a Dose-Escalation Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wielen, Gerard J. van der; Putten, Wim van; Incrocci, Luca

Purpose: The purpose of this study is to provide information about sexual function (SF) after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer while taking important factors into account that influence SF. Methods and Materials: Between June 1997 and February 2003, a total of 268 patients from a randomized dose-escalation trial comparing 68 Gy and 78 Gy agreed to participate in an additional part of the trial that evaluated SF. Results: At baseline 28% of patients had erectile dysfunction (ED). After 1 year, 27% of the pretreatment potent patients had developed ED. After 2 years this percentage had increased to 36%.more » After 3 years it almost stabilized at 38%. Satisfaction with sexual life was significantly correlated with ED. After 2 years one third of the pre-treatment potent patients still had considerable to very much sexual desire and found sex (very) important. No significant differences were found between the two dose-arms. Potency aids were used on a regular base by 14% of the patients. Conclusion: By taking adjuvant hormonal therapy (HT), HT during follow-up and potency aids into account, we found a lower percentage of ED after 3D-CRT than reported in previous prospective studies. A large group of patients still had sexual desire, considered sex important and 14% used potency aids after 3D-CRT.« less

LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models.

PubMed

King, Christopher R

2002-01-01

Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated (192)Ir HDR brachytherapy, and (125)I and (103)Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (<70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the alpha/beta ratio is low). Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low alpha/beta ratio) as the current evidence suggests.

ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodda, Sree; Tyldesley, Scott; Department of Surgery, University of British Columbia, Vancouver, British Columbia

Purpose: To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials: ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GUmore » and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results: The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT (P<.001). Compared with the cumulative incidence, the 5-year prevalence of grade 3 GU morbidity was substantially lower for both arms (8.6% vs 2.2%, P=.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT (P=.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT (P=.30). Conclusions: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of erectile dysfunction were observed.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gomez, Daniel R., E-mail: dgomez@mdanderson.org; Gillin, Michael; Liao, Zhongxing

Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectivenessmore » [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.« less

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

PubMed

Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

2017-10-03

SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest antitumor activity in patients with MET -amplified gastric cancer.

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

PubMed

Lee, Daniel W; Kochenderfer, James N; Stetler-Stevenson, Maryalice; Cui, Yongzhi K; Delbrook, Cindy; Feldman, Steven A; Fry, Terry J; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N; Steinberg, Seth M; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A; Wayne, Alan S; Mackall, Crystal L

2015-02-07

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. National Institutes of Health Intramural funds and St Baldrick's Foundation. Copyright © 2015 Elsevier Ltd. All rights reserved.

F-18-FDG-PET Confined Radiotherapy of Locally Advanced NSCLC With Concomitant Chemotherapy: Results of the PET-PLAN Pilot Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleckenstein, Jochen; Hellwig, Dirk; Kremp, Stephanie

2011-11-15

Purpose: The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. Methods and Materials: Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy wasmore » indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). Results: As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. Conclusions: FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, E; Yuan, F; Templeton, A

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on themore » targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.« less

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minsky, B.D.; Cohen, A.M.; Kemeny, N.

1993-04-02

The authors performed a Phase 1 trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily [times] 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy was not dose escalated; 5-FU: 425 mg/m2 and LV: 20more » mg/m2. The median follow-up was 14 months (7--16 months). Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, the authors do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate they remain encouraged with this approach. 31 refs., 1 fig., 2 tabs.« less

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

PubMed

de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

2017-06-01

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2 -mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers.

PubMed

Mendes, Gustavo D; dos Santos Filho, Hilton Oliveira; dos Santos Pereira, Alberto; Mendes, Fabiana D; Ilha, Jaime O; Alkharfy, Khalid M; De Nucci, Gilberto

2012-12-01

Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). The study was an open label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 ( ± 0.4) h and 3.3 ( ± 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.

PubMed

Gilbert, J; Baker, S D; Bowling, M K; Grochow, L; Figg, W D; Zabelina, Y; Donehower, R C; Carducci, M A

2001-08-01

Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration. Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected. The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug. PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

PubMed

Roberts, Andrew W; Davids, Matthew S; Pagel, John M; Kahl, Brad S; Puvvada, Soham D; Gerecitano, John F; Kipps, Thomas J; Anderson, Mary Ann; Brown, Jennifer R; Gressick, Lori; Wong, Shekman; Dunbar, Martin; Zhu, Ming; Desai, Monali B; Cerri, Elisa; Heitner Enschede, Sari; Humerickhouse, Rod A; Wierda, William G; Seymour, John F

2016-01-28

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Dose Escalation of Whole-Brain Radiotherapy for Brain Metastases From Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Heisterkamp, Christine; Huttenlocher, Stefan

2010-06-01

Purpose: The majority of patients with brain metastases from melanoma receive whole-brain radiotherapy (WBRT). However, the results are poor. Hypofractionation regimens failed to improve the outcome of these patients. This study investigates a potential benefit from escalation of the WBRT dose beyond the 'standard' regimen 30 Gy in 10 fractions (10x3 Gy). Methods and Materials: Data from 51 melanoma patients receiving WBRT alone were retrospectively analyzed. A dosage of 10x3 Gy (n = 33) was compared with higher doses including 40 Gy/20 fractions (n = 11) and 45 Gy/15 fractions (n = 7) for survival (OS) and local (intracerebral) controlmore » (LC). Additional potential prognostic factors were evaluated: age, gender, performance status, number of metastases, extracerebral metastases, and recursive partitioning analysis (RPA) class. Results: At 6 months, OS rates were 27% after 10x3 Gy and 50% after higher doses (p = 0.009). The OS rates at 12 months were 4% and 20%. On multivariate analysis, higher WBRT doses (p = 0.010), fewer than four brain metastases (p = 0.012), no extracerebral metastases (p = 0.006), and RPA class 1 (p = 0.005) were associated with improved OS. The LC rates at 6 months were 23% after 10x3 Gy and 50% after higher doses (p = 0.021). The LC rates at 12 months were 0% and 13%. On multivariate analysis, higher WBRT doses (p = 0.020) and fewer than brain metastases (p = 0.002) were associated with better LC. Conclusions: Given the limitations of a retrospective study, the findings suggest that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy. The hypothesis generated by this study must be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pollom, Erqi L.; Fujimoto, Dylann; Wynne, Jacob

Purpose: We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. Methods: HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory–Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (globalmore » quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. Results: With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01). Conclusion: On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.« less

A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).

PubMed

Frey, Sharon E; Lottenbach, Kathleen; Graham, Irene; Anderson, Edwin; Bajwa, Kanwaldeep; May, Ryan C; Mizel, Steven B; Graff, Aaron; Belshe, Robert B

2017-12-04

Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject's participation lasted 13months. Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited. Copyright © 2017. Published by Elsevier Ltd.

Biomarkers of skin toxicity induced by anti-epidermal growth factor receptor antibody treatment in colorectal cancer.

PubMed

Kubo, Akiko; Hashimoto, Hironobu; Takahashi, Naoki; Yamada, Yasuhide

2016-01-14

Skin toxicity is a common symptom of anti-epidermal growth factor receptor (EGFR) antibody treatment and is also a predictive marker of its efficacy in colorectal cancer patients. However, severe skin disorders induced by such antibodies negatively impact on the quality of life of patients and decreases drug compliance during treatment. If we can predict the high-risk group susceptible to severe skin toxicity before treatment, we can undertake the early management of any arising skin disorders and formulate a more accurate prognosis for anti-EGFR antibody treatment. Previous studies have identified molecular markers of skin toxicity induced by anti-EGFR antibody, such as EGFR polymorphisms, the expression of inflammatory chemokines and serum levels of EGFR ligands. A clinical trial was undertaken involving the escalation of cetuximab doses, guided by the grade of skin toxicity observed, such as no or low-grade, in metastatic colorectal cancer (the EVEREST study). The dose escalation of cetuximab was confirmed by a safety profile and had the tendency to achieve a higher response rate in KRAS wild-type patients. A large, prospective randomized trial is now ongoing (EVEREST 2) and the results of this trial may contribute to personalized medicine in KRAS wild-type colorectal cancer patients.

Biomarkers of skin toxicity induced by anti-epidermal growth factor receptor antibody treatment in colorectal cancer

PubMed Central

Kubo, Akiko; Hashimoto, Hironobu; Takahashi, Naoki; Yamada, Yasuhide

2016-01-01

Skin toxicity is a common symptom of anti-epidermal growth factor receptor (EGFR) antibody treatment and is also a predictive marker of its efficacy in colorectal cancer patients. However, severe skin disorders induced by such antibodies negatively impact on the quality of life of patients and decreases drug compliance during treatment. If we can predict the high-risk group susceptible to severe skin toxicity before treatment, we can undertake the early management of any arising skin disorders and formulate a more accurate prognosis for anti-EGFR antibody treatment. Previous studies have identified molecular markers of skin toxicity induced by anti-EGFR antibody, such as EGFR polymorphisms, the expression of inflammatory chemokines and serum levels of EGFR ligands. A clinical trial was undertaken involving the escalation of cetuximab doses, guided by the grade of skin toxicity observed, such as no or low-grade, in metastatic colorectal cancer (the EVEREST study). The dose escalation of cetuximab was confirmed by a safety profile and had the tendency to achieve a higher response rate in KRAS wild-type patients. A large, prospective randomized trial is now ongoing (EVEREST 2) and the results of this trial may contribute to personalized medicine in KRAS wild-type colorectal cancer patients. PMID:26811634

WE-G-BRB-02: The Role of Program Project Grants in Study of 3D Conformal Therapy, Dose Escalation and Motion Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fraass, B.

2015-06-15

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

Photons, protons or carbon ions for stage I non-small cell lung cancer - Results of the multicentric ROCOCO in silico study.

PubMed

Wink, Krista C J; Roelofs, Erik; Simone, Charles B; Dechambre, David; Santiago, Alina; van der Stoep, Judith; Dries, Wim; Smits, Julia; Avery, Stephen; Ammazzalorso, Filippo; Jansen, Nicolas; Jelen, Urszula; Solberg, Timothy; de Ruysscher, Dirk; Troost, Esther G C

2018-03-12

To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient. Copyright © 2018 Elsevier B.V. All rights reserved.

Anal Cancer: An Examination of Radiotherapy Strategies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glynne-Jones, Rob; Lim, Faye

2011-04-01

The Radiation Therapy Oncology Group 9811, ACCORD-03, and ACT II Phase III trials in anal cancer showed no benefit for cisplatin-based induction and maintenance chemotherapy, or radiation dose-escalation >59 Gy. This review examines the efficacy and toxicity of chemoradiation (CRT) in anal cancer, and discusses potential alternative radiotherapy strategies. The evidence for the review was compiled from randomized and nonrandomized trials of radiation therapy and CRT. A total of 103 retrospective/observational studies, 4 Phase I/II studies, 16 Phase II prospective studies, 2 randomized Phase II studies, and 6 Phase III trials of radiotherapy or chemoradiation were identified. There are nomore » meta-analyses based on individual patient data. A 'one-size-fits-all' approach for all stages of anal cancer is inappropriate. Early T1 tumors are probably currently overtreated, whereas T3/T4 lesions might merit escalation of treatment. Intensity-modulated radiotherapy or the integration of biological therapy may play a role in future.« less

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

PubMed Central

Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck

2016-01-01

Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

PubMed

Camacho, Luis H; Olson, Jon; Tong, William P; Young, Charles W; Spriggs, David R; Malkin, Mark G

2007-04-01

Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging.

PubMed

Wanet, Marie; Delor, Antoine; Hanin, François-Xavier; Ghaye, Benoît; Van Maanen, Aline; Remouchamps, Vincent; Clermont, Christian; Goossens, Samuel; Lee, John Aldo; Janssens, Guillaume; Bol, Anne; Geets, Xavier

2017-10-01

The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity. A total of 13 patients with stage II-III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTV PET ) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method. The average dose to PTV PET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis. These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity.

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.

PubMed

Bendell, J; O'Reilly, E M; Middleton, M R; Chau, I; Hochster, H; Fielding, A; Burke, W; Burris, H

2015-04-01

Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. NCT00515866. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

PubMed

Brown, Randall T; Nicholas, Christopher R; Cozzi, Nicholas V; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Thomas, Chantelle D; Hetzel, Scott J; Henriquez, Kelsey M; Ribaudo, Alexandra S; Hutson, Paul R

2017-12-01

Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. NCT02163707.

Mesalamine Dose Escalation Reduces Fecal Calprotectin In Patients With Quiescent Ulcerative Colitis

PubMed Central

Osterman, Mark T.; Aberra, Faten N; Cross, Raymond; Liakos, Steven; McCabe, Robert; Shafran, Ira; Wolf, Douglas; Hardi, Robert; Nessel, Lisa; Brensinger, Colleen; Gilroy, Erin; Lewis, James D.

2014-01-01

Background & Aims Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized, controlled trial to investigate whether increasing doses mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. Methods We screened 119 patients with UC in remission, based on Simple Clinical Colitis Activity Index scores, FC >50 mcg/g, and intake of no more than 3g/day of mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n=26) or a group that increased its dose by 2.4 g/day for 6 weeks (n=26). The primary outcome was continued remission with FC<50 mcg/g. Secondary outcomes were continued remission with FC<100 mcg/g or <200 mcg/g (among patients with pre-randomization values above these levels). Results The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P=.0496). More patients in the dose escalation group reduced FC to below 100 mcg/g (P=.04) and 200 mcg/g (P=.005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 mcg/g compared to those with FC <200 mcg/g (P=.01). Conclusion Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov: NCT00652145 PMID:24793028

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

PubMed Central

Flaherty, Keith T.; Puzanov, Igor; Kim, Kevin B.; Ribas, Antoni; McArthur, Grant A.; Sosman, Jeffrey A.; O'Dwyer, Peter J.; Lee, Richard J.; Grippo, Joseph F.; Nolop, Keith; Chapman, Paul B.

2013-01-01

Background The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) PMID:20818844

Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

PubMed Central

Malow, Beth A.; Adkins, Karen W.; McGrew, Susan G.; Wang, Lily; Goldman, Suzanne E.; Fawkes, Diane; Burnette, Courtney

2011-01-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population. PMID:22160300

Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes.

PubMed

Malow, Beth; Adkins, Karen W; McGrew, Susan G; Wang, Lily; Goldman, Suzanne E; Fawkes, Diane; Burnette, Courtney

2012-08-01

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

NASA Astrophysics Data System (ADS)

Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

2017-03-01

Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PubMed

Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

2011-05-01

To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT. Copyright © 2011 Elsevier Inc. All rights reserved.

[Clinical experience of carbon ion radiotherapy for malignant tumors].

PubMed

Ishikawa, Hitoshi; Tsuji, Hiroshi; Tsujii, Hirohiko

2006-04-01

The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.

Pelvic Nodal Radiotherapy in Patients With Unfavorable Intermediate and High-Risk Prostate Cancer: Evidence, Rationale, and Future Directions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morikawa, Lisa K.; Memorial Sloan-Kettering Cancer Center; Roach, Mack, E-mail: mroach@radonc.ucsf.ed

2011-05-01

Over the past 15 years, there have been three major advances in the use of external beam radiotherapy in the management of men with clinically localized prostate made. They include: (1) image guided (IG) three-dimensional conformal/intensity modulated radiotherapy; (2) radiation dose escalation; and (3) androgen deprivation therapy. To date only the last of these three advances have been shown to improve overall survival. The presence of occult pelvic nodal involvement could explain the failure of increased conformality and dose escalation to prolong survival, because the men who appear to be at the greatest risk of death from clinically localized prostatemore » cancer are those who are likely to have lymph node metastases. This review discusses the evidence for prophylactic pelvic nodal radiotherapy, including the key trials and controversies surrounding this issue.« less

An escalating dose study to assess the safety, tolerability and immunogenicity of a Herpes Simplex Virus DNA vaccine, COR-1.

PubMed

Dutton, Julie L; Woo, Wai-Ping; Chandra, Janin; Xu, Yan; Li, Bo; Finlayson, Neil; Griffin, Paul; Frazer, Ian H

2016-12-01

This paper describes a single site, open-label Phase I clinical trial evaluating the safety, tolerability and immunogenicity in healthy volunteers of a herpes simplex polynucleotide vaccine that has previously been shown to enhance immunogenicity and protect against lethal herpes simplex virus type 2 (HSV-2) challenge in mice. Five escalating doses of the vaccine, COR-1, were given by intradermal injection to HSV-1 and 2 seronegative healthy individuals. COR-1 was found to be safe and well-tolerated; the only vaccine-related adverse events were mild. While vaccine-induced antibody responses were not detectable, cell-mediated immune responses to HSV-specific peptide groups were identified in 19 of the 20 subjects who completed the study, and local inflammation at the immunisation site was observed. This study indicates COR-1 has potential to be used as a therapeutic vaccine for HSV-2 infection.

SU-E-T-183: Feasibility of Extreme Dose Escalation for Glioblastoma Multiforme Using 4π Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, D; Rwigema, J; Yu, V

Purpose: GBM recurrence primarily occurs inside or near the high-dose radiation field of original tumor site requiring greater than 100 Gy to significantly improve local control. We utilize 4π non-coplanar radiotherapy to test the feasibility of planning target volume (PTV) margin expansions or extreme dose escalations without incurring additional radiation toxicities. Methods: 11 GBM patients treated with VMAT to a prescription dose of 59.4 Gy or 60 Gy were replanned with 4π. Original VMAT plans were created with 2 to 4 coplanar or non-coplanar arcs using 3 mm hi-res MLC. The 4π optimization, using 5 mm MLC, selected and inversemore » optimized 30 beams from a candidate pool of 1162 beams evenly distributed through 4π steradians. 4π plans were first compared to clinical plans using the same prescription dose. Two more studies were then performed to respectively escalate the GTV and PTV doses to 100 Gy, followed by a fourth plan expanding the PTV by 5 mm and maintaining the prescription dose. Results: The standard 4π plan significantly reduced (p<0.01) max and mean doses to critical structures by a range of 47.0–98.4% and 61.0–99.2%, respectively. The high dose PTV/high dose GTV/expanded PTV studies showed a reduction (p<0.05) or unchanged* (p>0.05) maximum dose of 72.1%/86.7%/77.1% (chiasm), 7.2%*/27.7%*/30.7% (brainstem), 39.8%*/84.2%/51.9%* (spinal cord), 69.0%/87.0%/66.9% (L eye), 76.2%/88.1%/84.1% (R eye), 95.0%/98.6%/97.5% (L lens), 93.9%/98.8%/97.6% (R lens), 74.3%/88.5%/72.4% (L optical nerve), 80.4%/91.3%/75.7% (R optical nerve), 64.8%/84.2%/44.9%* (L cochlea), and 85.2%/93.0%/78.0% (R cochlea), respectively. V30 and V36 for both brain and (brain - PTV) were reduced for all cases except the high dose PTV plan. PTV dose coverage increased for all 4π plans. Conclusion: Extreme dose escalation or further margin expansion is achievable using 4π, maintaining or reducing OAR doses. This study indicates that clinical trials employing 4π delivery using prescription doses up to 100 Gy are feasible. Funding support partially contributed by Varian.« less

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

PubMed

Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

2015-09-01

Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Astex Pharmaceuticals, Stand Up To Cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reply to: Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection.

PubMed

Coburn, Brian W; Michaud, Kaleb; Bergman, Debra A; Mikuls, Ted R

2018-05-08

We thank Dr. Bredemeier for his comments regarding our manuscript on allopurinol dose escalation and mortality. He raises important evidence to consider in support of an interesting hypothesis that dose escalation may be unnecessary for allopurinol's cardiovascular (CV) protection and may actually be related to adverse CV outcomes. While we agree that evidence exists suggesting that low doses of allopurinol may be sufficient for CV protection, we believe that the studies cited highlight a number of areas where knowledge gaps remain which preclude any definitive conclusions about the effect of dose escalation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

PubMed

Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

1997-08-01

Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study.

PubMed

Marincek, Nicolas; Jörg, Ann-Catherine; Brunner, Philippe; Schindler, Christian; Koller, Michael T; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

2013-01-15

We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

Randomized, double-blind, dose-escalation trial of triptorelin for ovary protection in childhood-onset systemic lupus erythematosus.

PubMed

Brunner, Hermine I; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C; Imundo, Lisa; Williams, Calvin B; Wallace, Carol A; Aikawa, Nadia E; Nelson, Shannen; Klein-Gitelman, Marisa S; Rose, Susan R

2015-05-01

To determine the dose of triptorelin that is sufficient to maintain complete ovarian suppression in female patients with childhood-onset systemic lupus erythematosus (SLE) who require cyclophosphamide therapy, to determine the length of time needed to achieve ovarian suppression after initiation of triptorelin treatment, and to investigate the safety of triptorelin. In this randomized, double-blind, placebo-controlled, dose-escalation study, female patients ages <21 years were randomized 4:1 to receive triptorelin (n = 25) or placebo (n = 6). The starting doses of triptorelin were 25, 50, 75, and 100 μg/kg, and the dose was escalated until complete ovarian suppression was maintained. The primary outcome was the weight-adjusted dose of triptorelin that provided complete ovarian suppression in at least 90% of the patients, as determined by gonadotropin-releasing hormone agonist stimulation testing. The secondary outcome was the period of time required to achieve ovarian suppression, as measured by unstimulated follicle-stimulating hormone and luteinizing hormone levels after the initiation of triptorelin treatment. Treatment with triptorelin at a weight-adjusted dose of 120 μg/kg body weight provided sustained complete ovarian suppression in 90% of the patients. After administration of the initial dose of triptorelin, 22 days were required to achieve complete ovarian suppression. The rates of adverse events (AEs) and serious adverse events (SAEs) per 100 patient-months of followup were not higher in the triptorelin group compared with the placebo group (for AEs, 189 versus 362; for SAEs, 2.1 versus 8.5). High doses of triptorelin are needed to achieve and maintain complete ovarian suppression, but such doses appear to be well tolerated in adolescent female patients with childhood-onset SLE. Our data suggest that a lag time of 22 days after initiation of triptorelin treatment is required before cyclophosphamide therapy is started or continued. © 2015, American College of Rheumatology.

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.

PubMed

Burnett, Alan K; Milligan, Donald; Goldstone, Anthony; Prentice, Archibald; McMullin, Mary-Frances; Dennis, Michael; Sellwood, Elizabeth; Pallis, Monica; Russell, Nigel; Hills, Robert K; Wheatley, Keith

2009-05-01

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

Phase I Trial of Anti-CS1 Monoclonal Antibody Elotuzumab in Combination With Bortezomib in the Treatment of Relapsed/Refractory Multiple Myeloma

PubMed Central

Jakubowiak, Andrzej J.; Benson, Don M.; Bensinger, William; Siegel, David S.D.; Zimmerman, Todd M.; Mohrbacher, Ann; Richardson, Paul G.; Afar, Daniel E.H.; Singhal, Anil K.; Anderson, Kenneth C.

2012-01-01

Purpose To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM). Patients and Methods Elotuzumab (2.5, 5.0, 10, or 20 mg/kg intravenously [IV]) and bortezomib (1.3 mg/m2 IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria. Results Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months. Conclusion The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM. PMID:22291084

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

2014-08-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem.

PubMed

Roehrs, Timothy A; Roth, Thomas

2016-03-01

Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. CLINCIAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. © 2016 American Academy of Sleep Medicine.

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study.

PubMed

Dupuis, Jehan; Morschhauser, Franck; Ghesquières, Hervé; Tilly, Hervé; Casasnovas, Olivier; Thieblemont, Catherine; Ribrag, Vincent; Bossard, Céline; Le Bras, Fabien; Bachy, Emmanuel; Hivert, Bénédicte; Nicolas-Virelizier, Emmanuelle; Jardin, Fabrice; Bastie, Jean-Noel; Amorim, Sandy; Lazarovici, Julien; Martin, Antoine; Coiffier, Bertrand

2015-04-01

Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and oral prednisone 40 mg/m(2) on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m(2) intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m(2) had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m(2) of romidepsin, an additional three at 10 mg/m(2) (one dose-limiting toxicity), and six patients at 12 mg/m(2) (three dose-limiting toxicities). We chose romidepsin 12 mg/m(2) as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia. Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. Celgene. Copyright © 2015 Elsevier Ltd. All rights reserved.

Changing patterns of tumor necrosis factor inhibitor use in 9074 patients with rheumatoid arthritis.

PubMed

Yazici, Yusuf; Krasnokutsky, Svetlana; Barnes, Jaime P; Hines, Patricia L; Wang, Jason; Rosenblatt, Lisa

2009-05-01

Patients with rheumatoid arthritis (RA) commonly switch between tumor necrosis factor (TNF) inhibitors after failing to control disease activity. Much of the clinical data that support switching to a second TNF agent when one agent fails to work has come from small, short-term studies. We utilized a US insurance claims database to determine patterns of use such as dose escalation, time to discontinuation, and switching between TNF inhibitors in patients with RA. A retrospective analysis was performed using an insurance claims database in the US from 2000 to 2005. TNF inhibitor use, time to switch, dose escalation, and continuation times were analyzed in patients with RA. Nine thousand seventy-four patients with RA started TNF inhibitors during the period 2000 to 2005. Etanercept was the most commonly used TNF inhibitor; infliximab had the highest duration of continuation, about 50% at 2 years. In addition, infliximab showed higher rates of dose escalation compared to etanercept and adalimumab. For all TNF inhibitors, time to switching decreased from 2000 to 2005. TNF inhibitor use patterns changed from 2000 to 2005, with more frequent changes among the different TNF inhibitors and a shorter duration of treatment before the change. Only about 50% of TNF inhibitors are still continued at 2 years, reflecting the difference between randomized clinical trials and real-world experience.

THE EFFECTS OF FIXED VERSUS ESCALATING REINFORCEMENT SCHEDULES ON SMOKING ABSTINENCE

PubMed Central

Romanowich, Paul; Lamb, R. J.

2015-01-01

Studies indicate that when abstinence is initiated, escalating reinforcement schedules maintain continuous abstinence longer than fixed reinforcement schedules. However, these studies were conducted for shorter durations than most clinical trials and also resulted in larger reinforcer value for escalating participants during the 1st week of the experiment. We tested whether escalating reinforcement schedules maintained abstinence longer than fixed reinforcement schedules in a 12-week clinical trial. Smokers (146) were randomized to an escalating reinforcement schedule, a fixed reinforcement schedule, or a control condition. Escalating reinforcement participants received $5.00 for their first breath carbon monoxide (CO) sample <3 ppm, with a $0.50 increase for each consecutive sample. Fixed reinforcement participants received $19.75 for each breath CO sample <3 ppm. Control participants received payments only for delivering a breath CO sample. Similar proportions of escalating and fixed reinforcement participants met the breath CO criterion at least once. Escalating reinforcement participants maintained criterion breath CO levels longer than fixed reinforcement and control participants. Similar to previous short-term studies, escalating reinforcement schedules maintained longer durations of abstinence than fixed reinforcement schedules during a clinical trial. PMID:25640764

Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013.

PubMed

Suh, Hoon Young; Peck, Carl C; Yu, Kyung-Sang; Lee, Howard

2016-01-01

A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, P =0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.

Phase 2a, Open-Label, 4-Escalating-Dose, Randomized Multicenter Study Evaluating the Safety and Activity of Ferroquine (SSR97193) Plus Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men with Uncomplicated Plasmodium falciparum Malaria.

PubMed

Supan, Christian; Mombo-Ngoma, Ghyslain; Kombila, Maryvonne; Ospina Salazar, Carmen L; Held, Jana; Lell, Bertrand; Cantalloube, Cathy; Djeriou, Elhadj; Ogutu, Bernhards; Waitumbi, John; Otsula, Nekoye; Apollo, Duncan; Polhemus, Mark E; Kremsner, Peter G; Walsh, Douglas S

2017-08-01

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).

A Phase I Study of Zoledronic Acid and Low Dose Cyclophosphamide in Recurrent/Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) Study

PubMed Central

Russell, Heidi V.; Groshen, Susan G.; Ara, Tasnim; DeClerck, Yves A.; Hawkins, Randy; Jackson, Hollie A.; Daldrup-Link, Heike E.; Marachelian, Araz; Skerjanec, Andrej; Park, Julie R.; Katzenstein, Howard; Matthay, Katherine K.; Blaney, Susan M.; Villablanca, Judith G.

2010-01-01

Background Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. Procedure Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m2/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. Results Twenty-one patients, median age 7.5 (range 0.8 - 25.6) years were treated with 2 mg/m2 (n=4), 3 mg/m2 (n=3), or 4 mg/m2 (n=14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (Grade 3 hypophosphatemia) occurred at 4 mg/m2 zoledronic acid. Other Grade 3-4 toxicities included hypocalcemia (n=2), elevated transaminases (n=1), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. Conclusions Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m2 every 28 days. PMID:21671363

Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

PubMed Central

Infante, Jeffrey; Janku, Filip; Jones, Suzanne; Nguyen, Ly M.; Burris, Howard; Naing, Aung; Bauer, Todd M.; Piha-Paul, Sarina; Johnson, Faye M.; Kurzrock, Razelle; Golden, Lisa; Hynes, Scott; Lin, Ji; Lin, Aimee Bence; Bendell, Johanna

2016-01-01

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC. PMID:27044938

RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chinnaiyan, Prakash, E-mail: prakash.chinnaiyan@moffitt.org; Won, Minhee; Wen, Patrick Y.

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m{sup 2} per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m{sup 2} on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established dailymore » dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.« less

Efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: an open-label randomized controlled trial.

PubMed

Rattanaumpawan, Pinyo; Werarak, Peerawong; Jitmuang, Anupop; Kiratisin, Pattarachai; Thamlikitkul, Visanu

2017-03-01

Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria (GNB) infections. The study objectives were to evaluate efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae. We conducted a randomized controlled trial of adult patients with documented ESBL-producing Enterobacteriaceae infections who had received any group 2 carbapenem for less than 96 h. In the intervention group, the previously-prescribed group 2 carbapenem was de-escalated to ertapenem. In the control group, the group 2 carbapenem was continued. During June 2011-December 2014, 32 patients were randomized to the de-escalation group and 34 to the control group. Most common sites of infection were urinary tract infection (42%). Characteristics of both groups were comparable. By using a 15% predefined margin, ertapenem was non-inferior to control group regarding the clinical cure rate (%Δ = 14.0 [95% confidence interval: -2.4 to 31.1]), the microbiological eradication rate (%Δ = 4.1 [-5.0 to 13.4]), and the superimposed infection rate (%Δ = -16.5 [-38.4 to 5.3]). Patients in the de-escalation group had a significantly lower 28-day mortality rate (9.4% vs. 29.4%; P = .05), a significantly shorter median length of stay (16.5 days [4.0-73.25] vs. 20.0 days [1.0-112.25]; P = .04), and a significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P = .05). Ertapenem could be safely used as de-escalation therapy for ESBL-producing Enterobacteriaceae infections, once the susceptibility profiles are known. Future studies are needed to investigate ertapenem efficacy against ESBL-producing Enterobacteriaceae pneumonia to determine its applicability in life-threatening conditions. ClinicalTrials.gov identifier: NCT01297842 . Registered on 14 February 2011. First patient enrolled on 27 June 2011.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed Central

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Aim Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. PMID:27274277

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

PubMed

Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.

PubMed

Kepka, Lucyna; Tyc-Szczepaniak, Dobromira; Bujko, Krzysztof

2009-07-01

To determine the efficacy of accelerated hypofractionated three-dimensional conformal radiotherapy (3D-CRT) with dose-per-fraction escalation for treatment of stage III non-small cell lung cancer (NSCLC). Between 2001 and 2007, 173 patients with stage III NSCLC were treated using accelerated 3D-CRT and the simultaneous boost technique. Initially, the total dose of 56.7 Gy (including 39.9 Gy to the elective area) was delivered over 4 weeks in fractions of 2.7 Gy (1.9 Gy to the elective area). The dose-per-fraction escalation study commenced after the outcomes of 70 patients had been evaluated. The dose per fraction was increased from 2.7 through 2.8 Gy (level 1 escalation) to 2.9 Gy (level 2 escalation); the total dose increased, respectively, from 56.7 Gy through 58.8 Gy to 60.9 Gy. The dose to the elective area and the overall treatment time remained unchanged. Fit patients received two to three courses of chemotherapy before radiotherapy. The 2- and 3-year overall survival rates were 32 and 19%, respectively (median survival = 17 months). Of the patients, 7% had grade III acute esophageal toxicity and 6% had grade III or greater late pulmonary toxicity. Two of the nine patients who received the level 2 escalation (60.9 Gy) died of pulmonary toxicity. The study was terminated at a dose of 58.8 Gy and this schema was adopted as the institutional policy for treatment of stage III NSCLC. Although dose escalation with accelerated hypofractionated 3D-CRT was limited, the results and toxicity profiles obtained using this technique are promising.

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

PubMed

Maráz, Anikó; Cserháti, Adrienn; Uhercsák, Gabriella; Szilágyi, Éva; Varga, Zoltán; Révész, János; Kószó, Renáta; Varga, Linda; Kahán, Zsuzsanna

2018-03-15

In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

Acute and Late Toxicity After Dose Escalation to 82 GyE Using Conformal Proton Radiation for Localized Prostate Cancer: Initial Report of American College of Radiology Phase II Study 03-12

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coen, John J., E-mail: jcoen@partners.org; Bae, Kyounghwa; Zietman, Anthony L.

Purpose: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. Themore » study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.« less

Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garces, Yolanda I.; Okuno, Scott H.; Schild, Steven E.

Purpose: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). Methods and Materials: Treatment began with two cycles of topotecan (1 mg/m{sup 2}) Days 1 to 5 and paclitaxel (175 mg/m{sup 2}) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard 'cohortsmore » of 3' design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m{sup 2}) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade {>=}4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade {>=}3 dyspnea, or Grade {>=}2 pneumonitis. Results: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade {>=}3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. Conclusion: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine.« less

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffman, Karen E., E-mail: khoffman1@mdanderson.org; Voong, K. Ranh; Pugh, Thomas J.

Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men receivedmore » CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.« less

Do Patients Receiving Whole-Brain Radiotherapy for Brain Metastases From Renal Cell Carcinoma Benefit From Escalation of the Radiation Dose?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rades, Dirk, E-mail: Rades.Dirk@gmx.ne; Department of Radiation Oncology, University Hospital Hamburg-Eppendorf, Hamburg; Heisterkamp, Christine

2010-10-01

Purpose: Whole-brain radiotherapy (WBRT) is the most common treatment for brain metastases from renal cell carcinoma (RCC). Most patients cannot receive more aggressive therapies including surgery or radiosurgery. The standard WBRT regimen, 30 Gy/10 fractions (10 x 3 Gy), has resulted in poor survival (OS). This study investigates whether escalation of the WBRT dose improves treatment outcomes. Methods and Materials: Data from 60 patients receiving WBRT for brain metastases from RCC were retrospectively analyzed. A dose of 10 x 3 Gy (n = 31) was compared with higher doses (40 Gy/20 fractions or 45 Gy/15 fractions; n = 29) formore » OS and local control (LC). Additional factors evaluated were patient age, sex, performance status, number of metastases, interval from diagnosis of RCC to WBRT, extracerebral metastases, recursive partitioning analysis (RPA) class, and year of WBRT. Results: The OS at 6 months was 29% after 10 x 3 Gy and 52% after higher doses (p = 0.003). The OS at 12 months was 13% and 47%, respectively. On multivariate analysis, higher WBRT doses (p = 0.022), Karnofsky performance status score {>=}70 (p = 0.017), fewer than four brain metastases (p = 0.035), and RPA Class 1 (p = 0.003) resulted in better OS. The LC at 6 months was 21% after 10 x 3 Gy and 57% after higher doses (p = 0.013). The LC at 12 months was 7% and 35%, respectively. On multivariate analysis, fewer than four brain metastases (p < 0.001) were associated with LC. A trend was found for WBRT regimen (p = 0.06) and RPA class (p = 0.06). Conclusions: The findings suggest that escalation of the WBRT dose beyond 10 x 3 Gy improves outcomes in patients with brain metastases from RCC. The results should be confirmed in a randomized trial stratifying for significant prognostic factors.« less

Treatment-related mortality in patients with advanced-stage hodgkin lymphoma: an analysis of the german hodgkin study group.

PubMed

Wongso, Diana; Fuchs, Michael; Plütschow, Annette; Klimm, Beate; Sasse, Stephanie; Hertenstein, Bernd; Maschmeyer, Georg; Vieler, Tom; Dührsen, Ulrich; Lindemann, Walter; Aulitzky, Walter; Diehl, Volker; Borchmann, Peter; Engert, Andreas

2013-08-01

The introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated). In this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15. Among a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%. The individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

PubMed

van den Eertwegh, Alfons J M; Versluis, Jurjen; van den Berg, H Pieter; Santegoets, Saskia J A M; van Moorselaar, R Jeroen A; van der Sluis, Tim M; Gall, Helen E; Harding, Thomas C; Jooss, Karin; Lowy, Israel; Pinedo, Herbert M; Scheper, Rik J; Stam, Anita G M; von Blomberg, B Mary E; de Gruijl, Tanja D; Hege, Kristen; Sacks, Natalie; Gerritsen, Winald R

2012-05-01

The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam. Copyright © 2012 Elsevier Ltd. All rights reserved.

PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, Sean E., E-mail: semcguir@mdanderson.org; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; Lee, Andrew K.

2013-01-01

Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specificmore » mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.« less

A robust two-stage design identifying the optimal biological dose for phase I/II clinical trials.

PubMed

Zang, Yong; Lee, J Jack

2017-01-15

We propose a robust two-stage design to identify the optimal biological dose for phase I/II clinical trials evaluating both toxicity and efficacy outcomes. In the first stage of dose finding, we use the Bayesian model averaging continual reassessment method to monitor the toxicity outcomes and adopt an isotonic regression method based on the efficacy outcomes to guide dose escalation. When the first stage ends, we use the Dirichlet-multinomial distribution to jointly model the toxicity and efficacy outcomes and pick the candidate doses based on a three-dimensional volume ratio. The selected candidate doses are then seamlessly advanced to the second stage for dose validation. Both toxicity and efficacy outcomes are continuously monitored so that any overly toxic and/or less efficacious dose can be dropped from the study as the trial continues. When the phase I/II trial ends, we select the optimal biological dose as the dose obtaining the minimal value of the volume ratio within the candidate set. An advantage of the proposed design is that it does not impose a monotonically increasing assumption on the shape of the dose-efficacy curve. We conduct extensive simulation studies to examine the operating characteristics of the proposed design. The simulation results show that the proposed design has desirable operating characteristics across different shapes of the underlying true dose-toxicity and dose-efficacy curves. The software to implement the proposed design is available upon request. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A rule-based, dose-finding design for use in stroke rehabilitation research: methodological development.

PubMed

Colucci, E; Clark, A; Lang, C E; Pomeroy, V M

2017-12-01

Dose-optimisation studies as precursors to clinical trials are rare in stroke rehabilitation. To develop a rule-based, dose-finding design for stroke rehabilitation research. 3+3 rule-based, dose-finding study. Dose escalation/de-escalation was undertaken according to preset rules and a mathematical sequence (modified Fibonacci sequence). The target starting daily dose was 50 repetitions for the first cohort. Adherence was recorded by an electronic counter. At the end of the 2-week training period, the adherence record indicated dose tolerability (adherence to target dose) and the outcome measure indicated dose benefit (10% increase in motor function). The preset increment/decrease and checking rules were then applied to set the dose for the subsequent cohort. The process was repeated until preset stopping rules were met. Participants had a mean age of 68 (range 48 to 81) years, and were a mean of 70 (range 9 to 289) months post stroke with moderate upper limb paresis. A custom-built model of exercise-based training to enhance ability to open the paretic hand. Repetitions per minute of extension/flexion of paretic digits against resistance. Usability of the preset rules and whether the maximally tolerated dose was identifiable. Five cohorts of three participants were involved. Discernibly different doses were set for each subsequent cohort (i.e. 50, 100, 167, 251 and 209 repetitions/day). The maximally tolerated dose for the model training task was 209 repetitions/day. This dose-finding design is a feasible method for use in stroke rehabilitation research. Copyright © 2017 Chartered Society of Physiotherapy. All rights reserved.

Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors.

PubMed

Krick, Erika L; Sorenmo, Karin U; Rankin, Shelley C; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A

2012-01-01

To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. 6 client-owned dogs. A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

PubMed Central

Roehrs, Timothy A.; Roth, Thomas

2016-01-01

Study Objectives: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. Methods: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23–70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Results: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. Conclusions: In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. Clincial Trials Registration: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Roehrs TA, Roth T. Gender differences in the efficacy and safety of chronic nightly zolpidem. J Clin Sleep Med 2016;12(3):319–325. PMID:26446253

Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

PubMed

Timilsina, S; Brittan, K; O'Dell, J R; Brophy, M; Davis-Karim, A; Henrie, A M; Neogi, T; Newcomb, J; Palevsky, P M; Pillinger, M H; Pittman, D; Taylor, T H; Wu, H; Mikuls, T R

2018-05-01

Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management. Published by Elsevier Inc.

A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

PubMed Central

Jacobson, Terry A.

2010-01-01

Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D2–driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events. PMID:20360295

SU-E-T-69: A Radiobiological Investigation of Dose Escalation in Lower Oesophageal Tumours with a Focus On Gastric Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carrington, R; Staffurth, J; Spezi, E

2015-06-15

The incidence of lower third oesophageal tumours is increasing in most Western populations. With the role of radiotherapy dose escalation being identified as a research priority in improving outcomes, it is important to quantify the increased toxicity that this may pose to sites such as the lower oesophagus. This study therefore aims to investigate the feasibility of lower oesophageal dose escalation with a focus on stomach tissue toxicity.The original 3D-conformal plans (50Gy3D) from 10 patients in the SCOPE1 trial were reviewed and compared to two RapidArc plans created retrospectively to represent the treatment arms of the forthcoming SCOPE2 trial: 50GyRAmore » and 60GyRA (50Gy to PTV1 with a simultaneously integrated boost of 60Gy to PTV2). The stomach was contoured as stomach wall and dose constraints set according to QUANTEC. Normal tissue complication probability (NTCP) was estimated for the stomach wall for an endpoint of gastric bleeding. There was a mean increase of 5.93% in NTCP from 50Gy3D to 60GyRA and a mean increase of 8.15% in NTCP from the 50GyRA to 60GyRA. With NTCP modelling restricted to volumes outside PTV2, there was a mean decrease of 0.92% in NTCP from the 50Gy3D to 60GyRA, and a mean increase of 2.25% from 50GyRA to 60GyRA. There was a strong correlation between the NTCP and Stomach Wall/PTV1 overlap volume for all plans (R=0.80, 0.77 and 0.77 for 60GyRA, 50GyRA and 50Gy3D respectively). There was also a strong correlation between NTCP and the Stomach Wall/PTV2 overlap volume for 60GyRA (R= 0.82).Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach within the boost volume. It is recommended that stomach toxicity be closely monitored prospectively when treating patients with lower oesophageal tumours in the forthcoming SCOPE 2 trial. Rhys Carrington received a PhD studentship grant from Cancer Research Wales. Grant number: 2445; Dr Warren and Dr Partridge are supported by Cancer Research UK. Grant number: C5255/A15935. Dr Hawkins is supported by MRC grant MC-PC-12001/2.« less

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

PubMed

Osterman, Mark T; Aberra, Faten N; Cross, Raymond; Liakos, Steven; McCabe, Robert; Shafran, Ira; Wolf, Douglas; Hardi, Robert; Nessel, Lisa; Brensinger, Colleen; Gilroy, Erin; Lewis, James D

2014-11-01

Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 μg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 μg/g. Secondary outcomes were continued remission with FC <100 μg/g or <200 μg/g (among patients with pre-randomization values above these levels). The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 μg/g (P = .04) and 200 μg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 μg/g compared with those with FC <200 μg/g (P = .01). Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Radiation proctopathy in the treatment of prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garg, Amit K.; Mai Weiyan; McGary, John E.

2006-12-01

Purpose: To compile and review data on radiation proctopathy in the treatment of prostate cancer with respect to epidemiology, clinical manifestations, pathogenesis, risk factors, and treatment. Methods: Medical literature databases including PubMed and Medline were screened for pertinent reports, and critically analyzed for relevance in the scope of our purpose. Results: Rectal toxicity as a complication of radiotherapy has received attention over the past decade, especially with the advent of dose-escalation in prostate cancer treatment. A number of clinical criteria help to define acute and chronic radiation proctopathy, but lack of a unified grading scale makes comparing studies difficult. Amore » variety of risk factors, related to either radiation delivery or patient, are the subject of intense study. Also, a variety of treatment options, including medical therapy, endoscopic treatments, and surgery have shown varied results, but a lack of large randomized trials evaluating their efficacy prevents forming concrete recommendations. Conclusion: Radiation proctopathy should be an important consideration for the clinician in the treatment of prostate cancer especially with dose escalation. With further study of possible risk factors, the advent of a standardized grading scale, and more randomized trials to evaluate treatments, patients and physicians will be better armed to make appropriate management decisions.« less

Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, D.W. Nathan; Cho, L. Chinsoo; Straka, Christopher

2014-07-01

Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% ofmore » patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.« less

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

PubMed

Cassier, Philippe A; Italiano, Antoine; Gomez-Roca, Carlos A; Le Tourneau, Christophe; Toulmonde, Maud; Cannarile, Michael A; Ries, Carola; Brillouet, Anne; Müller, Claudia; Jegg, Anna-Maria; Bröske, Ann-Marie; Dembowski, Markus; Bray-French, Katharine; Freilinger, Christine; Meneses-Lorente, Georgina; Baehner, Monika; Harding, Ross; Ratnayake, Jayantha; Abiraj, Keelara; Gass, Nathalie; Noh, Karen; Christen, Randolph D; Ukarma, Lidia; Bompas, Emmanuelle; Delord, Jean-Pierre; Blay, Jean-Yves; Rüttinger, Dominik

2015-08-01

Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. F Hoffmann-La Roche. Copyright © 2015 Elsevier Ltd. All rights reserved.

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

PubMed

Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

2005-04-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, P; Kuo, L; Yorke, E

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after themore » full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach. MSKCC has a research agreement with Varian Medical System.« less

The Missing Pieces in Reporting of Randomized Controlled Trials of External Beam Radiation Therapy Dose Escalation for Prostate Cancer.

PubMed

Zaorsky, Nicholas G; Egleston, Brian L; Horwitz, Eric M; Dicker, Adam P; Nguyen, Paul L; Showalter, Timothy N; Den, Robert B

2016-08-01

Randomized controlled trials (RCTs) are the most rigorous way of determining whether a cause-effect relation exists between treatment and outcome and for assessing the cost-effectiveness of a treatment. For many patients, cancer is a chronic illness; RCTs evaluating treatments for indolent cancers must evolve to facilitate medical decision-making, as "concrete" patient outcomes (eg, survival) will likely be excellent independent of the intervention, and detecting a difference between trial arms may be impossible. In this commentary, we articulate 9 recommendations that we hope future clinical trialists and funding agencies (including those under the National Cancer Institute) will take into consideration when planning RCTs to help guide subsequent interpretation of results and clinical decision making, based on RCTs of external beam radiation therapy dose escalation for the most common indolent cancer in men, that is, prostate cancer. We recommend routinely reporting: (1) race; (2) medical comorbidities; (3) psychiatric comorbidities; (4) insurance status; (5) education; (6) marital status; (7) income; (8) sexual orientation; and (9) facility-related characteristics (eg, number of centers involved, type of facilities, yearly hospital volumes). We discuss how these factors independently affect patient outcomes and toxicities; future clinicians and governing organizations should consider this information to plan RCTs accordingly (to maximize patient accrual and total n), select appropriate endpoints (eg, toxicity, quality of life, sexual function), actively monitor RCTs, and report results so as to identify the optimal treatment among subpopulations.

Oral Sulforaphane increases Phase II antioxidant enzymes in the human upper airway

PubMed Central

Riedl, Marc A.; Saxon, Andrew; Diaz-Sanchez, David

2009-01-01

Background Cellular oxidative stress is an important factor in asthma and is thought to be the principle mechanism by which oxidant pollutants such as ozone and particulates mediate their pro-inflammatory effects. Endogenous Phase II enzymes abrogate oxidative stress through the scavenging of reactive oxygen species and metabolism of reactive chemicals. Objective We conducted a placebo-controlled dose escalation trial to investigate the in vivo effects of sulforaphane, a naturally occurring potent inducer of Phase II enzymes, on the expression of glutathione-s-transferase M1 (GSTM1), glutathione-s-transferase P1 (GSTP1), NADPH quinone oxidoreductase (NQO1), and hemoxygenase-1 (HO-1) in the upper airway of human subjects. Methods Study subjects consumed oral sulforaphane doses contained in a standardized broccoli sprout homogenate (BSH). RNA expression for selected Phase II enzymes was measured in nasal lavage cells by RT-PCR before and after sulforaphane dosing. Results All subjects tolerated oral sulforaphane dosing without significant adverse events. Increased Phase II enzyme expression in nasal lavage cells occurred in a dose-dependent manner with maximal enzyme induction observed at the highest dose of 200 grams broccoli sprouts prepared as BSH. Significant increases were seen in all sentinel Phase II enzymes RNA expression compared to baseline. Phase II enzyme induction was not seen with ingestion of non-sulforaphane containing alfalfa sprouts. Conclusion Oral sulforaphane safely and effectively induces mucosal Phase II enzyme expression in the upper airway of human subjects. This study demonstrates the potential of antioxidant Phase II enzymes induction in the human airway as a strategy to reduce the inflammatory effects of oxidative stress. Clinical Implications This study demonstrates the potential of enhancement of Phase II enzyme expression as a novel therapeutic strategy for oxidant induced airway disease. Capsule Summary A placebo-controlled dose escalation trial demonstrated that naturally occurring sulforaphane from broccoli sprouts can induce a potent increase in antioxidant Phase II enzymes in airway cells. PMID:19028145

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study

PubMed Central

2014-01-01

Introduction Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Methods Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Results Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. Conclusion The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. Trial Registration ClinicalTrials.gov NCT00930683 PMID:24559157

Effects of escalating doses of tirofiban on platelet aggregation and major receptor expression in diabetic patients: hitting the TARGET in the TENACITY trial?

PubMed

Serebruany, Victor; Malinin, Alex; Pokov, Alex; Arora, Umesh; Atar, Dan; Angiolillo, Dominick

2007-01-01

Ongoing search for the optimal dosing regimens, and valid concerns that some GPIIb/IIIa inhibitors may cause rebound platelet activation are limiting the use of these agents in patients with acute vascular events. We assessed the in vitro effects of preincubation with escalating (12.5-200 ng/mL) concentrations of tirofiban on platelet biomarkers in 20 diabetic patients. Platelet activity was assessed by ADP-, and collagen-induced conventional plasma aggregometry, and by whole blood flow cytometry measuring expression of PECAM-1, GPIb, GP IIb/IIIa antigen and activity, vitronectin, P-selectin, LAMP-1, GP 37, LAMP-3, activated and intact PAR-1 thrombin receptors, GPIV, and platelet-monocyte formation. All patients were treated with aspirin (at least 81 mg daily for 1 month); other antiplatelet agents were not allowed. Significant decrease of ADP-induced platelet aggregation was observed starting at the low 12.5 ng/mL concentration (p=0.0001), with total inhibition occurring at 50 ng/mL of tirofiban dose. Inhibition of collagen-induced platelet aggregability requires 25 ng/ml of tirofiban (p=0.002), and was complete at 100 ng/mL. Dose-dependent blockade of GP IIb/IIIa activity was observed with tirofiban concentrations over 50 ng/mL (p=0.003). Other receptors were unaffected even with the high doses of tirofiban (100-200 ng/mL). Tirofiban completely inhibits ADP- and, with the higher dose, collagen-induced platelet aggregation. Higher loading dose of tirofiban used in the ongoing TENACITY trial (100 ng/mL) may be superior with regard to clinical outcomes to the regimens used in PRISM-PLUS (25 ng/mL), or TARGET (50 ng/mL). Selective inhibition of GPIIb/IIIa activity, and lack of alternative platelet activation beyond the GP IIb/IIIa blockade may represent the therapeutic advantage of tirofiban over other agents.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. Daiichi Sankyo Co, Ltd. Copyright © 2017 Elsevier Ltd. All rights reserved.

Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: clinical article.

PubMed

Sloan, Andrew E; Ahluwalia, Manmeet S; Valerio-Pascua, Jose; Manjila, Sunil; Torchia, Mark G; Jones, Stephen E; Sunshine, Jeffrey L; Phillips, Michael; Griswold, Mark A; Clampitt, Mark; Brewer, Cathy; Jochum, Jennifer; McGraw, Mary V; Diorio, Dawn; Ditz, Gail; Barnett, Gene H

2013-06-01

Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).

Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA

PubMed Central

Richie, Thomas L.; Charoenvit, Yupin; Wang, Ruobing; Epstein, Judith E.; Hedstrom, Richard C.; Kumar, Sanjai; Luke, Thomas C.; Freilich, Daniel A.; Aguiar, Joao C.; Sacci, Jr., John B.; Sedegah, Martha; Nosek, Jr., Ronald A.; De La Vega, Patricia; Berzins, Mara P.; Majam, Victoria F.; Abot, Esteban N.; Ganeshan, Harini; Richie, Nancy O.; Banania, Jo Glenna; Baraceros, Maria Fe B.; Geter, Tanya G.; Mere, Robin; Bebris, Lolita; Limbach, Keith; Hickey, Bradley W.; Lanar, David E.; Ng, Jennifer; Shi, Meng; Hobart, Peter M.; Norman, Jon A.; Soisson, Lorraine A.; Hollingdale, Michael R.; Rogers, William O.; Doolan, Denise L.; Hoffman, Stephen L.

2012-01-01

When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997−1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparum circumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000–2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 μg of each plasmid plus escalating doses (0, 20, 100 or 500 μg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines. PMID:23151451

Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy.

PubMed

Speyer, J L; Beller, U; Colombo, N; Sorich, J; Wernz, J C; Hochster, H; Green, M; Porges, R; Muggia, F M; Canetta, R

1990-08-01

From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy.

A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer.

PubMed

Michael, M; Zalcberg, J; Gibbs, P; Lipton, L; Gouillou, M; Jefford, M; McArthur, G; Copeman, M; Lynch, K; Tebbutt, N C

2013-02-01

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.

Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal

PubMed Central

Reed, Brian; Ho, Ann; Kreek, Mary Jeanne

2011-01-01

Rationale/objectives Although continued heroin use and relapse are thought to be motivated, in part, by the positive incentive-motivational value attributed to heroin, little is understood about heroin’s incentive value during the relapse-prone state of withdrawal. This study uses place preference to measure the incentive value attributed to escalating-dose heroin in the context of heroin dependence. Methods Male Fischer rats were exposed chronically to escalating doses of heroin in the homecage and during place preference conditioning sessions. Conditioned preference for the context paired with escalating-dose heroin was tested after homecage exposure was discontinued and rats entered acute spontaneous withdrawal. Individuals’ behavioral and locomotor responses to heroin and somatic withdrawal signs were recorded. Results Conditioned preference for the heroin-paired context was strong in rats that received chronic homecage exposure to escalating-dose heroin and were tested in acute withdrawal. Behavioral responses to heroin (e.g., stereotypy) varied widely across individuals, with rats that expressed stronger heroin preference also expressing stronger behavioral activation in response to heroin. Individual differences in preference were also related to locomotor responses to heroin but not to overt somatic withdrawal signs. Conclusions Escalating doses of heroin evoked place preference in rats, suggesting that positive incentive-motivational value is attributed to this clinically relevant pattern of drug exposure. This study offers an improved preclinical model for studying dependence and withdrawal and provides insight into individual vulnerabilities to addiction-like behavior. PMID:21748254

Lack of Benefit for the Addition of Androgen Deprivation Therapy to Dose-Escalated Radiotherapy in the Treatment of Intermediate- and High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krauss, Daniel, E-mail: dkrauss@beaumont.edu; Kestin, Larry; Ye, Hong

2011-07-15

Purpose: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). Methods and Materials: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA {>=}20, or Stage T3. Patients were additionally divided specifically by Gleason score, presencemore » of palpable disease, and PSA level to further define subgroups benefitting from ADT. Results: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason {>=}8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. Conclusion: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.« less

Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

PubMed Central

Krick, Erika L.; Sorenmo, Karin U.; Rankin, Shelley C.; Cheong, Ian; Kobrin, Barry; Thornton, Katherine; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin; Diaz, Luis A.

2015-01-01

Objective To establish the maximum tolerated dose of Clostridium novyi–NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. Animals 6 client-owned dogs. Procedures A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C novyi–NT spores IV. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. Results The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C novyi–NT infection; both required surgical intervention. Clostridium novyi–NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Conclusions and Clinical Relevance Results indicated that C novyi–NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology. PMID:22204296

Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCath (registered) technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fransson, Per; Bergstroem, Per; Loefroth, Per-Olov

2006-10-01

Purpose: Late side effects were prospectively evaluated up to 5 years after dose-escalated external beam radiotherapy (EBRT) and were compared with a previously treated series with conventional conformal technique. Methods and Materials: Bladder and bowel symptoms were prospectively evaluated with the Prostate Cancer Symptom Scale (PCSS) questionnaire up to 5 years posttreatment. In all, 257 patients completed the questionnaire 5 years posttreatment. A total of 168 patients were treated with the conformal technique at doses <71 Gy, and 195 were treated with the dose-escalated stereotactic BeamCath (registered) technique comprising three dose levels: 74 Gy (n = 68), 76 Gy (nmore » = 74), and 78 Gy (n = 53). Results: For all dose groups analyzed together, 5 years after treatment, urinary starting problems decreased and urinary incontinence increased in comparison to baseline values. No increase in other bladder symptoms or frequency was detected. When comparing dose groups after 5 years, both the 74-Gy and 78-Gy groups reported increased urinary starting problems compared with patients given the conventional dose (<71 Gy). No increased incontinence was seen in the 76-Gy or the 78-Gy groups. Bowel symptoms were slightly increased during the follow-up period in comparison to baseline. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal late side effects after 5 years in comparison to doses <71 Gy. Conclusion: Dose-escalated EBRT with the BeamCath (registered) technique with doses up to 78 Gy is tolerable, and the toxicity profile is similar to that observed with conventional doses <71 Gy.« less

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

PubMed

Walter, Harriet S; Rule, Simon A; Dyer, Martin J S; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, Gilles

2016-01-28

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. © 2016 by The American Society of Hematology.

Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.

PubMed

Bell, D; Pediconi, C; Jacobs, A

2014-03-01

The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories. This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence. Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity. The regression analysis concluded that the doses were dose proportional. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1

PubMed Central

Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

2005-01-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 μM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants. PMID:15831235

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours.

PubMed

Molenaar, Remco J; Coelen, Robert J S; Khurshed, Mohammed; Roos, Eva; Caan, Matthan W A; van Linde, Myra E; Kouwenhoven, Mathilde; Bramer, Jos A M; Bovée, Judith V M G; Mathôt, Ron A; Klümpen, Heinz-Josef; van Laarhoven, Hanneke W M; van Noorden, Cornelis J F; Vandertop, W Peter; Gelderblom, Hans; van Gulik, Thomas M; Wilmink, Johanna W

2017-06-10

High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2 -mutated cancer cells produce the oncometabolite D -2-hydroxyglutarate ( D -2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2 -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2 -mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D -2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2 -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial.

PubMed

Crabb, Simon; Danson, Sarah J; Catto, James W F; McDowell, Cathy; Lowder, James N; Caddy, Joshua; Dunkley, Denise; Rajaram, Jessica; Ellis, Deborah; Hill, Stephanie; Hathorn, David; Whitehead, Amy; Kalevras, Mihalis; Huddart, Robert; Griffiths, Gareth

2018-04-03

Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m 2 , IV infusion, day 8; gemcitabine 1000 mg/m 2 , IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016).

Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management.

PubMed

Coburn, Brian W; Bendlin, Kayli A; Sayles, Harlan; Meza, Jane; Russell, Cynthia L; Mikuls, Ted R

2017-09-01

Patient and provider factors, including allopurinol medication adherence, affect gout treatment outcomes. The aim of this study was to examine associations of patient and provider factors with optimal gout management. Linking longitudinal health and pharmacy dispensing records to questionnaire data, we assessed patient and provider factors among 612 patients with gout receiving allopurinol during a recent 1-year period. Associations of patient (medication adherence and patient activation) and provider factors (dose escalation, low-dose initiation, and anti-inflammatory prophylaxis) with serum urate (SU) goal achievement of less than 6.0 mg/dL were examined using multivariable logistic regression. Medication adherence was assessed as a mediator of these factors with goal achievement. A majority of patients (63%) were adherent, whereas a minority received dose escalation (31%). Medication adherence was associated with initiation of daily allopurinol doses of 100 mg/d or less (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.20-2.76). In adjusted models, adherence (OR, 2.35; 95% CI, 1.50-3.68) and dose escalation (OR, 2.48; 95% CI, 2.48-4.25) were strongly associated with SU goal attainment. Low starting allopurinol dose was positively associated with SU goal attainment (OR, 1.11; 95% CI, 1.02-1.20) indirectly through early adherence, but also had a negative direct association with SU goal attainment (OR, 0.21; 95% CI, 0.12-0.37). Medication adherence and low starting dose combined with dose escalation represent promising targets for future gout quality improvement efforts. Low starting dose is associated with better SU goal attainment through increased medication adherence, but may be beneficial only in settings where appropriate dose escalation is implemented.

Treating locally advanced lung cancer with a 1.5T MR-Linac - Effects of the magnetic field and irradiation geometry on conventionally fractionated and isotoxic dose-escalated radiotherapy.

PubMed

Bainbridge, Hannah E; Menten, Martin J; Fast, Martin F; Nill, Simeon; Oelfke, Uwe; McDonald, Fiona

2017-11-01

This study investigates the feasibility and potential benefits of radiotherapy with a 1.5T MR-Linac for locally advanced non-small cell lung cancer (LA NSCLC) patients. Ten patients with LA NSCLC were retrospectively re-planned six times: three treatment plans were created according to a protocol for conventionally fractionated radiotherapy and three treatment plans following guidelines for isotoxic target dose escalation. In each case, two plans were designed for the MR-Linac, either with standard (∼7mm) or reduced (∼3mm) planning target volume (PTV) margins, while one conventional linac plan was created with standard margins. Treatment plan quality was evaluated using dose-volume metrics or by quantifying dose escalation potential. All generated treatment plans fulfilled their respective planning constraints. For conventionally fractionated treatments, MR-Linac plans with standard margins had slightly increased skin dose when compared to conventional linac plans. Using reduced margins alleviated this issue and decreased exposure of several other organs-at-risk (OAR). Reduced margins also enabled increased isotoxic target dose escalation. It is feasible to generate treatment plans for LA NSCLC patients on a 1.5T MR-Linac. Margin reduction, facilitated by an envisioned MRI-guided workflow, enables increased OAR sparing and isotoxic target dose escalation for the respective treatment approaches. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults

PubMed Central

Green, C A; Scarselli, E; Voysey, M; Capone, S; Vitelli, A; Nicosia, A; Cortese, R; Thompson, A J; Sande, C S; de Lara, Catherine; Klenerman, P; Pollard, A J

2015-01-01

Introduction Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults. Methods and analysis Heterologous and homologous ‘prime’/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18–50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60–75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK. Ethics and dissemination RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums. Trial registration number NCT01805921. PMID:26510727

A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia

PubMed Central

How, Jonathan; Minden, Mark D.; Brian, Leber; Chen, Eric X.; Brandwein, Joseph; Schuh, Andre C.; Schimmer, Aaron D.; Gupta, Vikas; Webster, Sheila; Degelder, Tammy; Haines, Patricia; Stayner, Lee-Anne; McGill, Shauna; Wang, Lisa; Piekarz, Richard; Wong, Tracy; Siu, Lillian L.; Espinoza-Delgado, Igor; Holleran, Julianne L.; Egorin, Merrill J.; Yee, Karen W. L.

2015-01-01

This phase I trial evaluated two schedules of escalating vorinostat in combination with decitabine every 28 days: (i) sequential or (ii) concurrent. There were three dose-limiting toxicities: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n = 1) and grade 3 fatigue on the concurrent schedule (n = 2). The maximum tolerated dose was not reached on both planned schedules. The overall response rate (ORR) was 23% (three complete response [CR], two CR with incomplete incomplete blood count recovery [CRi], one partial response [PR] and two morphological leukemic free state [MLFS]). The ORR for all and previously untreated patients in the sequential arm was 13% (one CRi; one MLFS) and 0% compared to 30% (three CR; one CRi; one PR; one MLFS) and 36% in the concurrent arm (p = 0.26 for both), respectively. Decitabine plus vorinostat was safe and has clinical activity in patients with previously untreated acute myeloid leukemia. Responses appear higher with the concurrent dose schedule. Cumulative toxicities may limit long-term usage on the current dose/schedules. PMID:25682963

Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma.

PubMed

Courtney, Kevin D; Infante, Jeffrey R; Lam, Elaine T; Figlin, Robert A; Rini, Brian I; Brugarolas, James; Zojwalla, Naseem J; Lowe, Ann M; Wang, Keshi; Wallace, Eli M; Josey, John A; Choueiri, Toni K

2018-03-20

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miah, Aisha B.; Bhide, Shreerang A.; Guerrero-Urbano, M. Teresa

2012-02-01

Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and latemore » toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study.« less

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

PubMed Central

2012-01-01

Background The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. Methods ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. Discussion This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. Trial registration ClinicalTrials.gov Identifier: NCT01301430 PMID:22436661

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

PubMed

Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

2018-02-01

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

A novel concept for tumour targeting with radiation: Inverse dose-painting or targeting the "Low Drug Uptake Volume".

PubMed

Yaromina, Ala; Granzier, Marlies; Biemans, Rianne; Lieuwes, Natasja; van Elmpt, Wouter; Shakirin, Georgy; Dubois, Ludwig; Lambin, Philippe

2017-09-01

We tested a novel treatment approach combining (1) targeting radioresistant hypoxic tumour cells with the hypoxia-activated prodrug TH-302 and (2) inverse radiation dose-painting to boost selectively non-hypoxic tumour sub-volumes having no/low drug uptake. 18 F-HX4 hypoxia tracer uptake measured with a clinical PET/CT scanner was used as a surrogate of TH-302 activity in rhabdomyosarcomas growing in immunocompetent rats. Low or high drug uptake volume (LDUV/HDUV) was defined as 40% of the GTV with the lowest or highest 18 F-HX4 uptake, respectively. Two hours post TH-302/saline administration, animals received either single dose radiotherapy (RT) uniformly (15 or 18.5Gy) or a dose-painted non-uniform radiation (15Gy) with 50% higher dose to LDUV or HDUV (18.5Gy). Treatment plans were created using Eclipse treatment planning system and radiation was delivered using VMAT. Tumour response was quantified as time to reach 3 times starting tumour volume. Non-uniform RT boosting tumour sub-volume with low TH-302 uptake (LDUV) was superior to the same dose escalation to HDUV (p<0.0001) and uniform RT with the same mean dose 15Gy (p=0.0077). Noteworthy, dose escalation to LDUV required on average 3.5Gy lower dose to the GTV to achieve similar tumour response as uniform dose escalation. The results support targeted dose escalation to non-hypoxic tumour sub-volume with no/low activity of hypoxia-activated prodrugs. This strategy applies on average a lower radiation dose and is as effective as uniform dose escalation to the entire tumour. It could be applied to other type of drugs provided that their distribution can be imaged. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Radiobiological evaluation of simultaneously dose-escalated versus non-escalated intensity-modulated radiation therapy for patients with upper thoracic esophageal cancer.

PubMed

Huang, Bao-Tian; Wu, Li-Li; Guo, Long-Jia; Xu, Liang-Yu; Huang, Rui-Hong; Lin, Pei-Xian; Chen, Jian-Zhou; Li, De-Rui; Chen, Chuang-Zhen

2017-01-01

To compare the radiobiological response between simultaneously dose-escalated and non-escalated intensity-modulated radiation therapy (DE-IMRT and NE-IMRT) for patients with upper thoracic esophageal cancer (UTEC) using radiobiological evaluation. Computed tomography simulation data sets for 25 patients pathologically diagnosed with primary UTEC were used in this study. DE-IMRT plan with an escalated dose of 64.8 Gy/28 fractions to the gross tumor volume (GTV) and involved lymph nodes from 25 patients pathologically diagnosed with primary UTEC, was compared to an NE-IMRT plan of 50.4 Gy/28 fractions. Dose-volume metrics, tumor control probability (TCP), and normal tissue complication probability for the lung and spinal cord were compared. In addition, the risk of acute esophageal toxicity (AET) and late esophageal toxicity (LET) were also analyzed. Compared with NE-IMRT plan, we found the DE-IMRT plan resulted in a 14.6 Gy dose escalation to the GTV. The tumor control was predicted to increase by 31.8%, 39.1%, and 40.9% for three independent TCP models. The predicted incidence of radiation pneumonitis was similar (3.9% versus 3.6%), and the estimated risk of radiation-induced spinal cord injury was extremely low (<0.13%) in both groups. Regarding the esophageal toxicities, the estimated grade ≥2 and grade ≥3 AET predicted by the Kwint model were increased by 2.5% and 3.8%. Grade ≥2 AET predicted using the Wijsman model was increased by 14.9%. The predicted incidence of LET was low (<0.51%) in both groups. Radiobiological evaluation reveals that the DE-IMRT dosing strategy is feasible for patients with UTEC, with significant gains in tumor control and minor or clinically acceptable increases in radiation-induced toxicities.

Gastroesophageal Acid Reflux Control 5 Years After Antireflux Surgery, Compared With Long-term Esomeprazole Therapy.

PubMed

Hatlebakk, Jan G; Zerbib, Frank; Bruley des Varannes, Stanislas; Attwood, Stephen E; Ell, Christian; Fiocca, Roberto; Galmiche, Jean-Paul; Eklund, Stefan; Långström, Göran; Lind, Tore; Lundell, Lars R

2016-05-01

We compared the ability of laparoscopic antireflux surgery (LARS) and esomeprazole to control esophageal acid exposure, over a 5-year period, in patients with chronic gastroesophageal reflux disease (GERD). We also studied whether intraesophageal and intragastric pH parameters off and on therapy were associated with long-term outcomes. We analyzed data from a prospective, randomized, open-label trial comparing the efficacy and safety of LARS vs esomeprazole (20 or 40 mg/d) over 5 years in patients with chronic GERD. Ambulatory intraesophageal and intragastric 24-hour pH monitoring data were compared between groups before LARS or the start of esomeprazole treatment, and 6 months and 5 years afterward. A secondary aim was to evaluate the association between baseline and 6-month pH parameters and esomeprazole dose escalation, reappearance of GERD symptoms, and treatment failure over 5 years in patients receiving LARS or esomeprazole. In the LARS group (n = 116), the median 24-hour esophageal acid exposure was 8.6% at baseline and 0.7% after 6 months and 5 years (P < .001 vs baseline). In the esomeprazole group (n = 151), the median 24-hour esophageal acid exposure was 8.8% at baseline, 2.1% after 6 months, and 1.9% after 5 years (P < .001, therapy vs baseline, and LARS vs esomeprazole). Gastric acidity was stable in both groups. Patients who required a dose increase to 40 mg/d had more severe supine reflux at baseline, and decreased esophageal acid exposure (P < .02) and gastric acidity after dose escalation. Esophageal and intragastric pH parameters, off and on therapy, did not predict long-term symptom breakthrough. In a prospective study of patients with chronic GERD, esophageal acid reflux was reduced greatly by LARS or esomeprazole therapy. However, patients receiving LARS had significantly greater reductions in 24-hour esophageal acid exposure after 6 months and 5 years. Esophageal and gastric pH, off and on therapy, did not predict long-term outcomes of patients. Abnormal supine acid exposure predicted esomeprazole dose escalation. ClinicalTrials.Gov identifier: NCT00251927 (available: http://clinicaltrials.gov/ct2/show/NCT00251927). Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer: a phase 1b study.

PubMed

Czito, Brian G; Deming, Dustin A; Jameson, Gayle S; Mulcahy, Mary F; Vaghefi, Houman; Dudley, Matthew W; Holen, Kyle D; DeLuca, Angela; Mittapalli, Rajendar K; Munasinghe, Wijith; He, Lei; Zalcberg, John R; Ngan, Samuel Y; Komarnitsky, Philip; Michael, Michael

2017-06-01

Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20-400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5-10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy (<400 mg, n=16; 400 mg, n=15). During dose escalation, grade 2 dose-limiting toxic effects occurred in two patients; no grade 3-4 dose-limiting toxic effects were noted. Therefore, the maximum tolerated dose was not reached; the recommended phase 2 dose was selected as 400 mg twice daily. The most common treatment-emergent adverse events in all 32 patients were nausea (17 [53%]), diarrhoea (16 [50%]), and fatigue (16 [50%]). Grade 3 diarrhoea was noted in three (9%) of 32 patients; no grade 4 events were reported. Veliparib pharmacokinetics were dose proportional, with no effect on capecitabine pharmacokinetics. Tumour downstaging after surgery was noted in 22 (71%) of 31 patients; nine (29%) of 31 patients achieved a pathological complete response. Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. AbbVie Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

PubMed

Trucco, Matteo; Barredo, Julio C; Goldberg, John; Leclerc, Gilles M; Hale, Gregory A; Gill, Jonathan; Setty, Bhuvana; Smith, Tiffany; Lush, Richard; Lee, Jae K; Reed, Damon R

2018-06-01

Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m 2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m 2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels. © 2018 Wiley Periodicals, Inc.

Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy.

PubMed

Tran, Ly-Binh-An; Bol, Anne; Labar, Daniel; Karroum, Oussama; Bol, Vanesa; Jordan, Bénédicte; Grégoire, Vincent; Gallez, Bernard

2014-11-01

Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions. Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas. For 9L-gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen. (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F-FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non-responsive to carbogen. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Normal tissue toxicity after small field hypofractionated stereotactic body radiation.

PubMed

Milano, Michael T; Constine, Louis S; Okunieff, Paul

2008-10-31

Stereotactic body radiation (SBRT) is an emerging tool in radiation oncology in which the targeting accuracy is improved via the detection and processing of a three-dimensional coordinate system that is aligned to the target. With improved targeting accuracy, SBRT allows for the minimization of normal tissue volume exposed to high radiation dose as well as the escalation of fractional dose delivery. The goal of SBRT is to minimize toxicity while maximizing tumor control. This review will discuss the basic principles of SBRT, the radiobiology of hypofractionated radiation and the outcome from published clinical trials of SBRT, with a focus on late toxicity after SBRT. While clinical data has shown SBRT to be safe in most circumstances, more data is needed to refine the ideal dose-volume metrics.

High-dose chemotherapy with autologous hematopoietic stem cell support for solid tumors in adults.

PubMed

Pedrazzoli, Paolo; Rosti, Giovanni; Secondino, Simona; Carminati, Ornella; Demirer, Taner

2007-10-01

Supported by experimental evidence and convincing results of early phase II studies, since the 1980s high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support (AHSCT) has been uncritically adopted by many oncologists as a potentially curative option for several solid tumors. As a result, the number (and size) of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) in this setting was limited and the benefit of a greater escalation of dose of chemotherapy with stem cell transplantation in solid tumors remains, with the possible exception of breast carcinoma (BC) and germ cell tumors (GCT), largely unsettled. In this article, we review and comment on the data from studies to date of HDC for solid tumors in adults.

Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by (18)FDG-PET/CT for esophageal cancer.

PubMed

Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

2015-02-01

To observe the safety of selective dose boost to the pre-treatment high (18)F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Dose escalation in esophageal cancer based on (18)FDG-PET/CT has been safely achieved up to 70Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

PubMed Central

Mazcko, Christina; Hanna, Engy; Kachala, Stefan; LeBlanc, Amy; Newman, Shelley; Vail, David; Henry, Carolyn; Thamm, Douglas; Sorenmo, Karin; Hajitou, Amin; Pasqualini, Renata; Arap, Wadih

2009-01-01

Background Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5×1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies. PMID:19330034

Treatment of Common Cold Patients with the Shi-Cha Capsule: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-Escalation Trial

PubMed Central

Chang, Jing; Dong, Shou-Jin; She, Bin; Zhang, Rui-Ming; Meng, Mao-Bin; Xu, Yan-Ling; Wan, Li-Ling; Shi, Ke-Hua; Pan, Jun-Hun; Mao, Bing

2012-01-01

This study was designed to determine the therapeutic efficacy and safety of the Shi-cha capsule, a Chinese herbal formula, in the treatment of patients with wind-cold type common cold. In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with wind-cold type common cold received 0.6 g of Shi-cha capsule plus 0.6 g placebo (group A), 1.2 g of Shi-cha capsule (group B), or 1.2 g placebo (group C), three times daily for 3 days and followed up to 10 days. The primary end point was all symptom duration. The secondary end points were main symptom duration, minor symptom duration, the changes in cumulative symptom score, main symptom score, and minor symptom score 4 days after the treatment, as well as adverse events. A total of 377 patients were recruited and 360 met the inclusive criteria; 120 patients constituted each treatment group. Compared with patients in group C, patients in groups A and B had significant improvement in the all symptom duration, main symptom duration, minor symptom duration, as well as change from baseline of cumulative symptom score, main symptom score, and minor symptom score at day 4. The symptom durations and scores showed slight superiority of group B over group A, although these differences were not statistically significant. There were no differences in adverse events. The Shi-cha capsule is efficacious and safe for the treatment of patients with wind-cold type common cold. Larger trials are required to fully assess the benefits and safety of this treatment for common cold. PMID:23346193

Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for {sup 18}F-FDG-PET-guided dose escalation in oropharyngeal cancer: A planning study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teoh, May, E-mail: m.teoh@nhs.net; Beveridge, Sabeena; Wood, Katie

2013-04-01

Fluorine-18-fluorodeoxyglucose-positron emission tomography ({sup 18}F-FDG-PET)–guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to {sup 18}F-FDG-PET–positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gymore » in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI{sub Paddick}) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI{sub Paddick} scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8–49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). {sup 18}F-FDG-PET–guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.« less

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramroth, Johanna; Cutter, David J.; Darby, Sarah C.

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, highermore » versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.« less

Does Proton Therapy Offer Demonstrable Clinical Advantages for Treating Thoracic Tumors?

PubMed

Liao, Zhongxing; Gandhi, Saumil J; Lin, Steven H; Bradley, Jeffrey

2018-04-01

The finite range of proton beams in tissues offers unique dosimetric advantages that theoretically allow dose to the target to be escalated while minimizing exposure of surrounding tissues and thus minimizing radiation-induced toxicity. This theoretical advantage has led to widespread adoption of proton therapy around the world for a wide variety of tumors at different anatomical sites. Many treatment-planning comparisons have shown that proton therapy has substantial dosimetric advantages over conventional radiotherapy. However, given the significant difference in cost for proton vs conventional photon therapy, thorough investigation of the evidence of proton therapy's clinical benefits in terms of toxicity and survival is warranted. Some data from retrospective studies, single-arm prospective studies, and a very few randomized clinical trials comparing these modalities are beginning to emerge. In this review, we examine the available data with regard to proton therapy for thoracic malignancies. We begin by discussing the unique challenges involved in treating moving targets with significant tissue heterogeneity and the technologic efforts underway to overcome these challenges. We then discuss the rationale for minimizing normal tissue toxicity, particularly pulmonary, cardiac, and hematologic toxicity, within the context of previously unsuccessful attempts at dose escalation for lung and esophageal cancer. Finally, we explore strategies for accelerating the development of trials aimed at measuring meaningful clinical endpoints and for maximizing the value of proton therapy by personalizing its use for individual patients. Copyright © 2018 Elsevier Inc. All rights reserved.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

PubMed

Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

2017-09-12

Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

PubMed

Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

2012-06-01

MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

Intensity-modulated radiotherapy in the standard management of head and neck cancer: promises and pitfalls.

PubMed

Mendenhall, William M; Amdur, Robert J; Palta, Jatinder R

2006-06-10

The purpose of this article is to review the role of intensity-modulated radiotherapy (IMRT) in the standard management of patients with head and neck cancer through a critical review of the pertinent literature. IMRT may result in a dose distribution that is more conformal than that achieved with three-dimensional conformal radiotherapy (3D CRT), allowing dose reduction to normal structures and thus decreasing toxicity and possibly enhancing locoregional control through dose escalation. Disadvantages associated with IMRT include increased risk of a marginal miss, decreased dose homogeneity, increased total body dose, and increased labor and expense. Outcomes data after IMRT are limited, and follow-up is relatively short. Locoregional control rates appear to be comparable to those achieved with 3D CRT and, depending on the location and extent of the tumor, late toxicity may be lower. Despite limited data on clinical outcomes, IMRT has been widely adopted as a standard technique in routine practice and clinical trials. The use of IMRT involves a learning curve for the practitioner and will continue to evolve, requiring continuing education and monitoring of outcomes from routine practice. Additional standards pertaining to a variety of issues, including target definitions and dose specification, need to be developed. Phase III trials will better define the role of IMRT in coming years.

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

PubMed Central

Kong, Feng-Ming; Ten Haken, Randall K.; Schipper, Matthew; Frey, Kirk A.; Hayman, James; Gross, Milton; Ramnath, Nithya; Hassan, Khaled A.; Matuszak, Martha; Ritter, Timothy; Bi, Nan; Wang, Weili; Orringer, Mark; Cease, Kemp B.; Lawrence, Theodore S.; Kalemkerian, Gregory P.

2017-01-01

IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01190527 PMID:28570742

SU-C-BRB-02: Automatic Planning as a Potential Strategy for Dose Escalation for Pancreas SBRT?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, S; Zheng, D; Ma, R

Purpose: Stereotactic body radiation therapy (SBRT) has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process, and may impede further escalation of the prescription dose. The present study evaluates the potential of an automatic planning system as a dose escalation strategy. Methods: Ten pancreatic cancer patients treated with SBRT were studied retrospectively. SBRT was delivered over 5 consecutive fractions with 6 ∼ 8Gy/fraction. Two plans were generated by Pinnacle Auto-Planning with the original prescription and escalated prescription, respectively. Escalated prescriptionmore » adds 1 Gy/fraction to the original prescription. Manually-created planning volumes were excluded in the optimization goals in order to assess the planning efficiency and quality simultaneously. Critical organs with closest proximity were used to determine the plan normalization to ensure the OAR sparing. Dosimetric parameters including D100, and conformity index (CI) were assessed. Results: Auto-plans directly generate acceptable plans for 70% of the cases without necessity of further improvement, and two more iterations at most are necessary for the rest of the cases. For the pancreas SBRT plans with the original prescription, autoplans resulted in favorable target coverage and PTV conformity (D100 = 96.3% ± 1.48%; CI = 0.88 ± 0.06). For the plans with the escalated prescriptions, no significant target under-dosage was observed, and PTV conformity remains reasonable (D100 = 93.3% ± 3.8%, and CI = 0.84 ± 0.05). Conclusion: Automatic planning, without substantial human-intervention process, results in reasonable PTV coverage and PTV conformity on the premise of adequate OAR sparing for the pancreas SBRT plans with escalated prescription. The results highlight the potential of autoplanning as a dose escalation strategy for pancreas SBRT treatment planning. Further investigations with a larger number of patients are necessary. The project is partially supported by Philips Medical Systems.« less

Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

ClinicalTrials.gov

2016-02-18

Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

PubMed

Guiu, Boris; Jouve, Jean-Louis; Schmitt, Antonin; Minello, Anne; Bonnetain, Franck; Cassinotto, Christophe; Piron, Lauranne; Cercueil, Jean-Pierre; Loffroy, Romaric; Latournerie, Marianne; Wendremaire, Maëva; Lepage, Côme; Boulin, Mathieu

2018-06-01

Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean C max of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the C max after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chuong, Michael D.; Hallemeier, Christopher L.; Jabbour, Salma K.

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with protonmore » beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.« less

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy.

PubMed

Chuong, Michael D; Hallemeier, Christopher L; Jabbour, Salma K; Yu, Jen; Badiyan, Shahed; Merrell, Kenneth W; Mishra, Mark V; Li, Heng; Verma, Vivek; Lin, Steven H

2016-05-01

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT. Copyright © 2016 Elsevier Inc. All rights reserved.

Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.

PubMed

Taher, Ali; Al Jefri, Abdullah; Elalfy, Mohsen Saleh; Al Zir, Kusai; Daar, Shahina; Rofail, Diana; Baladi, Jean François; Habr, Dany; Kriemler-Krahn, Ulrike; El-Beshlawy, Amal

2010-01-01

Patient-reported outcomes of once-daily oral deferasirox (Exjade) in iron-overloaded patients with beta-thalassemia not achieving successful chelation with prior deferoxamine and/or deferiprone were investigated in a prospective, open-label, 1-year, multicenter study in the Middle East (ESCALATOR). The initial dose of deferasirox was 20 mg/kg/day, with subsequent dose adjustments. At baseline and the end of study (EOS), patients (n = 237) completed a 5-point rating scale for treatment satisfaction and convenience, and recorded time lost to treatment. At EOS, 90.7% of patients were 'satisfied'/'very satisfied' with their iron chelation therapy (ICT) versus 23.2% at baseline. 92.8% (EOS) versus 21.5% (baseline) of patients considered their therapy to be 'convenient'/'very convenient'. Time lost to therapy for daily activities was substantially reduced (3.2 +/- 8.6 [mean +/- SD; EOS] vs. 30.1 +/- 44.2 [baseline] h/month). Patients reported greater satisfaction and convenience, and lower impact on daily activities, with deferasirox than with previous ICT. This may help improve adherence to lifelong ICT in iron-overloaded beta-thalassemia patients. 2010 S. Karger AG, Basel.

MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial

PubMed Central

Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

2015-01-01

Objectives To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Methods Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Results Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. Conclusions MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. Trial registration number NCT01023256 PMID:24534756

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study.

PubMed

Haslett, Kate; Franks, Kevin; Hanna, Gerard G; Harden, Susan; Hatton, Matthew; Harrow, Stephen; McDonald, Fiona; Ashcroft, Linda; Falk, Sally; Groom, Nicki; Harris, Catherine; McCloskey, Paula; Whitehurst, Philip; Bayman, Neil; Faivre-Finn, Corinne

2016-04-15

The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of 'isotoxic' radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West-Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. NCT01836692; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Study protocol: a dose-escalating, phase-2 study of oral lisdexamfetamine in adults with methamphetamine dependence.

PubMed

Ezard, Nadine; Dunlop, Adrian; Clifford, Brendan; Bruno, Raimondo; Carr, Andrew; Bissaker, Alexandra; Lintzeris, Nicholas

2016-12-01

The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder. This is a phase 2 dose escalation study of lisdexamfetamine for the treatment of methamphetamine dependence. Twenty individuals seeking treatment for methamphetamine dependence will be recruited at two Australian drug and alcohol services. All participants will undergo a single-blinded ascending-descending dose regime of 100 to 250 mg lisdexamfetamine, dispensed daily on site, over an 8-week period. Participants will be offered counselling as standard care. For the primary objectives the outcome variables will be adverse events monitoring, drug tolerability and regimen completion. Secondary outcomes will be changes in methamphetamine use, craving, withdrawal, severity of dependence, risk behaviour and other substance use. Medication acceptability, potential for non-prescription use, adherence and changes in neurocognition will also be measured. Determining the safety of lisdexamfetamine will enable further research to develop pharmacotherapies for the treatment of methamphetamine dependence. Australian and New Zealand Clinical Trials Registry ACTRN12615000391572 Registered 28 th April 2015.

Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

NASA Astrophysics Data System (ADS)

Bass, Christopher Paul

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

PubMed

Ang, Joo Ern; Pandher, Rupinder; Ang, Joo Chew; Asad, Yasmin J; Henley, Alan T; Valenti, Melanie; Box, Gary; de Haven Brandon, Alexis; Baird, Richard D; Friedman, Lori; Derynck, Mika; Vanhaesebroeck, Bart; Eccles, Suzanne A; Kaye, Stan B; Workman, Paul; de Bono, Johann S; Raynaud, Florence I

2016-06-01

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR. ©2016 American Association for Cancer Research.

Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma.

PubMed

Poklepovic, Andrew; Youssefian, Leena E; Youseffian, Leena; Winning, Mary; Birdsell, Christine A; Crosby, Nancy A; Ramakrishnan, Viswanathan; Ernstoff, Marc S; Roberts, John D

2013-08-01

Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer.

PubMed

Timmer-Bonte, J N H; Punt, C J A; vd Heijden, H F M; van Die, C E; Bussink, J; Beijnen, J H; Huitema, A D R; Tjan-Heijnen, V C G

2008-05-01

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100mg/m(2) days 1, 3, 5 and cisplatin 80 mg/m(2) day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m(2) resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m(2). The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m(2) without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

PubMed

Creelan, Ben C; Gabrilovich, Dmitry I; Gray, Jhanelle E; Williams, Charles C; Tanvetyanon, Tawee; Haura, Eric B; Weber, Jeffrey S; Gibney, Geoffrey T; Markowitz, Joseph; Proksch, Joel W; Reisman, Scott A; McKee, Mark D; Chin, Melanie P; Meyer, Colin J; Antonia, Scott J

2017-01-01

Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

PubMed

Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

2016-04-01

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

Development of a pharmacokinetic‐guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia

PubMed Central

Dong, Min; McGann, Patrick T.; Mizuno, Tomoyuki; Ware, Russell E.

2016-01-01

AIMS Hydroxyurea has emerged as the primary disease‐modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic‐guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Methods Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non‐linear mixed effects modelling (nonmem 7.2). A D‐optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration–time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. Results PK profiles were best described by a one compartment with Michaelis–Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre‐dose (baseline), 15–20 min, 50–60 min and 3 h after an initial 20 mg kg–1 oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l–1 h. Conclusion We developed a PK model‐based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. PMID:26615061

Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

PubMed Central

Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

2014-01-01

CMX-2043 is an α-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.

PubMed

Bologa, Monica; Kamtchoua, Thierry; Hopfer, Robert; Sheng, Xiaohua; Hicks, Bryony; Bixler, Garvin; Hou, Victor; Pehlic, Vildana; Yuan, Tao; Gurunathan, Sanjay

2012-12-14

Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 μg) or PhtD-PcpA (10 μg each), participants in the main study received AH-adjuvanted PcpA (25 μg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 μg each), unadjuvanted PhtD-PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases. Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339). Copyright © 2012 Elsevier Ltd. All rights reserved.

Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents

PubMed Central

Narasingam, Megala; Pandy, Vijayapandi; Mohamed, Zahurin

2016-01-01

The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal. PMID:26744024

Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents.

PubMed

Narasingam, Megala; Pandy, Vijayapandi; Mohamed, Zahurin

2016-05-20

The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal.

Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia: Efficacy and Tolerability

PubMed Central

Brown, Patrick; Megason, Gail; Ahn, Hyo Seop; Cho, Bin; Kirov, Ivan; Frankel, Lawrence; Aplenc, Richard; Bensen-Kennedy, Debra; Munteanu, Mihaela; Weaver, Jennifer; Harker-Murray, Paul

2014-01-01

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m2. In phase II, 32 patients received bendamustine 120 mg/m2. Two patients with ALL (bendamustine 90 mg/m2) experienced complete response (CR). Among patients who received bendamustine 120 mg/m2, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials. PMID:24072240

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

PubMed

Fathi, Amir T; Wander, Seth A; Blonquist, Traci M; Brunner, Andrew M; Amrein, Philip C; Supko, Jeffrey; Hermance, Nicole M; Manning, Amity L; Sadrzadeh, Hossein; Ballen, Karen K; Attar, Eyal C; Graubert, Timothy A; Hobbs, Gabriela; Joseph, Christelle; Perry, Ashley M; Burke, Meghan; Silver, Regina; Foster, Julia; Bergeron, Meghan; Ramos, Aura Y; Som, Tina T; Fishman, Kaitlyn M; McGregor, Kristin L; Connolly, Christine; Neuberg, Donna S; Chen, Yi-Bin

2017-04-01

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. ( clinicaltrials.gov Identifier:01779843 ). Copyright© Ferrata Storti Foundation.

A phase I dose-escalation study to a predefined dose of a transforming growth factor-β1 monoclonal antibody (TβM1) in patients with metastatic cancer

PubMed Central

COHN, ALLEN; LAHN, MICHAEL M.; WILLIAMS, KRISTEN E.; CLEVERLY, ANN L.; PITOU, CELINE; KADAM, SUNIL K.; FARMEN, MARK W.; DESAIAH, DURISALA; RAJU, ROBERT; CONKLING, PAUL; RICHARDS, DONALD

2014-01-01

Transforming growth factor β (TGF-β) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-β ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TβM1 is a humanized mAb optimized for neutralizing activity against TGF-β1. The objective of this clinical trial was to assess the safety and tolerability of TβM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤2 on the ECOG scale were administered TβM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TβM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TβM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-β1 expression signature in patients’ whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study PMID:25270361

Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer.

PubMed

Daga, Haruko; Takeda, Koji; Okada, Hideaki; Miyazaki, Masaki; Ueda, Shinya; Kaneda, Hiroyasu; Okamoto, Isamu; Yoh, Kiyotaka; Goto, Koichi; Konishi, Koichi; Sarashina, Akiko; Tanaka, Tetsuya; Kaiser, Rolf; Nakagawa, Kazuhiko

2015-12-01

This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.

Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS

PubMed Central

Madigan, Nicolas N.; Morris, Jonathan; Jentoft, Mark; Sorenson, Eric J.; Butler, Greg; Gastineau, Dennis; Dietz, Allan; Windebank, Anthony J.

2016-01-01

Objective: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS). Methods: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 107 (single dose) to 1 × 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis. Results: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients. Conclusions: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials. Classification of evidence: This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe. PMID:27784774

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

A phase I trial of Flavopiridol in relapsed multiple myeloma

PubMed Central

Hofmeister, Craig C.; Poi, Ming; Bowers, Mindy A.; Zhao, Weiqiang; Phelps, Mitch A.; Benson, Don M.; Kraut, Eric H.; Farag, Sherif; Efebera, Yvonne A.; Sexton, Jennifer; Lin, Thomas S.; Grever, Michael; Byrd, John C.

2014-01-01

Purpose Flavopiridol is primarily a cyclin-dependent kinase (CDK)-9 inhibitor and we performed a dose escalation trial to determine the maximum tolerated dose, safety, and generate a pharmacokinetic profile. Methods Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus then continuous infusion weekly for 4 weeks in a 6 week cycle. Results Fifteen patients were treated at three dose levels (30 mg/m2 bolus, 30 mg/m2 CIV to 50 mg/m2 bolus, 50 mg/m2 CIV). Cytopenias were significant and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients, grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein greater than 50% percent that did not persist. Pharmacokinetic properties were similar to prior publications and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. Conclusions Flavopiridol as a single agent given by bolus then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723). PMID:24241210

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

PubMed

Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

2002-06-01

To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jakobsen, Anders, E-mail: anders.jakobsen@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2012-11-15

Purpose: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation. Methods and Materials: The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of {<=}5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; armmore » B). Concomitant chemotherapy, uftoral 300 mg/m{sup 2} and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0). Results: The study included 248 patients. No significant difference was found in toxicity or surgical complications between the 2 groups. Based on intention to treat, no significant difference was found in the complete pathologic remission rate between the 2 arms (18% and 18%). The rate of R0 resection was different in T3 tumors (90% and 99%; P=.03). The same applied to the rate of major response (tumor regression grade, 1+2), 29% and 44%, respectively (P=.04). Conclusions: This first randomized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50% in T3 tumors. The endorectal boost is feasible, with no significant increase in toxicity or surgical complications.« less

Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

NASA Astrophysics Data System (ADS)

Pervez, Nadeem

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

Phase I Clinical Trial of O6-Benzylguanine and Topical Carmustine in the Treatment of Cutaneous T-Cell Lymphoma, Mycosis Fungoides Type

PubMed Central

Apisarnthanarax, Narin; Wood, Gary S.; Stevens, Seth R.; Carlson, Sean; Chan, Derek V.; Liu, Lili; Szabo, Sarolta K.; Fu, Pingfu; Gilliam, Anita C.; Gerson, Stanton L.; Remick, Scot C.; Cooper, Kevin D.

2012-01-01

Objectives To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions. Design Open-label, dose-escalation, phase I trial. Setting Dermatology outpatient clinic and clinical research unit at a university teaching hospital. Patients A total of 21 adult patients (11 male, 10 female) with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine. Intervention Treatment once every 2 weeks with 120 mg/m2 intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity. Main Outcome Measures Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens. Results A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyl-transferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzyl-guanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P= .02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P= .01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55–0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug. Conclusion O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses. Trial Registration clinicaltrials.gov Identifier: NCT00003613 PMID:22250189

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

PubMed Central

López-Cortés, Luis Eduardo; Rosso-Fernández, Clara; Núñez-Núñez, María; Lavín-Alconero, Lucía; Bravo-Ferrer, José; Barriga, Ángel; Delgado, Mercedes; Lupión, Carmen; Retamar, Pilar; Rodríguez-Baño, Jesús

2017-01-01

Introduction Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. Methods and analysis The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic ‘real-practice’ trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Ethics and dissemination Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. Discussion Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. Trial registration number The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry. PMID:28601833

First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

PubMed

Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

2015-01-01

To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase. These data support the development of BG00010 for the treatment of neuropathic pain. ClinicalTrials.gov NCT00961766.

Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer.

PubMed

Johnson, Skyler B; Lester-Coll, Nataniel H; Kelly, Jacqueline R; Kann, Benjamin H; Yu, James B; Nath, Sameer K

2017-11-01

There are limited comparative survival data for prostate cancer (PCa) patients managed with a low-dose rate brachytherapy (LDR-B) boost and dose-escalated external-beam radiotherapy (DE-EBRT) alone. To compare overall survival (OS) for men with unfavorable PCa between LDR-B and DE-EBRT groups. Using the National Cancer Data Base, we identified men with unfavorable PCa treated between 2004 and 2012 with androgen suppression (AS) and either EBRT followed by LDR-B or DE-EBRT (75.6-86.4Gy). Treatment selection was evaluated using logistic regression and annual percentage proportions. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards, and propensity score matching. We identified 25038 men between 2004 and 2012, during which LDR-B boost utilization decreased from 29% to 14%. LDR-B was associated with better OS on univariate (7-yr OS: 82% vs 73%; p<0.001) and multivariate analyses (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.64-0.77). Propensity score matching verified an OS benefit associated with LDR-B boost (HR 0.74, 95% CI 0.66-0.89). The OS benefit of LDR-B boost persisted when limited to men aged <60 yr with no comorbidities. On subset analysis, there was no interaction between treatment and age, risk group, or radiation dose. Limitations include the retrospective design, nonrandomized selection bias, and the absence of treatment toxicity, hormone duration, and cancer-specific outcomes. Between 2004 and 2012, LDR-B boost utilization declined and was associated with better OS compared to DE-EBRT alone. LDR-B boost is probably the ideal treatment option for men with unfavorable PCa, pending long-term results of randomized trials. We compared radiotherapy utilization and survival for prostate cancer (PCa) patients using a national database. We found that low-dose rate brachytherapy (LDR-B) boost, a method being used less frequently, was associated with better overall survival when compared to dose-escalated external-beam radiotherapy alone for men with unfavorable PCa. Randomized trials are needed to confirm that LDR-B boost is the ideal treatment. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation.

PubMed

Wong, Jeffrey Y C; Rosenthal, Joseph; Liu, An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

2009-01-01

Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.

A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

PubMed

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V Ann; Remich, Shon A; Cohen, Joe; Ballou, W Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D Gray

2006-11-24

Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. The study was conducted in a rural population in Kombewa Division, western Kenya. Subjects were 135 children, aged 12-47 mo. Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine). We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

PubMed Central

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V. Ann; Remich, Shon A; Cohen, Joe; Ballou, W. Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D. Gray

2006-01-01

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12–47 mo. Interventions: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F3,1047 = 10.78, or F3, 995 = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F1,1047 = 0.05; p = 0.82). Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 μg doses was superior to that of the 10 μg dose. PMID:17124529

A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy

PubMed Central

Williams, Brent A.; Law, Arjun Datt; Routy, Bertrand; denHollander, Neal; Gupta, Vikas; Wang, Xing-Hua; Chaboureau, Amélie; Viswanathan, Sowmya; Keating, Armand

2017-01-01

Background Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials. Materials and Methods We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 109 cells/m2, 3 × 109 cells/m2 and 5 × 109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. Results Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial. Conclusions Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation. PMID:29179517

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia

PubMed Central

Dolzhikova, I. V.; Zubkova, O. V.; Tukhvatulin, A. I.; Dzharullaeva, A. S.; Tukhvatulina, N. M.; Shcheblyakov, D. V.; Shmarov, M. M.; Tokarskaya, E. A.; Simakova, Y. V.; Egorova, D. A.; Scherbinin, D. N.; Tutykhina, I. L.; Lysenko, A. A.; Kostarnoy, A. V.; Gancheva, P. G.; Ozharovskaya, T. A.; Belugin, B. V.; Kolobukhina, L. V.; Pantyukhov, V. B.; Syromyatnikova, S. I.; Shatokhina, I. V.; Sizikova, T. V.; Rumyantseva, I. G.; Andrus, A. F.; Boyarskaya, N. V.; Voytyuk, A. N.; Babira, V. F.; Volchikhina, S. V.; Kutaev, D. A.; Bel'skih, A. N.; Zhdanov, K. V.; Zakharenko, S. M.; Borisevich, S. V.; Logunov, D. Y.; Naroditsky, B. S.; Gintsburg, A. L.

2017-01-01

ABSTRACT Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401–4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055). PMID:28152326

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia.

PubMed

Dolzhikova, I V; Zubkova, O V; Tukhvatulin, A I; Dzharullaeva, A S; Tukhvatulina, N M; Shcheblyakov, D V; Shmarov, M M; Tokarskaya, E A; Simakova, Y V; Egorova, D A; Scherbinin, D N; Tutykhina, I L; Lysenko, A A; Kostarnoy, A V; Gancheva, P G; Ozharovskaya, T A; Belugin, B V; Kolobukhina, L V; Pantyukhov, V B; Syromyatnikova, S I; Shatokhina, I V; Sizikova, T V; Rumyantseva, I G; Andrus, A F; Boyarskaya, N V; Voytyuk, A N; Babira, V F; Volchikhina, S V; Kutaev, D A; Bel'skih, A N; Zhdanov, K V; Zakharenko, S M; Borisevich, S V; Logunov, D Y; Naroditsky, B S; Gintsburg, A L

2017-03-04

Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications.

PubMed

Adelaiye, Remi; Ciamporcero, Eric; Miles, Kiersten Marie; Sotomayor, Paula; Bard, Jonathan; Tsompana, Maria; Conroy, Dylan; Shen, Li; Ramakrishnan, Swathi; Ku, Sheng-Yu; Orillion, Ashley; Prey, Joshua; Fetterly, Gerald; Buck, Michael; Chintala, Sreenivasulu; Bjarnason, Georg A; Pili, Roberto

2015-02-01

Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. ©2014 American Association for Cancer Research.

A phase I trial of pharmacokinetic modulation of carboxyamidotriazole (CAI) with ketoconazole in patients with advanced cancer.

PubMed

Desai, Apurva A; Innocenti, Federico; Janisch, Linda; DeMario, Mark; Shepard, Dale; Ramirez, Jacqueline; Fleming, Gini F; Ratain, Mark J

2004-11-01

Carboxyamidotriazole (CAI) is a novel antineoplastic agent in clinical development with limited oral bioavailability. In vitro, ketoconazole has been demonstrated to inhibit CYP3A4-mediated metabolism of CAI. We performed this phase I trial to determine if ketoconazole-mediated CYP3A4 inhibition would lead to favorable alteration of CAI pharmacokinetics, and to evaluate the safety, toxicity and tolerability of the proposed combination. Forty-seven patients were treated using a standard three patients per cohort CAI dose-escalation scheme. In cycle 1, CAI was administered alone on day-6 followed by a single dose of ketoconazole (200 mg) on day 0. CAI and ketoconazole (200 mg/day) were subsequently coadministered on days 1 and 3-28. Plasma samples for pharmacokinetic analysis were obtained following the doses on days-6 and 1. All subsequent cycles were of 28-day duration, and consisted of daily CAI and ketoconazole coadministration. Pharmacokinetic analysis was performed on samples from 44 patients. In most patients administration of ketoconazole produced an increase in CAI AUC and Cmax with a decrease in CAI clearance. Seven patients experienced stable disease for up to 12 months. Gastrointestinal and constitutional toxicities were the most common toxicities. Coadministration of CAI with ketoconazole increased CAI exposure in most of the patients without altering the toxicity profile of CAI. The highest CAI dose administered on the trial was 300 mg/day. The clinical utility of such a modulation strategy might be explored in future clinical trials of CAI.

Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale

PubMed Central

Brock, Penelope R.; Knight, Kristin R.; Freyer, David R.; Campbell, Kathleen C.M.; Steyger, Peter S.; Blakley, Brian W.; Rassekh, Shahrad R.; Chang, Kay W.; Fligor, Brian J.; Rajput, Kaukab; Sullivan, Michael; Neuwelt, Edward A.

2012-01-01

Purpose The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important. Patients and Methods This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. Results Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss. Conclusion Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal. PMID:22547603

Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection: Comment on Coburn et al.

PubMed

Bredemeier, Markus

2018-05-09

We read with interest the study by Coburn et al. (1), a methodologically sound propensity-score matched cohort study evaluating the effect of dose escalation of allopurinol on cardiovascular (CV) and overall mortality. The results indicate that increasing doses carry a higher risk of mortality, but the authors comment that failure in achieving doses up to 600 mg may have contributed to the absence of protective effect. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

PubMed

Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

2016-06-01

Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer.

PubMed

Harada, Hideyuki; Fuji, Hiroshi; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Yamashita, Haruo; Asakura, Hirofumi; Nishimura, Tetsuo; Takahashi, Toshiaki; Murayama, Shigeyuki

2016-07-01

The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non-small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m(2) , day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as four cycles every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

PubMed Central

Richardson, Paul G.; Weller, Edie; Jagannath, Sundar; Avigan, David E.; Alsina, Melissa; Schlossman, Robert L.; Mazumder, Amitabha; Munshi, Nikhil C.; Ghobrial, Irene M.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; McKenney, Mary; Delaney, Carol; Mitsiades, Constantine S.; Hideshima, Teru; Dalton, William; Knight, Robert; Esseltine, Dixie-Lee; Anderson, Kenneth C.

2009-01-01

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID:19786667

Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies.

PubMed

Awan, Farrukh T; Gore, Lia; Gao, Lei; Sharma, Jyoti; Lager, Joanne; Costa, Luciano J

2016-10-01

This phase Ib, dose-escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose-escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty-seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose-limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co-administration with rituximab or rituximab+bendamustine. Of 35 efficacy-evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti-tumour activity in relapsed or refractory B-cell malignancies. © 2016 John Wiley & Sons Ltd.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

PubMed

Baulac, Michel; Coulbaut, Safia; Doty, Pamela; McShea, Cindy; De Backer, Marc; Bartolomei, Fabrice; Vlaicu, Mihaela

2017-06-01

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.

Therapeutic Drug Monitoring Guides the Management of Crohn's Patients with Secondary Loss of Response to Adalimumab.

PubMed

Restellini, Sophie; Chao, Che-Yung; Lakatos, Peter L; Aruljothy, Achuthan; Aziz, Haya; Kherad, Omar; Bitton, Alain; Wild, Gary; Afif, Waqqas; Bessissow, Talat

2018-04-13

Managing loss of response (LOR) in Crohn's disase (CD) patients remains challenging. Compelling evidence supports therapeutic drug monitoring (TDM) to guide management in patients on infliximab, but data for other biologics are less robust. We aimed to asses if empiric dose escalation led to improved clinical outcome in addition to TDM-guided optimization in CD patients with LOR to adalimumab (ADA). Retrospective chart review of patients followed between 2014 and 2016 at McGill IBD Center with index TDM for LOR to ADA was performed. Primary outcomes were composite remission at 3, 6, and 12 months in those with empiric adjustments versus TDM-guided optimization. There were 104 patients (54.8% men) who were included in the study. Of this group, 81 patients (77.9%) had serum level (SL) ≥5µg/ml at index TDM with a median value of 12µg/ml (IQR 6.1-16.5). There were 10 patients (9.6%) who had undetectable SL with high anti-ADA antibodies and 48 (46.2%) received empiric escalation. TDM led to change in treatment in 58 patients (55.8%). Among them, 28 (48.3%) had discontinued ADA, 12 (21.7%) had addition of immunomodulator or steroid, and 18 (31%) had ADA dose escalation. Empiric dose escalation before TDM-based optimization was not associated with improved outcomes at 3, 6, and 12 months, irrespective of SL levels. Clear SL cutoff associated with composite remission was not identified. Our data do not support empiric dose adjustment beyond that based on the result of the TDM in patients with LOR to ADA. TDM limits unnecessary dose escalation and provides appropriate treatment strategy without compromising clinical outcomes. 10.1093/ibd/izy044_video1izy044.video15768828880001.

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

PubMed

Moore, Kathleen N; Borghaei, Hossein; O'Malley, David M; Jeong, Woondong; Seward, Shelly M; Bauer, Todd M; Perez, Raymond P; Matulonis, Ursula A; Running, Kelli L; Zhang, Xiaoyan; Ponte, Jose F; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-08-15

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society. © 2017 American Cancer Society.

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency.

PubMed

Wasserstein, Melissa P; Jones, Simon A; Soran, Handrean; Diaz, George A; Lippa, Natalie; Thurberg, Beth L; Culm-Merdek, Kerry; Shamiyeh, Elias; Inguilizian, Haig; Cox, Gerald F; Puga, Ana Cristina

2015-01-01

Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. Copyright © 2015. Published by Elsevier Inc.

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

PubMed Central

Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

2014-01-01

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

Quality of Life Analysis of a Radiation Dose-Escalation Study of Patients With Non-Small-Cell Lung Cancer: A Secondary Analysis of the Radiation Therapy Oncology Group 0617 Randomized Clinical Trial.

PubMed

Movsas, Benjamin; Hu, Chen; Sloan, Jeffrey; Bradley, Jeffrey; Komaki, Ritsuko; Masters, Gregory; Kavadi, Vivek; Narayan, Samir; Michalski, Jeff; Johnson, Douglas W; Koprowski, Christopher; Curran, Walter J; Garces, Yolanda I; Gaur, Rakesh; Wynn, Raymond B; Schallenkamp, John; Gelblum, Daphna Y; MacRae, Robert M; Paulus, Rebecca; Choy, Hak

2016-03-01

A recent randomized radiation dose-escalation trial in unresectable stage III non-small-cell lung cancer (NSCLC) (Radiation Therapy Oncology Group [RTOG] 0617) showed a lower survival rate in the high-dose radiation therapy (RT) arm (74 Gy) than in the low-dose arm (60 Gy) with concurrent chemotherapy. The primary QOL hypothesis predicted a clinically meaningful decline in quality of life (QOL) via the Functional Assessment of Cancer Therapy (FACT)-Lung Cancer Subscale (LCS) in the high-dose RT arm at 3 months. The RTOG 0617 trial was a randomized phase 3 study (conducted from November 2007 to November 2011) in stage III NSCLC using a 2 × 2 factorial design and stratified by histology, positron emission tomography staging, performance status, and irradiation technique (3-dimensional conformal RT [3D-CRT] vs intensity-modulated RT [IMRT]). A total of 185 institutions in the United States and Canada took part. Of 424 eligible patients with stage III NSCLC randomized, 360 (85%) consented to QOL evaluation, of whom 313 (88%) completed baseline QOL assessments. Treatment with 74-Gy vs 60-Gy RT with concurrent and consolidation carboplatin/paclitaxel with or without cetuximab. The QOL data were collected prospectively via FACT Trial Outcome Index (FACT-TOI), calculated as the sum of the following measures: Physical Well Being (PWB), Functional Well Being (FWB), and the LCS. Data are presented at baseline and 3 and 12 months via minimal clinically meaningful changes of 2 points or more for PWB, FWB, and LCS or 5 points or more for TOI. Of the 313 patients who completed baseline QOL assessments, 219 patients (70%) completed the 3-month QOL assessments, and 137 of the living patients (57%) completed the 12-month assessment. Patient demographics and baseline QOL scores were comparable between the 74-Gy and 60-Gy arms. Significantly more patients in the 74-Gy arm than in the 60-Gy arm had clinically meaningful decline in FACT-LCS at 3 months (45% vs 30%; P = .02). At 12 months, fewer patients who received IMRT (vs 3D-CRT) had clinically meaningful decline in FACT-LCS (21% vs 46%; P = .003). Baseline FACT-TOI was associated with overall survival in multivariate analysis. Despite few differences in clinician-reported toxic effects between treatment arms, QOL analysis demonstrated a clinically meaningful decline in QOL in the 74-Gy arm at 3 months, confirming the primary QOL hypothesis. Baseline QOL was an independent prognostic factor for survival. clinicaltrials.gov Identifier: NCT00533949.

Safety and Toxicity of Saw palmetto in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Trial

PubMed Central

Avins, Andrew L.; Lee, Jeannette Y.; Meyers, Catherine M.; Barry, Michael J.

2013-01-01

Purpose Extracts of the saw palmetto berry are used by many men in the U.S. as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are few data on the toxicity of saw palmetto. Materials and Methods 369 patients were randomized in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) trial; 357 participants are included in this modified intention-to-treat analysis. Participants were randomized to 320mg, 640mg, and 960mg daily of an ethanolic saw palmetto extract or an identical-appearing placebo, in an escalating manner at 6-month intervals, for a total of 18 months follow-up. Adverse-event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. Results There were no statistically significant differences between groups in rates of serious or non-serious adverse events, changes in vital signs, digital prostate exam findings, or study withdrawal rates. Overall, there were no significant inter-group differences in the occurrence of laboratory-test abnormalities; differences in individual laboratory tests were uncommon and small in magnitude. No evidence of significant dose-response phenomena were identified. Conclusions The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to three times the usual clinical dose over a period of 18 months. PMID:23063633

Safety and toxicity of saw palmetto in the CAMUS trial.

PubMed

Avins, Andrew L; Lee, Jeannette Y; Meyers, Catherine M; Barry, Michael J

2013-04-01

Extracts of the saw palmetto berry are used by many men in the United States as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are sparse data on saw palmetto toxicity. A total of 369 patients were randomized in the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, of whom 357 were included in this modified intent to treat analysis. Participants were randomized to 320, 640 and 960 mg daily of an ethanolic saw palmetto extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of followup. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified. The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-month period. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: an open label, phase 1 clinical trial.

PubMed

Meng, Fan-Yue; Li, Jing-Xin; Li, Xiu-Ling; Chu, Kai; Zhang, Yun-Tao; Ji, Hong; Li, Liang; Liang, Zheng-Lun; Zhu, Feng-Cai

2012-05-01

In this open labeled phase 1 clinical trial with enterovirus 71 (EV71) vaccine (ClinicalTrials.gov number: NCT01267903) performed in Donghai County, Jiangsu Province, China, in January 2011. A total of 100 healthy participants, stratified by age (40 adults aged 16-22 y and 60 children aged 6-15 y), were enrolled from volunteers and sequentially received EV71 vaccines of 160U (only for children), 320U, or 640U on day 0 and 28, in a manner of dose escalation. All the participants were followed for 28 d after each shot. During the study period, 37 participants reported at least one injection-site or systemic adverse reaction. No case of grade 3 adverse reaction or serious adverse event (SAE) was observed. Also no dose-related increase in reaction rate was noticed. Pain at injection-site and fever were the most frequently reported local and systematic reaction, respectively. The studied EV71 vaccines demonstrated acceptable tolerability and no anti-nuclear antibody (ANA) seropositive was detected pre or post vaccinations in participants. Also, no clinically significant abnormal change for the liver or kidney function indexes was found. In the according-to-protocol cohort for immunogenicity, it was observed one dose of EV71 vaccine elicited good immune response in the participants, especially for the ones with sero-positive baseline. No obvious dose-response relationship for immunogenicity was found.

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

PubMed

Egle, Alexander; Steurer, Michael; Melchardt, Thomas; Weiss, Lukas; Gassner, Franz Josef; Zaborsky, Nadja; Geisberger, Roland; Catakovic, Kemal; Hartmann, Tanja Nicole; Pleyer, Lisa; Voskova, Daniela; Thaler, Josef; Lang, Alois; Girschikofsky, Michael; Petzer, Andreas; Greil, Richard

2018-06-04

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).

Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study.

PubMed

Welsh, James; Gomez, Daniel; Palmer, Matthew B; Riley, Beverly A; Mayankkumar, Amin V; Komaki, Ritsuko; Dong, Lei; Zhu, X Ronald; Likhacheva, Anna; Liao, Zhongxing; Hofstetter, Wayne L; Ajani, Jaffer A; Cox, James D

2011-12-01

We have previously found that ≤ 75% of treatment failures after chemoradiotherapy for unresectable esophageal cancer appear within the gross tumor volume and that intensity-modulated (photon) radiotherapy (IMRT) might allow dose escalation to the tumor without increasing normal tissue toxicity. Proton therapy might allow additional dose escalation, with even lower normal tissue toxicity. In the present study, we compared the dosimetric parameters for photon IMRT with that for intensity-modulated proton therapy (IMPT) for unresectable, locally advanced, distal esophageal cancer. Four plans were created for each of 10 patients. IMPT was delivered using anteroposterior (AP)/posteroanterior beams, left posterior oblique/right posterior oblique (LPO/RPO) beams, or AP/LPO/RPO beams. IMRT was delivered with a concomitant boost to the gross tumor volume. The dose was 65.8 Gy to the gross tumor volume and 50.4 Gy to the planning target volume in 28 fractions. Relative to IMRT, the IMPT (AP/posteroanterior) plan led to considerable reductions in the mean lung dose (3.18 vs. 8.27 Gy, p<.0001) and the percentage of lung volume receiving 5, 10, and 20 Gy (p≤.0006) but did not reduce the cardiac dose. The IMPT LPO/RPO plan also reduced the mean lung dose (4.9 Gy vs. 8.2 Gy, p<.001), the heart dose (mean cardiac dose and percentage of the cardiac volume receiving 10, 20, and 30 Gy, p≤.02), and the liver dose (mean hepatic dose 5 Gy vs. 14.9 Gy, p<.0001). The IMPT AP/LPO/RPO plan led to considerable reductions in the dose to the lung (p≤.005), heart (p≤.003), and liver (p≤.04). Compared with IMRT, IMPT for distal esophageal cancer lowered the dose to the heart, lung, and liver. The AP/LPO/RPO beam arrangement was optimal for sparing all three organs. The dosimetric benefits of protons will need to be tailored to each patient according to their specific cardiac and pulmonary risks. IMPT for esophageal cancer will soon be investigated further in a prospective trial at our institution. Copyright © 2011 Elsevier Inc. All rights reserved.

The effect of anterior proton beams in the setting of a prostate-rectum spacer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Christodouleas, John P., E-mail: christojo@uphs.upenn.edu; Tang, Shikui; Susil, Robert C.

2013-10-01

Studies suggest that anterior beams with in vivo range verification would improve rectal dosimetry in proton therapy for prostate cancer. We investigated whether prostate-rectum spacers would enhance or diminish the benefits of anterior proton beams in these treatments. Twenty milliliters of hydrogel was injected between the prostate and rectum of a cadaver using a transperineal approach. Computed tomography (CT) and magnetic resonance (MR) images were used to generate 7 uniform scanning (US) and 7 single-field uniform dose pencil-beam scanning (PBS) plans with different beam arrangements. Pearson correlations were calculated between rectal, bladder, and femoral head dosimetric outcomes and beam arrangementmore » anterior scores, which characterize the degree to which dose is delivered anteriorly. The overall quality of each plan was compared using a virtual dose-escalation study. For US plans, rectal mean dose was inversely correlated with anterior score, but for PBS plans there was no association between rectal mean dose and anterior score. For both US and PBS plans, full bladder and empty bladder mean doses were correlated with anterior scores. For both US and PBS plans, femoral head mean doses were inversely correlated with anterior score. For US plans and a full bladder, 4 beam arrangements that included an anterior beam tied for the highest maximum prescription dose (MPD). For US plans and an empty bladder, the arrangement with 1 anterior and 2 anterior oblique beams achieved the highest MPD in the virtual dose-escalation study. The dose-escalation study did not differentiate beam arrangements for PBS. All arrangements in the dose-escalation study were limited by bladder constraints except for the arrangement with 2 posterior oblique beams. The benefits of anterior proton beams in the setting of prostate-rectum spacers appear to be proton modality dependent and may not extend to PBS.« less

The effect of anterior proton beams in the setting of a prostate-rectum spacer

PubMed Central

Christodouleas, John P.; Tang, Shikui; Susil, Robert C.; McNutt, Todd R.; Song, Danny Y.; Bekelman, Justin; Deville, Curtiland; Vapiwala, Neha; DeWeese, Theodore L.; Lu, Hsiao-Ming; Both, Stefan

2014-01-01

Studies suggest that anterior beams with in vivo range verification would improve rectal dosimetry in proton therapy for prostate cancer. We investigated whether prostate-rectum spacers would enhance or diminish the benefits of anterior proton beams in these treatments. Twenty milliliters of hydrogel was injected between the prostate and rectum of a cadaver using a transperineal approach. Computed tomography (CT) and magnetic resonance (MR) images were used to generate 7 uniform scanning (US) and 7 single-field uniform dose pencil-beam scanning (PBS) plans with different beam arrangements. Pearson correlations were calculated between rectal, bladder, and femoral head dosimetric outcomes and beam arrangement anterior scores, which characterize the degree to which dose is delivered anteriorly. The overall quality of each plan was compared using a virtual dose-escalation study. For US plans, rectal mean dose was inversely correlated with anterior score, but for PBS plans there was no association between rectal mean dose and anterior score. For both US and PBS plans, full bladder and empty bladder mean doses were correlated with anterior scores. For both US and PBS plans, femoral head mean doses were inversely correlated with anterior score. For US plans and a full bladder, 4 beam arrangements that included an anterior beam tied for the highest maximum prescription dose (MPD). For US plans and an empty bladder, the arrangement with 1 anterior and 2 anterior oblique beams achieved the highest MPD in the virtual dose-escalation study. The dose-escalation study did not differentiate beam arrangements for PBS. All arrangements in the dose-escalation study were limited by bladder constraints except for the arrangement with 2 posterior oblique beams. The benefits of anterior proton beams in the setting of prostate-rectum spacers appear to be proton modality dependent and may not extend to PBS. PMID:23578497

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma.

PubMed

Bradley, Jeffrey; Graham, Mary V; Winter, Kathryn; Purdy, James A; Komaki, Ritsuko; Roa, Wilson H; Ryu, Janice K; Bosch, Walter; Emami, Bahman

2005-02-01

To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer. A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method. The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V(20). The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50-78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure. The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.

Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

PubMed

Skoetz, Nicole; Will, Andrea; Monsef, Ina; Brillant, Corinne; Engert, Andreas; von Tresckow, Bastian

2017-05-25

There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) SELECTION CRITERIA: We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression.We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events.Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. We screened 1796 records and identified five eligible trials in total i.e. one trial could be added on the previous review. These trials included only adults (16 to 65 years of age). We included all five trials with 3427 people in the meta-analyses: the HD9 and HD14 trials were co-ordinated in Germany, the HD2000 and GSM-HD trials were performed in Italy and the EORTC 20012 was conducted in Belgium. The overall risk of performance and detection bias was low for overall survival (OS), but was high for other outcomes, as therapy blinding was not feasible. The remaining 'Risk of bias' domains were low and unclear.All trials reported results for OS and progression-free survival (PFS). In contrast to the our first published review (2011) the addition of results from the EORTC 20012 BEACOPP escalated increases OS (3142 participants; HR 0.74 (95% confidence interval (CI) 0.57 to 0.97; high-quality evidence). This means that only 90 (70 to 117) patients will die after five years in the BEACOPP escalated arm compared to 120 in the ABVD arm. This survival advantage is also reflected in an increased PFS with BEACOPP escalated (3142 participants; HR 0.54 (95% CI 0.45 to 0.64); moderate-quality evidence), meaning that after five years only 144 (121 to 168) patients will experience a progress, relapse or death in the BEACOPP escalated arm compared to 250 in the ABVD arm.There is no evidence for a difference for treatment-related mortality (2700 participants, RR 2.15 (95% CI = 0.93 to 4.95), low-quality evidence).Although the occurrence of MDS or AML may increase with BEACOPP escalated (3332 participants, RR 3.90 (95% CI 1.36 to 11.21); low-quality evidence)), there is no evidence for a difference between both regimens for overall secondary malignancies (3332 participants, RR 1.00 (95% CI 0.68 to 1.48), low-quality evidence). However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours which would not be expected to show significance until around 15 years after treatment.We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured (106 participants, RR 1.37 (95% CI 0.83 to 2.26), very low-quality evidence). This is a very small sample, and the age of the patients was not detailed. No analysis of male fertility was provided.Five trials reported adverse events and the analysis shows that the escalated BEACOPP regimens probably causes more haematological toxicities WHO grade III or IV ((anaemia: 2425 participants, RR 10.67 (95% CI 7.14 to 15.93); neutropenia: 519 participants, RR 1.80 (95% CI 1.52 to 2.13); thrombocytopenia: 2425 participants, RR 18.12 (95% CI 11.77 to 27.92); infections: 2425 participants, RR 3.73 (95% CI 2.58 to 5.38), all low-quality evidence).Only one trial (EORTC 20012) planned to assess quality of life, however, no results were reported. This meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does for the first time suggest a survival benefit. However, it is clear from this review that BEACOPP escalated may be more toxic that ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet.

Phase I Trial of a Pathotropic Retroviral Vector Expressing a Cytocidal Cyclin G1 Construct (Rexin-G) in Patients With Advanced Pancreatic Cancer

PubMed Central

Galanis, Evanthia; Carlson, Stephanie K; Foster, Nathan R; Lowe, Val; Quevedo, Fernando; McWilliams, Robert R; Grothey, Axel; Jatoi, Aminah; Alberts, Steven R; Rubin, Joseph

2009-01-01

Rexin-G is a pathotropic retroviral vector displaying a von Willebrand factor–targeting motif and expressing a dominant negative cyclin G1 gene. We undertook a phase I trial of intravenous (IV) administration of Rexin-G in patients with gemcitabine refractory, metastatic pancreatic adenocarcinoma. Twelve patients were treated. Dose escalation was performed from a dose of 1 × 1011 colony forming units (CFU) per cycle to 6 × 1011 CFU per cycle. The treatment was well tolerated. One dose-limiting toxicity (DLT) at dose level 2 (1.5 × 1011 CFU per cycle) was observed, consisting of grade 3 transaminitis. There was no detection of replication-competent virus in patients’ peripheral blood mononuclear cells (PBMCs) or viral integration in DNA obtained from PBMCs, and no development of neutralizing antibodies. No evidence of antitumor activity was observed. The best objective response was progressive disease in 11 of the 12 study patients, while 1 patient showed radiographically stable disease with clinical deterioration and increase in the CA19.9 tumor marker. Median time to progression was 32 days. The median duration of survival of the study patients was 3.5 months from treatment initiation. Rexin-G is well tolerated in doses up to 6 × 1011 CFU in patients with recurrent pancreatic cancer, but there was no evidence of clinical antitumor activity. PMID:18388964

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

PubMed

Agnandji, Selidji T; Huttner, Angela; Zinser, Madeleine E; Njuguna, Patricia; Dahlke, Christine; Fernandes, José F; Yerly, Sabine; Dayer, Julie-Anne; Kraehling, Verena; Kasonta, Rahel; Adegnika, Akim A; Altfeld, Marcus; Auderset, Floriane; Bache, Emmanuel B; Biedenkopf, Nadine; Borregaard, Saskia; Brosnahan, Jessica S; Burrow, Rebekah; Combescure, Christophe; Desmeules, Jules; Eickmann, Markus; Fehling, Sarah K; Finckh, Axel; Goncalves, Ana Rita; Grobusch, Martin P; Hooper, Jay; Jambrecina, Alen; Kabwende, Anita L; Kaya, Gürkan; Kimani, Domtila; Lell, Bertrand; Lemaître, Barbara; Lohse, Ansgar W; Massinga-Loembe, Marguerite; Matthey, Alain; Mordmüller, Benjamin; Nolting, Anne; Ogwang, Caroline; Ramharter, Michael; Schmidt-Chanasit, Jonas; Schmiedel, Stefan; Silvera, Peter; Stahl, Felix R; Staines, Henry M; Strecker, Thomas; Stubbe, Hans C; Tsofa, Benjamin; Zaki, Sherif; Fast, Patricia; Moorthy, Vasee; Kaiser, Laurent; Krishna, Sanjeev; Becker, Stephan; Kieny, Marie-Paule; Bejon, Philip; Kremsner, Peter G; Addo, Marylyn M; Siegrist, Claire-Anne

2016-04-28

The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

Phase I Dose Escalation Trial of Vandetanib With Fractionated Radiosurgery in Patients With Recurrent Malignant Gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fields, Emma C.; Damek, Denise; Gaspar, Laurie E.

2012-01-01

Purpose: To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas. Methods and Materials: Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor {<=}6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose ofmore » 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity. Results: Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease. Conclusion: The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.« less

Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy.

PubMed

Akdim, Fatima; Stroes, Erik S G; Sijbrands, Eric J G; Tribble, Diane L; Trip, Mieke D; Jukema, J Wouter; Flaim, Joann D; Su, John; Yu, Rosie; Baker, Brenda F; Wedel, Mark K; Kastelein, John J P

2010-04-13

The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations >or=3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569). Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment

PubMed Central

Xue, Cong; Hong, Shaodong; Li, Ning; Feng, Weineng; Jia, Jun; Peng, Jiewen; Lin, Daren; Cao, Xiaolong; Wang, Siyang; Zhang, Weimin; Zhang, Hongyu; Dong, Wei; Zhang, Li

2015-01-01

There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment. PMID:26216071

Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

PubMed Central

Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam

2015-01-01

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID:25815766

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

PubMed

Palanca-Wessels, Maria Corinna A; Czuczman, Myron; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H; Flinn, Ian; Patel, Manish R; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana; Tilly, Herve; Casasnovas, Olivier; Press, Oliver W; Yalamanchili, Sreeni; Kahn, Robert; Dere, Randall C; Lu, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu-Waye; Morschhauser, Franck

2015-06-01

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ketamine as an adjuvant to opioids for cancer pain.

PubMed

Bell, Rae F; Eccleston, Christopher; Kalso, Eija A

2017-06-28

This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects. To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults. For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017. The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial. Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The second study with 10 participants examined the addition of intravenous ketamine bolus in two different doses to ongoing morphine therapy, compared with placebo. Both of these studies reported reduction in pain intensity and reduction in morphine requirements when ketamine was added to opioid for refractory cancer pain. The new study identified by the updated search had a parallel group design and 185 participants. This placebo-controlled study examined rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids. There were no differences between groups for patient-reported pain intensity.Pooling of the data from the three included trials was not appropriate because of clinical heterogeneity.The study examining intrathecal drug administration reported no adverse events related to ketamine. In the study using intravenous bolus administration, ketamine caused hallucinations in four of 10 participants. In the rapid dose escalation/high-dose subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group, compared to the placebo group, with the most common adverse events being needle site irritation and cognitive disturbance. Two serious adverse events (bradyarrhythmia and cardiac arrest) thought to be related to ketamine were also reported in this trial.For all three studies there was an unclear risk of bias overall. Using GRADE, we judged the quality of the evidence to be very low due to study limitations and imprecision due to the small number of participants in all comparisons. Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain. The evidence was of very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is high. Rapid dose escalation of ketamine to high dose (500 mg) does not appear to have clinical benefit and may be associated with serious adverse events. More randomised controlled trials (RCTs) examining specific low-dose ketamine clinical regimens in current use are needed.

Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer.

PubMed

Al-Mamgani, Abrahim; van Putten, Wim L J; Heemsbergen, Wilma D; van Leenders, Geert J L H; Slot, Annerie; Dielwart, Michel F H; Incrocci, Luca; Lebesque, Joos V

2008-11-15

To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer. A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 microe secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity. After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04). The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

PubMed

Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G; Liu, Xiaowei; Kim, AeRang; Bernhardt, Melanie Brooke; Kudgus, Rachel A; Reid, Joel M; Voss, Stephan D; Blaney, Susan; Fox, Elizabeth; Weigel, Brenda J

2018-04-25

We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted. © 2018 Wiley Periodicals, Inc.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

PubMed

Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn; El-Deiry, Wafik S

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent

PubMed Central

Allen, Joshua E.; Crowder, Roslyn; El-Deiry, Wafik S.

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer. PMID:26580220

The Effect of Increasing Doses of Saw Palmetto Fruit Extract on Serum PSA Levels: Analysis of the CAMUS Randomized Trial

PubMed Central

Andriole, Gerald L.; McCullum-Hill, Christie; Sandhu, Gurdarshan S.; Crawford, E. David; Barry, Michael J.; Cantor, Alan

2014-01-01

Purpose Saw palmetto extracts are used for treating lower urinary tract symptoms in men despite level I evidence concluding that saw palmetto was ineffective in reducing lower urinary symptoms. We sought to determine whether higher doses of saw palmetto as studied in CAMUS affect serum PSA levels. Materials and Methods The CAMUS trial was a randomized, placebo-controlled double blind multi-centered North American trial conducted between June 5, 2008 and October 10, 2012 in which 369 men >45 years of age with AUA symptom score ≥ 8 and ≤ 24 were randomly assigned to placebo or dose escalation saw palmetto, which consisted of 320mg for first 24 weeks to 640mg for next 24 weeks to 960mg for last 24 weeks of this 72 week trial. Serum PSA levels (Beckman-Coulter) were obtained at baseline and at weeks 24, 48 and 72 and were compared between treatment groups using the pooled t and Fisher's exact tests. Results Serum PSA levels were similar at baseline for the placebo (1.93 ± 1.59 ng/ml) and saw palmetto groups (2.20 ± 1.95, p = 0.16). Changes in PSA levels over the course of the study were similar: placebo group mean change 0.16 ± 1.08 ng/ml and saw palmetto group mean change 0.23 ± 0.83 ng/ml (p value 0.50). Additionally, no differential effect on serum PSA levels was observed between treatment arms when groups were stratified by baseline PSA values. Conclusions Saw palmetto extract does not affect serum PSA levels more than placebo even at relatively high doses. PMID:23253958

Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.

PubMed

Creech, C Buddy; Dekker, Cornelia L; Ho, Dora; Phillips, Shanda; Mackey, Sally; Murray-Krezan, Cristina; Grazia Pau, Maria; Hendriks, Jenny; Brown, Valerie; Dally, Leonard G; Versteege, Isabella; Edwards, Kathryn M

2013-12-01

Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma

PubMed Central

Siegel, Abby B.; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S.; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.; Flaig, Thomas W.; Tsai, Wei Yann; Wu, David P. H.; Lee, Valerie; Greenlee, Heather

2013-01-01

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests. PMID:23757319

Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer.

PubMed

Terrill, Kelly R; Lemons, Richard S; Goldsby, Robert E

2003-11-01

Recombinant tissue plasminogen activator, alteplase, began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s. However, alteplase often requires an extended dwell time to restore patency to occluded CVCs. In adults, reteplase, a newer thrombolytic agent, has been reported to restore patency to CVCs in 30 minutes. The authors prospectively evaluated the safety and efficacy of reteplase in restoring patency to occluded CVCs in children with cancer. This was a dose escalation trial. The dose of reteplase was initiated at 0.1 units and increased by increments of 0.1 units to a maximum dose of 0.4 units. Each dose was tested on at least three participants. Time to patency after reteplase administration was recorded by nurses caring for the patients. Attempts to access the line occurred every 15 minutes for 1 hour. CVCs that remained occluded after 1 hour were treated with alteplase. Reteplase was administered to 15 clotted CVCs. Twelve of the 15 were cleared with an average dwell time of 38 minutes. The time to patency did not appear to correlate with the dose. No adverse events were reported. Reteplase can restore patency to occluded CVCs in a pediatric population. Reteplase appears to have comparable efficacy with alteplase, but reteplase may require shorter dwell times. A prospective, randomized, clinical trial is warranted to determine whether reteplase is as effective as alteplase in restoring patency to occluded CVCs.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDGmore » PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.« less

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial.

PubMed

López-Cortés, Luis Eduardo; Rosso-Fernández, Clara; Núñez-Núñez, María; Lavín-Alconero, Lucía; Bravo-Ferrer, José; Barriga, Ángel; Delgado, Mercedes; Lupión, Carmen; Retamar, Pilar; Rodríguez-Baño, Jesús

2017-06-09

Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare-associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic 'real-practice' trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae . The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation. The European Union Clinical Trials Register: EudraCT number 2015-004219-19. Clinical trials.gov: NCT02795949. Protocol version: V.2.0, dated 16 May 2016. All items from the WHO Trial Registration Data Set are included in the registry. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

PubMed Central

Paoloni, Melissa C.; Mazcko, Christina; Fox, Elizabeth; Fan, Timothy; Lana, Susan; Kisseberth, William; Vail, David M.; Nuckolls, Kaylee; Osborne, Tanasa; Yalkowsy, Samuel; Gustafson, Daniel; Yu, Yunkai; Cao, Liang; Khanna, Chand

2010-01-01

Background Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. Methodology/Principal Findings This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. Conclusions/Significance Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease. PMID:20543980

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ben-Josef, Edgar, E-mail: edgar.ben-josef@uphs.upenn.edu; Schipper, Mathew; Francis, Isaac R.

2012-12-01

Purpose: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). Methods and Materials: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of {>=}1500/mm{sup 3}, platelets {>=}100,000/mm{sup 3}, creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase {<=}2.5 Multiplication-Sign upper limit of normal. FDR-G (1000 mg/m{sup 2}/100 min intravenously) wasmore » given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) {>=}3, neutropenic fever, or deterioration in performance status to {>=}3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. Results: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. Conclusions: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.« less

Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.

PubMed

Gettinger, Scott N; Bazhenova, Lyudmila A; Langer, Corey J; Salgia, Ravi; Gold, Kathryn A; Rosell, Rafael; Shaw, Alice T; Weiss, Glen J; Tugnait, Meera; Narasimhan, Narayana I; Dorer, David J; Kerstein, David; Rivera, Victor M; Clackson, Timothy; Haluska, Frank G; Camidge, David Ross

2016-12-01

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR T790M -positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461. Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). ARIAD Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnan, Sunil, E-mail: skrishnan@mdanderson.org; Chadha, Awalpreet S.; Suh, Yelin

2016-03-15

Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume wasmore » treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.« less

Is oral immunotherapy the cure for food allergies?

PubMed

Nowak-Wegrzyn, Anna; Fiocchi, Alessandro

2010-06-01

To review current evidence on food oral immunotherapy (OIT). Desensitized state, defined as the ingestion of a substantial amount of food in the home diet that protects from severe reactions to accidental exposures, can be achieved by approximately 50-75% of the children treated with OIT. The rate of permanent tolerance is unknown; the longer duration of OIT may result in permanent tolerance. Side effects are common both during the initial dose escalation and during home dosing. Most reactions are mild (oral pruritus, abdominal discomfort, and rashes) and decrease in frequency with the longer duration of OIT. Severe reactions treated with epinephrine have been reported during home dosing. Factors associated with increased risk of reactions to previously tolerated doses during home dosing include exercise, viral infection, dosing on empty stomach, menses, and asthma exacerbation. These preliminary data on OIT are encouraging. Additional studies must answer multiple questions including optimal dose, ideal duration of oral/sublingual immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment and need for patient protection during home administration. Until these questions are answered in rigorous multicenter randomized and placebo-controlled trials, OIT remains an experimental approach with not sufficiently well established risk-to-benefit ratio.

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

PubMed

Bahleda, Rastislav; Grilley-Olson, Juneko E; Govindan, Ramaswamy; Barlesi, Fabrice; Greillier, Laurent; Perol, Maurice; Ray-Coquard, Isabelle; Strumberg, Dirk; Schultheis, Beate; Dy, Grace K; Zalcman, Gérard; Weiss, Glen J; Walter, Annette O; Kornacker, Martin; Rajagopalan, Prabhu; Henderson, David; Nogai, Hendrik; Ocker, Matthias; Soria, Jean-Charles

2017-06-06

To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.

COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the Prospective Phase 2 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensen, Alexandra D., E-mail: alexdjensen@gmx.de; Nikoghosyan, Anna V.; Lossner, Karen

Purpose: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. Patients and Methods: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scoredmore » according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. Results: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n=20), gross residual disease (R2, n=17), and inoperable disease (n=16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The most common site of failure was distant (55%). Local relapse was predominantly in field (79%). Conclusion: Treatment was tolerated, with moderate acute and late toxicity. The LC at 3 years was promising. No significant difference could be shown regarding resection status; hence, extensive and mutilating surgical procedures should be rediscussed. Further dose escalation may be limited in view of potential vascular adverse events.« less

A Phase 1 Trial of MSP2-C1, a Blood-Stage Malaria Vaccine Containing 2 Isoforms of MSP2 Formulated with Montanide® ISA 720

PubMed Central

McCarthy, James S.; Marjason, Joanne; Elliott, Suzanne; Fahey, Paul; Bang, Gilles; Malkin, Elissa; Tierney, Eveline; Aked-Hurditch, Hayley; Adda, Christopher; Cross, Nadia; Richards, Jack S.; Fowkes, Freya J. I.; Boyle, Michelle J.; Long, Carole; Druilhe, Pierre; Beeson, James G.; Anders, Robin F.

2011-01-01

Background In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion. Methodology/Principal Findings The trial was designed to include three dose cohorts (10, 40, and 80 µg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 µg dose; no subjects received the 80 µg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 µg and 40 µg dose cohorts, with antibody levels by ELISA higher in the 40 µg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. Conclusions/Significance As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant. Trial Registration Australian New Zealand Clinical Trials Registry 12607000552482 PMID:21949716

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial

PubMed Central

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-01-01

Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1–4, prednisone at a dose of 1.5 mg/kg also on days 1–4 and thalidomide at a dose of 50–100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1–4 and 1.6, 3.2, or 4.8 g on days 5–35. Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3–4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1–4 followed by 4.8 g p.o. on days 5–35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). PMID:20053869

A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells

PubMed Central

Rosenthal, Mark; McArthur, Grant A.; Pattison, Scott T.; Pattison, Stacey L.; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Scott, Andrew M.

2015-01-01

Background We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors. Methodology Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity. Principal Findings Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response. Conclusions/Significance This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000672257 PMID:26659127

Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Felix Y., E-mail: ffeng@med.umich.edu; Department of Radiation Oncology, Veterans Affairs Medical Center, Ann Arbor, Michigan; Blas, Kevin

2013-05-01

Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64more » months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.« less

Effect of a simple dose-escalation schedule on tramadol tolerability : assessment in the clinical setting.

PubMed

Tagarro, I; Herrera, J; Barutell, C; Díez, M C; Marín, M; Samper, D; Busquet, C; Rodríguez, M J

2005-01-01

To assess the effect of a very simple dose-escalation schedule on tramadol tolerability in clinical practice. This schedule consists of starting treatment with sustained-release tramadol 50mg twice daily, and escalating the dose around 7 days later to 100mg twice daily. Data from 1925 outpatients with non-malignant chronic pain were collected in this multicentre, prospective, comparative, non-randomised, open, observational study. A total of 1071 patients (55.6%) were included in the dose-escalation group (50mg group) and 854 patients (44.4%) in the control group (sustained-release tramadol 100mg twice daily; 100mg group). The proportion of patients who interrupted tramadol treatment due to the occurrence of adverse reactions was significantly lower in the 50mg group (5.6%) than in the 100mg group (12.6%) [p = 0.001]. In line with this, the proportion of patients who experienced at least one adverse reaction was significantly lower in the 50mg group (18.4%) than in the 100mg group (30.4%) [p = 0.001] and, interestingly, the two most frequently reported adverse reactions, nausea and dizziness, were found with a significantly lower frequency in the 50mg group (p < 0.001). Multivariate analysis showed that the risk of safety-related treatment cessations was 2.3 times higher in the 100mg group than in the 50mg group, and 2.2 times higher in females than in males. The two treatments were equally effective in reducing pain intensity (p = 0.121), measured as a reduction in pain score obtained by means of a visual analogue scale. The instauration of tramadol treatment, starting with sustained-release 50mg capsules twice daily and escalating the dose some days later to 100mg twice daily, was shown to be an effective and easy way to improve tramadol tolerability in clinical practice, whilst maintaining its analgesic efficacy.

Safety and Immunogenicity of an AMA-1 Malaria Vaccine in Malian Adults: Results of a Phase 1 Randomized Controlled Trial

PubMed Central

Thera, Mahamadou A.; Doumbo, Ogobara K.; Coulibaly, Drissa; Diallo, Dapa A.; Kone, Abdoulaye K.; Guindo, Ando B.; Traore, Karim; Dicko, Alassane; Sagara, Issaka; Sissoko, Mahamadou S.; Baby, Mounirou; Sissoko, Mady; Diarra, Issa; Niangaly, Amadou; Dolo, Amagana; Daou, Modibo; Diawara, Sory I.; Heppner, D. Gray; Stewart, V. Ann; Angov, Evelina; Bergmann-Leitner, Elke S.; Lanar, David E.; Dutta, Sheetij; Soisson, Lorraine; Diggs, Carter L.; Leach, Amanda; Owusu, Alex; Dubois, Marie-Claude; Cohen, Joe; Nixon, Jason N.; Gregson, Aric; Takala, Shannon L.; Lyke, Kirsten E.; Plowe, Christopher V.

2008-01-01

Background The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria. Methodology/Principal Findings A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18–55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 µg/AS02A 0.25 mL or FMP2.1 50 µg/AS02A 0.5 mL) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively. Conclusion/Significance The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site. Trial Registration ClinicalTrials.gov NCT00308061 PMID:18213374

A phase I/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy (HAART) in HIV-positive patients with cancer: AIDS Malignancy Consortium Trial AMC 061

PubMed Central

Rudek, Michelle A; Moore, Page C.; Mitsuyasu, Ronald T.; Dezube, Bruce J.; Aboulafia, David; Gerecitano, John; Sullivan, Ryan; Cianfrocca, Mary E.; Henry, David H.; Ratner, Lee; Haigentz, Missak; Dowlati, Afshin; Little, Richard F.; Ivy, S. Percy; Deeken, John F.

2014-01-01

Background Treatment of non-AIDS defining cancers (NADCs) may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium assessing targeted therapies and HAART in HIV+ cancer patients (ClinicalTrials.gov NCT00890747). Methods Patients were stratified into two arms based on whether they were taking ritonavir, a potent CYP3A4 inhibitor, in a modified phase I study of sunitinib. Patients in arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50mg/day). Arm 2 (ritonavir-based HAART) used a phase I, 3+3 dose escalation design (from 25 to 50mg/day). Cycles were with four weeks on treatment followed by a two week break (6 weeks total). Pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Results Nineteen patients were enrolled and evaluable. Patients on Arm 1 tolerated treatment with one observed dose limiting toxicity (DLT). In Arm 2, a DLT was experienced at 37.5mg, and an additional 3 of 5 patients experienced grade 3 neutropenia, an uncommon toxicity of sunitinib. No patient had a response, but 10 had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Conclusions Patients on non-ritonavir based HAART regimens tolerated standard dosing of sunitinib. Patients on ritonavir-based therapy treated with 37.5mg/day experienced higher toxicities. Dose reduction of sunitinib to 37.5mg may be warranted in patients on ritonavir. PMID:24474568

More about masitinib

PubMed Central

Walker, Ulrich A

2009-01-01

A dose-escalating phase II trial studied masitinib, an oral tyrosine kinase inhibitor, in 43 patients with rheumatoid arthritis. Masitinib induced American College of Rheumatology (ACR)20, ACR50 and ACR70 responses in 54%, 26% and 8% of patients, respectively. A placebo group was not included. Thirty-seven per cent of the patients withdrew before the 12-week end-point was reached, primarily because of adverse events. These findings are the first on the efficacy of tyrosine kinase inhibition in a sizeable population. Future work should focus on delineating the tyrosine kinase that is most important in maintaining rheumatoid activity and address potential long-term toxicities such as gonadal insufficiency, teratogenicity and cardiotoxicity. PMID:19664170

Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients.

PubMed

Veizi, I Elias; Hayek, Salim M; Narouze, Samer; Pope, Jason E; Mekhail, Nagy

2011-10-01

The purpose of this study was to examine the effect of intrathecal (IT) coadministration of bupivacaine with opioids during the initial phase of opioid titration and up to 1 year after implantation of an IT drug delivery system (IDDS). The study was designed as a retrospective study. OUTCOMES ANALYZED: The outcomes analyzed for this study were pain relief, oral opioid consumption, IT opioid, and bupivacaine dosage. METHODS AND PATIENT POPULATION: The patient population for this study were consecutively implanted patients over a period of 6 years in a tertiary single center with multiple practitioners. In this retrospective study, 126 consecutive noncancer intractable pain patients were implanted with IDDS and initiated with an IT opioid (O) as a single medication or an IT opioid and bupivacaine (O + B). Pain intensity, amount of oral opioids, dose, rate, and concentration of IT opioids and bupivacaine, and number and type of IT medication used were recorded at preimplant, implant, and at 3, 6, and 12 months postimplant. The intervention used for the study was the IT delivery device implant. Significant reduction in pain intensity was observed in both groups at 12 months postimplant (O group: baseline 7.42 ± 2.1 to 5.85 ± 2.8 [n = 72, P < 0.001]; O + B group 7.35 ± 2 to 5.03 ± 2.4 (n = 54; P < 0.001]). The combination of opioids with bupivacaine from the start of IT infusion treatment resulted in a reduced progression of opioid dose escalation in comparison to patients started with opioids (O group). The rate of increase of IT opioids in the O group at 12 months was 535 ± 180%, whereas in the O + B, the dose increase was significantly lower at 185 ± 85% (P < 0.004). In both groups, there was a statistically significant decrease in oral opioid consumption compared with preimplant doses. Concomitant initial coadministration of IT bupivacaine with opioids blunts the rate of IT opioid dose escalation during the first year after implant of an IDDS. More studies are necessary to thoroughly examine IT opioid dose escalation and the effects of addition of bupivacaine to IT opioids. Blunting IT opioid dose escalation may be a beneficial long-term effect of IT bupivacaine. Wiley Periodicals, Inc.

A double-blind, randomized controlled trial to compare the effect of biannual peripheral magnetic resonance imaging, radiography and standard of care disease progression monitoring on pharmacotherapeutic escalation in rheumatoid and undifferentiated inflammatory arthritis: study protocol for a randomized controlled trial

PubMed Central

2014-01-01

Background Permanent joint damage is a major consequence of rheumatoid arthritis (RA), the most common and destructive form of inflammatory arthritis. In aggressive disease, joint damage can occur within 6 months from symptom onset. Early, intensive treatment with conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) can delay the onset and progression of joint damage. The primary objective of the study is to investigate the value of magnetic resonance imaging (MRI) or radiography (X-ray) over standard of care as tools to guide DMARD treatment decision-making by rheumatologists for the care of RA. Methods A double-blind, randomized controlled trial has been designed. Rheumatoid and undifferentiated inflammatory arthritis patients will undergo an MRI and X-ray assessment every 6 months. Baseline adaptive randomization will be used to allocate participants to MRI, X-ray, or sham-intervention groups on a background of standard of care. Prognostic markers, treating physician, and baseline DMARD therapy will be used as intervention allocation parameters. The outcome measures in rheumatology RA MRI score and the van der Heijde-modified Sharp score will be used to evaluate the MRI and X-ray images, respectively. Radiologists will score anonymized images for all patients regardless of intervention allocation. Disease progression will be determined based on the study-specific, inter-rater smallest detectable difference. Allocation-dependent, intervention-concealed reports of positive or negative disease progression will be reported to the treating rheumatologist. Negative reports will be delivered for the sham-intervention group. Study-based radiology clinical reports will be provided to the treating rheumatologists for extra-study X-ray requisitions to limit patient radiation exposure as part of diagnostic imaging standard of care. DMARD treatment dose escalation and therapy changes will be measured to evaluate the primary objective. A sample size of 186 (62 per group) patients will be required to determine a 36% difference in pharmacological treatment escalation between the three groups with intermediate dispersion of data with 90% power at a 5% level of significance. Discussion This study will determine if monitoring RA and undifferentiated inflammatory arthritis patients using MRI and X-ray every 6 months over 2 years provides incremental evidence over standard of care to influence pharmacotherapeutic decision-making and ultimately hinder disease progression. Trial registration This trial has been registered at ClinicalTrials.gov: NCT00808496 (registered on 12 December 2008). PMID:24997587

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour-bearing dogs: A phase I dose finding study.

PubMed

Wouda, R M; Hocker, S E; Higginbotham, M L

2018-03-01

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg -1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m -2 . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m -2 . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m -2 IV every 21 days and approximately 2.75 mg kg -1 PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials. © 2017 John Wiley & Sons Ltd.

A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam.

PubMed

Tvete, Ingunn Fride; Bjørner, Trine; Skomedal, Tor

2016-04-01

Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. © British Journal of General Practice 2016.

Alectinib Dose Escalation Re-induces Central Nervous System Responses in ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients Relapsing on Standard Dose Alectinib

PubMed Central

Gainor, Justin F.; Chi, Andrew S.; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S.; Brastianos, Priscilla K.; Shih, Helen A.; Shaw, Alice T.

2015-01-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in ALK-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard-dose alectinib (600 mg twice daily), but subsequently recurred with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. PMID:26845119

Whole-Pelvic Nodal Radiation Therapy in the Context of Hypofractionation for High-Risk Prostate Cancer Patients: A Step Forward

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaidar-Person, Orit; Roach, Mack; Créhange, Gilles, E-mail: gcrehange@cgfl.fr

2013-07-15

Given the low α/β ratio of prostate cancer, prostate hypofractionation has been tested through numerous clinical studies. There is a growing body of literature suggesting that with high conformal radiation therapy and even with more sophisticated radiation techniques, such as high-dose-rate brachytherapy or image-guided intensity modulated radiation therapy, morbidity associated with shortening overall treatment time with higher doses per fraction remains low when compared with protracted conventional radiation therapy to the prostate only. In high-risk prostate cancer patients, there is accumulating evidence that either dose escalation to the prostate or hypofractionation may improve outcome. Nevertheless, selected patients who have amore » high risk of lymph node involvement may benefit from whole-pelvic radiation therapy (WPRT). Although combining WPRT with hypofractionated prostate radiation therapy is feasible, it remains investigational. By combining modern advances in radiation oncology (high-dose-rate prostate brachytherapy, intensity modulated radiation therapy with an improved image guidance for soft-tissue sparing), it is hypothesized that WPRT could take advantage of recent results from hypofractionation trials. Moreover, the results from hypofractionation trials raise questions as to whether hypofractionation to pelvic lymph nodes with a high risk of occult involvement might improve the outcomes in WPRT. Although investigational, this review discusses the challenging idea of WPRT in the context of hypofractionation for patients with high-risk prostate cancer.« less

Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity.

PubMed

Awada, Ahmad; Dumez, Herlinde; Aftimos, Philippe G; Costermans, Jo; Bartholomeus, Sylvie; Forceville, Kathleen; Berghmans, Thierry; Meeus, Marie-Anne; Cescutti, Jessica; Munzert, Gerd; Pilz, Korinna; Liu, Dan; Schöffski, Patrick

2015-06-01

This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

SU-G-BRA-12: Development of An Intra-Fractional Motion Tracking and Dose Reconstruction System for Adaptive Stereotactic Body Radiation Therapy in High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rezaeian, N Hassan; Chi, Y; Tian, Z

Purpose: A clinical trial on stereotactic body radiation therapy (SBRT) for high-risk prostate cancer is undergoing at our institution. In addition to escalating dose to the prostate, we have increased dose to intra-prostatic lesions. Intra-fractional prostate motion deteriorates well planned radiation dose, especially for the small intra-prostatic lesions. To solve this problem, we have developed a motion tracking and 4D dose-reconstruction system to facilitate adaptive re-planning. Methods: Patients in the clinical trial were treated with VMAT using four arcs and 10 FFF beam. KV triggered x-ray projections were taken every 3 sec during delivery to acquire 2D projections of 3Dmore » anatomy at the direction orthogonal to the therapeutic beam. Each patient had three implanted prostate markers. Our developed system first determined 2D projection locations of these markers and then 3D prostate translation and rotation via 2D/3D registration of the markers. Using delivery log files, our GPU-based Monte Carlo tool (goMC) reconstructed dose corresponding to each triggered image. The calculated 4D dose distributions were further aggregated to yield the delivered dose. Results: We first tested each module in our system. MC dose engine were commissioned to our treatment planning system with dose difference of <0.5%. For motion tracking, 1789 kV projections from 7 patients were acquired. The 2D marker location error was <1 mm. For 3D motion tracking, root mean square (RMS) errors along LR, AP, and CC directions were 0.26mm, 0.36mm, and 0.01mm respectively in simulation studies and 1.99mm, 1.37mm, and 0.22mm in phantom studies. We also tested the entire system workflow. Our system was able to reconstruct delivered dose. Conclusion: We have developed a functional intra-fractional motion tracking and 4D dose re-construction system to support our clinical trial on adaptive high-risk prostate cancer SBRT. Comprehensive evaluations have shown the capability and accuracy of our system.« less

Acute Toxicity and Tumor Response in Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy With Shortening of the Overall Treatment Time Using Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost: A Phase 2 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

But-Hadzic, Jasna, E-mail: jbut@onko-i.si; Anderluh, Franc; Brecelj, Erik

Background and Purpose: This phase 2 study investigated the efficacy and safety of preoperative intensity modulated radiation therapy with a simultaneous integrated boost (IMRT-SIB) without dose escalation, concomitant with standard capecitabine chemotherapy in locally advanced rectal cancer. Methods and Materials: Between January 2014 and March 2015, 51 patients with operable stage II-III rectal adenocarcinoma received preoperative IMRT with pelvic dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/3 and 48.4 Gy to T4 tumor in 22 fractions, concomitant with capecitabine, 825 mg/m{sup 2}/12 hours, including weekends. The primary endpoint was pathologic complete response (pCR). Results: Fifty patients completed preoperative treatment according to themore » protocol, and 47 underwent surgical resection. The sphincter preservation rate for the low rectal tumors was 62%, and the resection margins were free in all but 1 patient. Decrease in tumor and nodal stage was observed in 32 (68%) and 39 (83%) patients, respectively, with pCR achieved in 12 (25.5%) patients. There were only 2 G ≥ 3 acute toxicities, with infectious enterocolitis in 1 patient and dermatitis over the sacral area caused by the bolus effect of the treatment table in the second patient. Conclusions: Preoperative IMRT-SIB without dose escalation is well tolerated, with a low acute toxicity profile, and can achieve a high rate of pCR and downstaging.« less

Acute Toxicity and Tumor Response in Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy With Shortening of the Overall Treatment Time Using Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost: A Phase 2 Trial.

PubMed

But-Hadzic, Jasna; Anderluh, Franc; Brecelj, Erik; Edhemovic, Ibrahim; Secerov-Ermenc, Ajra; Hudej, Rihard; Jeromen, Ana; Kozelj, Miran; Krebs, Bojan; Oblak, Irena; Omejc, Mirko; Vogrin, Andrej; Velenik, Vaneja

2016-12-01

This phase 2 study investigated the efficacy and safety of preoperative intensity modulated radiation therapy with a simultaneous integrated boost (IMRT-SIB) without dose escalation, concomitant with standard capecitabine chemotherapy in locally advanced rectal cancer. Between January 2014 and March 2015, 51 patients with operable stage II-III rectal adenocarcinoma received preoperative IMRT with pelvic dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/3 and 48.4 Gy to T4 tumor in 22 fractions, concomitant with capecitabine, 825 mg/m 2 /12 hours, including weekends. The primary endpoint was pathologic complete response (pCR). Fifty patients completed preoperative treatment according to the protocol, and 47 underwent surgical resection. The sphincter preservation rate for the low rectal tumors was 62%, and the resection margins were free in all but 1 patient. Decrease in tumor and nodal stage was observed in 32 (68%) and 39 (83%) patients, respectively, with pCR achieved in 12 (25.5%) patients. There were only 2 G ≥ 3 acute toxicities, with infectious enterocolitis in 1 patient and dermatitis over the sacral area caused by the bolus effect of the treatment table in the second patient. Preoperative IMRT-SIB without dose escalation is well tolerated, with a low acute toxicity profile, and can achieve a high rate of pCR and downstaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murthy, Vedang, E-mail: vmurthy@actrec.gov.in; Masodkar, Renuka; Kalyani, Nikhil

Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gymore » in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2]{sub 10} = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder preservation is clinically feasible, with good oncological outcomes and low rates of acute and late toxicities. Dose escalation is safe and possibly improves outcomes in bladder preservation.« less

Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.

PubMed

van Herwaarden, Noortje; van der Maas, Aatke; Minten, Michiel J M; van den Hoogen, Frank H J; Kievit, Wietske; van Vollenhoven, Ronald F; Bijlsma, Johannes W J; van den Bemt, Bart J F; den Broeder, Alfons A

2015-04-09

To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. Randomised controlled, open label, non-inferiority strategy trial. Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval -12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216. © van Herwaarden et al 2015.

The effect of increasing doses of saw palmetto fruit extract on serum prostate specific antigen: analysis of the CAMUS randomized trial.

PubMed

Andriole, Gerald L; McCullum-Hill, Christie; Sandhu, Gurdarshan S; Crawford, E David; Barry, Michael J; Cantor, Alan

2013-02-01

Saw palmetto extracts are used to treat lower urinary tract symptoms in men despite level I evidence that saw palmetto is ineffective in reducing these lower urinary tract symptoms. We determined whether higher doses of saw palmetto as studied in the CAMUS (Complementary and Alternative Medicine for Urologic Symptoms) trial affect serum prostate specific antigen levels. The CAMUS trial was a randomized, placebo controlled, double-blind, multicenter, North American trial conducted between June 5, 2008 and October 10, 2012, in which 369 men older than 45 years with an AUA symptom score of 8 to 24 were randomly assigned to placebo or dose escalation of saw palmetto, which consisted of 320 mg for the first 24 weeks, 640 mg for the next 24 weeks and 960 mg for the last 24 weeks of this 72-week trial. Serum prostate specific antigen levels were obtained at baseline and at weeks 24, 48 and 72, and were compared between treatment groups using the pooled t test and Fisher's exact test. Serum prostate specific antigen was similar at baseline for the placebo (mean ± SD 1.93 ± 1.59 ng/ml) and saw palmetto groups (2.20 ± 1.95, p = 0.16). Changes in prostate specific antigen during the study were similar, with a mean change in the placebo group of 0.16 ± 1.08 ng/ml and 0.23 ± 0.83 ng/ml in the saw palmetto group (p = 0.50). In addition, no differential effect on serum prostate specific antigen was observed between treatment arms when the groups were stratified by baseline prostate specific antigen. Saw palmetto extract does not affect serum prostate specific antigen more than placebo, even at relatively high doses. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases.

PubMed

Raskind, M A; Dobie, D J; Kanter, E D; Petrie, E C; Thompson, C E; Peskind, E R

2000-02-01

Central nervous system (CNS) adrenergic hyperresponsiveness may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). Two Vietnam combat veterans with PTSD prescribed the centrally active alpha1-adrenergic antagonist prazosin for symptoms of benign prostatic hypertrophy unexpectedly reported elimination of combat trauma nightmares. This observation prompted an open-label feasibility trial of prazosin for combat trauma nightmares in chronic combat-induced PTSD. Four consecutively identified combat veterans with chronic DSM-IV PTSD and severe intractable combat trauma nightmares participated in an 8-week open trial of escalating-dose prazosin. Nightmare severity response was rated using the nightmare item of the Clinician Administered PTSD Scale and the Clinical Global Impressions-Change scale. The 2 patients who achieved a daily prazosin dose of at least 5 mg were markedly improved, with complete elimination of trauma nightmares and resumption of normal dreaming. The 2 subjects limited to 2 mg of prazosin to avoid excessive blood pressure reduction were moderately improved with at least 50% reduction in nightmare severity. These clinical observations, together with neurobiological evidence for alpha1-adrenergic regulation of CNS neurobiological systems relevant to PTSD, provide rationale for placebo-controlled trials of prazosin for PTSD combat trauma nightmares.

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

PubMed Central

STOMMEL, ELIJAH W.; COHEN, JEFFREY A.; FADUL, CAMILO E.; COGBILL, CHRISTOPHER H.; GRABER, DAVID J.; KINGMAN, LINDA; MACKENZIE, TODD; SMITH, JACQUELINE Y. CHANNON; HARRIS, BRENT T.

2013-01-01

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects. PMID:19922130

Phase I evaluation of delta virG Shigella sonnei live, attenuated, oral vaccine strain WRSS1 in healthy adults.

PubMed

Kotloff, Karen L; Taylor, David N; Sztein, Marcelo B; Wasserman, Steven S; Losonsky, Genevieve A; Nataro, James P; Venkatesan, Malabi; Hartman, Antoinette; Picking, William D; Katz, David E; Campbell, James D; Levine, Myron M; Hale, Thomas L

2002-04-01

We conducted a phase I trial with healthy adults to evaluate WRSS1, a live, oral Delta virG Shigella sonnei vaccine candidate. In a double-blind, randomized, dose-escalating fashion, inpatient volunteers received a single dose of either placebo (n = 7) or vaccine (n = 27) at 3 x 10(3) CFU (group 1), 3 x 10(4) CFU (group 2), 3 x 10(5) CFU (group 3), or 3 x 10(6) CFU (group 4). The vaccine was generally well tolerated, although a low-grade fever or mild diarrhea occurred in six (22%) of the vaccine recipients. WRSS1 was recovered from the stools of 50 to 100% of the vaccinees in each group. The geometric mean peak anti-lipopolysaccharide responses in groups 1 to 4, respectively, were 99, 39, 278, and 233 for immunoglobulin (IgA) antibody-secreting cell counts; 401, 201, 533, and 284 for serum reciprocal IgG titers; and 25, 3, 489, and 1,092 for fecal IgA reciprocal titers. Postvaccination increases in gamma interferon production in response to Shigella antigens occurred in some volunteers. We conclude that WRSS1 vaccine is remarkably immunogenic in doses ranging from 10(3) to 10(6) CFU but elicits clinical reactions that must be assessed in further volunteer trials.

Phase I Evaluation of ΔvirG Shigella sonnei Live, Attenuated, Oral Vaccine Strain WRSS1 in Healthy Adults

PubMed Central

Kotloff, Karen L.; Taylor, David N.; Sztein, Marcelo B.; Wasserman, Steven S.; Losonsky, Genevieve A.; Nataro, James P.; Venkatesan, Malabi; Hartman, Antoinette; Picking, William D.; Katz, David E.; Campbell, James D.; Levine, Myron M.; Hale, Thomas L.

2002-01-01

We conducted a phase I trial with healthy adults to evaluate WRSS1, a live, oral ΔvirG Shigella sonnei vaccine candidate. In a double-blind, randomized, dose-escalating fashion, inpatient volunteers received a single dose of either placebo (n = 7) or vaccine (n = 27) at 3 × 103 CFU (group 1), 3 × 104 CFU (group 2), 3 × 105 CFU (group 3), or 3 × 106 CFU (group 4). The vaccine was generally well tolerated, although a low-grade fever or mild diarrhea occurred in six (22%) of the vaccine recipients. WRSS1 was recovered from the stools of 50 to 100% of the vaccinees in each group. The geometric mean peak anti-lipopolysaccharide responses in groups 1 to 4, respectively, were 99, 39, 278, and 233 for immunoglobulin (IgA) antibody-secreting cell counts; 401, 201, 533, and 284 for serum reciprocal IgG titers; and 25, 3, 489, and 1,092 for fecal IgA reciprocal titers. Postvaccination increases in gamma interferon production in response to Shigella antigens occurred in some volunteers. We conclude that WRSS1 vaccine is remarkably immunogenic in doses ranging from 103 to 106 CFU but elicits clinical reactions that must be assessed in further volunteer trials. PMID:11895966

Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Puntel, Mariana; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689; Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048

2013-05-01

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, andmore » can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression “on” or “off” according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1 × 10{sup 8}, 1 × 10{sup 9}, or 1 × 10{sup 10} viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1 × 10{sup 9} vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma. - Highlights: ► High capacity Ad vectors elicit sustained therapeutic gene expression in the brain. ► HC-Ad-TK/TetOn-Flt3L encodes two therapeutic genes and a transcriptional switch. ► We performed a dose escalation study at acute and chronic time points. ► Doses up to 1 × 10{sup 9} vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered in the brain. ► Efficacy and safety of HC-Ad-TK/TetOn-Flt3L merits its use in a GBM Phase I trial.« less

SU-E-J-124: 18F-FDG PET Imaging to Improve RT Treatment Outcome for Locally Advanced Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shusharina, N; Khan, F; Sharp, G

2015-06-15

Purpose: To investigate spatial correlation between high uptake regions of pre- and 10-days-post therapy{sup 1} {sup 8}F-FDG PET in recurrent lung cancer and to evaluate the feasibility of dose escalation boosting only regions with high FDG uptake identified on baseline PET. Methods: Nineteen patients with stages II– IV inoperable lung cancer were selected. Volumes of interest (VOI) on pre-therapy FDG-PET were defined using an isocontour at ≥50% of SUVmax. VOI of pre- and post-therapy PET images were correlated for the extent of overlap. A highly optimized IMRT plan to 60 Gy prescribed to PTV defined on the planning CT wasmore » designed using clinical dose constraints for the organs at risk. A boost of 18 Gy was prescribed to the VOI defined on baseline PET. A composite plan of the total 78 Gy was compared with the base 60 Gy plan. Increases in dose to the lungs, spinal cord and heart were evaluated. IMRT boost plan was compared with proton RT and SBRT boost plans. Results: Overlap fraction of baseline PET VOI with the VOI on 10 days-post therapy PET was 0.8 (95% CI: 0.7 – 0.9). Using baseline VOI as a boosting volume, dose could be escalated to 78 Gy for 15 patients without compromising the dose constraints. For 4 patients, the dose limiting factors were V20Gy and Dmean for the total lung, and Dmax for the spinal cord. An increase of the dose to OARs correlated significantly with the relative size of the boost volume. Conclusion: VOI defined on baseline 18F-FDG PET by the SUVmax-≥50% isocontour may be a biological target volume for escalated radiation dose. Dose escalation to this volume may provide improved tumor control without breaching predefined dose constraints for OARs. The best treatment outcome may be achieved with proton RT for large targets and with SBRT for small targets.« less

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772)

PubMed Central

Sheridan, Juliette; Coe, Carol Ann; Doran, Peter; Egan, Laurence; Cullen, Garret; Kevans, David; Leyden, Jan; Galligan, Marie; O’Toole, Aoibhlinn; McCarthy, Jane; Doherty, Glen

2018-01-01

Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC. The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). Aim The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. Methods and analysis A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. Ethics and dissemination The study protocol was approved by the Research Ethics committee of St. Vincent’s University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration numbers EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results. PMID:29379609

First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A, in Patients with Advanced Solid Tumors

PubMed Central

Fischer, Richard; Scharr, Dirk; Büchert, Martin; Stern, Angelika; Gille, Hendrik; Audoly, Laurent P.; Scheulen, Max E.

2013-01-01

Background To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). Methods Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. Results Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti–PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug’s activity. Conclusions PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. Trial Registration ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257 PMID:24349470

Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial.

PubMed

Cortes, Jorge E; De Souza, Carmino Antonio; Ayala, Manuel; Lopez, Jose Luis; Bullorsky, Eduardo; Shah, Sandip; Huang, Xiaojun; Babu, K Govind; Abdulkadyrov, Kudrat; de Oliveira, José Salvador Rodrigues; Shen, Zhi-Xiang; Sacha, Tomasz; Bendit, Israel; Liang, Zhizhou; Owugah, Tina; Szczudlo, Tomasz; Khanna, Sadhvi; Fellague-Chebra, Rafik; le Coutre, Philipp D

2016-12-01

Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Novartis Pharmaceuticals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Adaptive Radiation Therapy for Localized Mesothelioma with Mediastinal Metastasis Using Helical Tomotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renaud, James; Yartsev, Slav; Department of Oncology, University of Western Ontario, London, Ontario

2009-10-01

The purpose of this study was to compare 2 adaptive radiotherapy strategies with helical tomotherapy. A patient having mesothelioma with mediastinal nodes was treated using helical tomotherapy with pretreatment megavoltage CT (MVCT) imaging. Gross tumor volumes (GTVs) were outlined on every MVCT study. Two alternatives for adapting the treatment were investigated: (1) keeping the prescribed dose to the targets while reducing the dose to the OARs and (2) escalating the target dose while maintaining the original level of healthy tissue sparing. Intensity modulated radiotherapy (step-and-shoot IMRT) and 3D conformal radiotherapy (3DCRT) plans for the patient were generated and compared. Themore » primary lesion and nodal mass regressed by 16.2% and 32.5%, respectively. Adapted GTVs and reduced planning target volume (PTV) margins of 4 mm after 22 fractions decrease the planned mean lung dose by 19.4%. For dose escalation, the planned prescribed doses may be increased from 50.0 to 58.7 Gy in PTV{sub 1} and from 60.0 to 70.5 Gy in PTV{sub 2}. The step-and-shoot IMRT plan was better in sparing healthy tissue but did not provide target coverage as well as the helical tomotherapy plan. The 3DCRT plan resulted in a prohibitively high planned dose to the spinal cord. MVCT studies provide information both for setup correction and plan adaptation. Improved healthy tissue sparing and/or dose escalation can be achieved by adaptive planning.« less

The Safety and Tolerability of 5-Aminolevulinic Acid Phosphate with Sodium Ferrous Citrate in Patients with Type 2 Diabetes Mellitus in Bahrain

PubMed Central

Al-Saber, Feryal; Aldosari, Waleed; Alselaiti, Mariam; Khalfan, Hesham; Kaladari, Ahmed; Khan, Ghulam; Harb, George; Rehani, Riyadh; Kudo, Sizuka; Koda, Aya; Tanaka, Tohru

2016-01-01

Type 2 diabetes mellitus is prevalent especially in Gulf countries and poses serious long-term risks to patients. A multifaceted treatment approach can include nutritional supplements with antioxidant properties such as 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC). This prospective, randomized, single-blind, placebo-controlled, dose escalating pilot clinical trial assessed the safety of 5-ALA with SFC at doses up to 200 mg 5-ALA/229.42 mg SFC per day in patients living in Bahrain with type 2 diabetes mellitus that was uncontrolled despite the use of one or more antidiabetic drugs. Fifty-three patients (n = 53) from 3 sites at one center were enrolled by Dr. Feryal (Site #01), Dr. Hesham (Site #02), and Dr. Waleed (Site #03) (n = 35, 5-ALA-SFC; n = 18, placebo). There was no significant difference in incidence of adverse events reported, and the most frequent events reported were gastrointestinal in nature, consistent with the known safety profile of 5-ALA in patients with diabetes. No significant changes in laboratory values and no difference in hypoglycemia between patients receiving 5-ALA and placebo were noted. Overall, the current results support that use of 5-ALA-SFC up to 200 mg per day taken as 2 divided doses is safe in patients taking concomitant oral antidiabetic medications and may offer benefits in the diabetic population. This trial is registered with ClinicalTrials.gov NCT02481141. PMID:27738640

Transdermal rotigotine in advanced Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Nomoto, Masahiro; Mizuno, Yoshikuni; Kondo, Tomoyoshi; Hasegawa, Kazuko; Murata, Miho; Takeuchi, Masahiro; Ikeda, Junji; Tomida, Takayuki; Hattori, Nobutaka

2014-10-01

Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson's disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on-off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were -10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and -4.4 ± 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off-time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.

Dose-finding trial of a combined regimen with bevacizumab, immunotherapy, and chemotherapy in patients with metastatic renal cell cancer: An Italian Oncology Group for Clinical Research (GOIRC) study.

PubMed

Buti, Sebastiano; Lazzarelli, Silvia; Chiesa, Matteo Dalla; Simonelli, Cecilia; Re, Giovanni Lo; Lheshi, Arvin; Simon, Spazzapan; Mattioli, Rodolfo; Caminiti, Caterina; Mazza, Giancarlo; Donini, Maddalena; Passalacqua, Rodolfo

2010-09-01

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma.

PubMed

Davids, Matthew S; Roberts, Andrew W; Seymour, John F; Pagel, John M; Kahl, Brad S; Wierda, William G; Puvvada, Soham; Kipps, Thomas J; Anderson, Mary Ann; Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Peale, Franklin; Ross, Jeremy A; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A; Gordon, Gary B; Gerecitano, John F

2017-03-10

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

PubMed Central

Roberts, Andrew W.; Seymour, John F.; Pagel, John M.; Kahl, Brad S.; Wierda, William G.; Puvvada, Soham; Kipps, Thomas J.; Anderson, Mary Ann; Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Peale, Franklin; Ross, Jeremy A.; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A.; Gordon, Gary B.; Gerecitano, John F.

2017-01-01

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. PMID:28095146

Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour.

PubMed

Wagner, Andrew J; Agulnik, Mark; Heinrich, Michael C; Mahadevan, Daruka; Riedel, Richard F; von Mehren, Margaret; Trent, Jonathan; Demetri, George D; Corless, Christopher L; Yule, Murray; Lyons, John F; Oganesian, Aram; Keer, Harold

2016-07-01

Gastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST. In this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150-220 mg/m(2)) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored. Common onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43-165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d. The combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population. Trial registration ID: clinicaltrials.gov: NCT01294202. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen.

PubMed

Kong, Anthony; Rea, Daniel; Ahmed, Samreen; Beck, J Thaddeus; López López, Rafael; Biganzoli, Laura; Armstrong, Anne C; Aglietta, Massimo; Alba, Emilio; Campone, Mario; Hsu Schmitz, Shu-Fang; Lefebvre, Caroline; Akimov, Mikhail; Lee, Soo-Chin

2016-06-21

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.

A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors.

PubMed

Jimeno, Antonio; Gordon, Michael; Chugh, Rashmi; Messersmith, Wells; Mendelson, David; Dupont, Jakob; Stagg, Robert; Kapoun, Ann M; Xu, Lu; Uttamsingh, Shailaja; Brachmann, Rainer K; Smith, David C

2017-12-15

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR . ©2017 American Association for Cancer Research.

A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

PubMed

Lindman, H; Andersson, M; Ahlgren, J; Balslev, E; Sverrisdottir, A; Holmberg, S B; Bengtsson, N O; Jacobsen, E H; Jensen, A B; Hansen, J; Tuxen, M K; Malmberg, L; Villman, K; Anderson, H; Ejlertsen, B; Bergh, J; Blomqvist, C

2018-05-01

Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m 2 , epirubicin 60 mg/m 2 , cyclophosphamide 600 mg/m 2 ). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m 2 , C 900-1200 mg/m 2 ) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Salvage low-dose-rate 125I partial prostate brachytherapy after dose-escalated external beam radiotherapy

PubMed Central

Chang, Lynn

2014-01-01

Purpose To report outcomes on 5 patients treated with salvage partial low-dose-rate (LDR) 125-iodine (125I) permanent prostate seed brachytherapy (BT) for biopsy-proven locally persistent prostate cancer, following failure of dose-escalated external beam radiotherapy (EBRT). Material and methods A retrospective review of the Fox Chase Cancer Center prostate cancer database identified five patients treated with salvage partial LDR 125I seed implant for locally persistent disease following dose-escalated EBRT to 76-84 Gy in 2 Gy per fraction equivalent. All patients had post-EBRT biopsies confirming unilateral locally persistent prostate cancer. Pre-treatment, EBRT and BT details, as well as post-treatment characteristics were documented and assessed. Results The median follow-up post-implant was 41 months. All five patients exhibited low acute genitourinary and gastrointestinal toxicities. Increased erectile dysfunction was noted in three patients. There were no biochemical failures following salvage LDR 125I seed BT to date, with a median post-salvage PSA of 0.4 ng/mL. Conclusions In carefully selected patients with local persistence of disease, partial LDR 125I permanent prostate seed implant appears to be a feasible option for salvage local therapy with an acceptable toxicity profile. Further study is needed to determine long-term results of this approach. PMID:25337135

Clinical studies of the effectiveness and safety of antivenoms.

PubMed

Williams, David J; Habib, Abdulrazaq G; Warrell, David A

2018-05-07

In the 1890s, hyperimmune sera proved effective in animals against challenge by the snake venom against which they had been raised. They were first used, apparently successfully, in a human patient in about 1895. Since then, antivenoms have become accepted as the only reliable specific treatment for snake-bite envenoming. Despite decades of accumulated clinical experience and a number of published randomized comparative and observational studies, the clinical effectiveness and safety of some antivenoms remain open to question, due to a lack of robust randomized controlled trial data. Antivenoms in some poorly regulated markets may have high rates of potentially fatal adverse effects and their use must be balanced by demonstrable effectiveness. Even those manufactured to strict regulatory requirements may pose a rare risk of severe adverse reactions. Most antivenoms currently marketed around the world were registered without first being studied clinically. There is increasing pressure to subject antivenoms, even those that are long-established, to the same protocols of rigorous pre-clinical and clinical assessment that are standard regulatory requirements for other drugs. Conventional clinical testing progresses through Phases I, II, III to IV. Most authorities consider antivenoms too dangerous to be used in Phase I studies in healthy volunteers. An alternative method for preliminary estimation of safety, dose-finding and effectiveness, is proposed - the "3 + 3" dose escalation or de-escalation design, in volunteer patients, as used in oncology to test cytotoxic drugs. Antivenoms are so widely used and well trusted, that there are few ethical justifications for placebo controls. However, placebo might be ethically justified if there were no proven effective treatment and or if withholding or delaying treatment posed acceptably negligible risks to the participants. Antivenom trials are most urgently needed in low-to middle-income countries where there are many practical, logistical and funding challenges. Basic requirements for clinical trials include identification of the biting species of snake in every case; the use of objective, clinically-relevant endpoints, such as restoration of blood coagulability; definition of inclusion, exclusion and withdrawal criteria; assurance of antivenom safety; ethical considerations; inclusion of one or more control (comparator) groups; and analysis based on intention to treat. The highest quality evidence comes from Phase II and larger Phase III studies that have been designed as statistically powerful, randomized, controlled trials (RCTs), ideally with blinding of patients and investigators to avoid bias. Because of the challenges to carrying out clinical trials of antivenoms, Phase IV trials (post-marketing surveillance) are potentially more important and useful than for most other drugs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma.

PubMed

O'Reilly, Eileen M; Lee, Jonathan W; Lowery, Maeve A; Capanu, Marinela; Stadler, Zsofia K; Moore, Malcolm J; Dhani, Neesha; Kindler, Hedy L; Estrella, Hayley; Maynard, Hannah; Golan, Talia; Segal, Amiel; Salo-Mullen, Erin E; Yu, Kenneth H; Epstein, Andrew S; Segal, Michal; Brenner, Robin; Do, Richard K; Chen, Alice P; Tang, Laura H; Kelsen, David P

2018-04-01

A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Gemcitabine and cisplatin were dosed at 600 and 25 mg/m 2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society. © 2018 American Cancer Society.

A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.

PubMed

Regules, Jason A; Beigel, John H; Paolino, Kristopher M; Voell, Jocelyn; Castellano, Amy R; Hu, Zonghui; Muñoz, Paula; Moon, James E; Ruck, Richard C; Bennett, Jason W; Twomey, Patrick S; Gutiérrez, Ramiro L; Remich, Shon A; Hack, Holly R; Wisniewski, Meagan L; Josleyn, Matthew D; Kwilas, Steven A; Van Deusen, Nicole; Mbaya, Olivier Tshiani; Zhou, Yan; Stanley, Daphne A; Jing, Wang; Smith, Kirsten S; Shi, Meng; Ledgerwood, Julie E; Graham, Barney S; Sullivan, Nancy J; Jagodzinski, Linda L; Peel, Sheila A; Alimonti, Judie B; Hooper, Jay W; Silvera, Peter M; Martin, Brian K; Monath, Thomas P; Ramsey, W Jay; Link, Charles J; Lane, H Clifford; Michael, Nelson L; Davey, Richard T; Thomas, Stephen J

2017-01-26

The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.

Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the targetmore » volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.« less

A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab.

PubMed

Velayos, Fernando S; Kahn, James G; Sandborn, William J; Feagan, Brian G

2013-06-01

Patients with Crohn's disease who become unresponsive to therapy with tumor necrosis factor antagonists are managed initially with either empiric dose escalation or testing-based strategies. The comparative cost effectiveness of these 2 strategies is unknown. We investigated whether a testing-based strategy is more cost effective than an empiric dose-escalation strategy. A decision analytic model that simulated 2 cohorts of patients with Crohn's disease compared outcomes for the 2 strategies over a 1-year time period. The incremental cost-effectiveness ratio of the empiric strategy was expressed as cost per quality-adjusted life-year (QALY) gained, compared with the testing-based strategy. We performed 1-way, probabilistic, and prespecified secondary analyses. The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). In sensitivity analyses, the incremental cost-effectiveness ratio of the empiric strategy ranged from $500,000 to more than $5 million per QALY gained. Similar rates of remission (63% vs 66%) and response (28% vs 26%) were achieved through differential use of available interventions. The testing-based strategy resulted in a higher percentage of surgeries (48% vs 34%) and lower percentage use of high-dose biological therapy (41% vs 54%). A testing-based strategy is a cost-effective alternative to the current strategy of empiric dose escalation for managing patients with Crohn's disease who have lost responsiveness to infliximab. The basis for this difference is lower cost at similar outcomes. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Factors associated with opioid dose increases: a chart review of patients’ first year on long-term opioids

PubMed Central

Bautista, Christopher A.; Iosif, Ana-Maria; Wilsey, Barth L.; Melnikow, Joy A.; Crichlow, Althea; Henry, Stephen G.

2016-01-01

OBJECTIVE To examine encounter-level factors associated with opioid dose increases during patients’ first year on opioid therapy for chronic pain. DESIGN Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type; opioid dose change; documented prescribing rationale; documentation of guideline-concordant opioid prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. RESULTS 674 encounters were coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with email encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared to face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95%CI 0.11 – 0.28) and email (OR 0.23, 95%CI 0.12 – 0.47) encounters; documentation of prescribing rationale was significantly more likely for email (OR 5.06, 95%CI 1.87–13.72) and less likely for telephone (OR 0.30, 95%CI 0.18–0.51) encounters. CONCLUSION Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation. PMID:27477581

A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

PubMed Central

Bendell, Johanna C; Javle, Milind; Bekaii-Saab, Tanios S; Finn, Richard S; Wainberg, Zev A; Laheru, Daniel A; Weekes, Colin D; Tan, Benjamin R; Khan, Gazala N; Zalupski, Mark M; Infante, Jeffrey R; Jones, Suzanne; Papadopoulos, Kyriakos P; Tolcher, Anthony W; Chavira, Renae E; Christy-Bittel, Janna L; Barrett, Emma; Patnaik, Amita

2017-01-01

Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population. PMID:28152546

Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGarry, Ronald C.; Papiez, Lech; Williams, Mark

Purpose: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. Methods and Materials: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. Results: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy),more » but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses {<=}16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. Conclusions: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.« less

De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit

PubMed Central

2010-01-01

Introduction Most data on de-escalation of empirical antimicrobial therapy has focused on ventilator-associated pneumonia. In this retrospective monocentric study, we evaluated de-escalation as part of a global strategy of empiric antibiotherapy management irrespective of the location and the severity of the infection. The goal of this trial was to assess the application of a de-escalation strategy and the impact in terms of re-escalation, recurrent infection and to identify variables associated with de-escalation. Methods All consecutive patients treated with empiric antibiotic therapy and hospitalized in the intensive care unit for at least 72 hours within a period of 16 months were included. We compared the characteristics and outcome of patients who have experienced de-escalation therapy with those who have not. Results A total of 116 patients were studied corresponding to 133 infections. Antibiotic therapy was de-escalated in 60 cases (45%). De-escalation, primarily accomplished by a reduction in the number of antibiotics used, was observed in 52% of severe sepsis or septic shock patients. Adequate empiric antibiotic and use of aminoglycoside were independently linked with de-escalation. De-escalation therapy was associated with a significant reduction of recurrent infection (19% vs 5% P = 0.01). Mortality was not changed by de-escalation. Conclusions As part of a global management of empiric antibiotherapy in an intensive care unit, de-escalation might be safe and feasible in a large proportion of patients. PMID:21167047

De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit.

PubMed

Morel, Jérôme; Casoetto, Julie; Jospé, Richard; Aubert, Gérald; Terrana, Raphael; Dumont, Alain; Molliex, Serge; Auboyer, Christian

2010-01-01

Most data on de-escalation of empirical antimicrobial therapy has focused on ventilator-associated pneumonia. In this retrospective monocentric study, we evaluated de-escalation as part of a global strategy of empiric antibiotherapy management irrespective of the location and the severity of the infection. The goal of this trial was to assess the application of a de-escalation strategy and the impact in terms of re-escalation, recurrent infection and to identify variables associated with de-escalation. All consecutive patients treated with empiric antibiotic therapy and hospitalized in the intensive care unit for at least 72 hours within a period of 16 months were included. We compared the characteristics and outcome of patients who have experienced de-escalation therapy with those who have not. A total of 116 patients were studied corresponding to 133 infections. Antibiotic therapy was de-escalated in 60 cases (45%). De-escalation, primarily accomplished by a reduction in the number of antibiotics used, was observed in 52% of severe sepsis or septic shock patients. Adequate empiric antibiotic and use of aminoglycoside were independently linked with de-escalation. De-escalation therapy was associated with a significant reduction of recurrent infection (19% vs 5% P = 0.01). Mortality was not changed by de-escalation. As part of a global management of empiric antibiotherapy in an intensive care unit, de-escalation might be safe and feasible in a large proportion of patients.

Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.

PubMed

Tapia, Milagritos D; Sow, Samba O; Lyke, Kirsten E; Haidara, Fadima Cheick; Diallo, Fatoumata; Doumbia, Moussa; Traore, Awa; Coulibaly, Flanon; Kodio, Mamoudou; Onwuchekwa, Uma; Sztein, Marcelo B; Wahid, Rezwanul; Campbell, James D; Kieny, Marie-Paule; Moorthy, Vasee; Imoukhuede, Egeruan B; Rampling, Tommy; Roman, Francois; De Ryck, Iris; Bellamy, Abbie R; Dally, Len; Mbaya, Olivier Tshiani; Ploquin, Aurélie; Zhou, Yan; Stanley, Daphne A; Bailer, Robert; Koup, Richard A; Roederer, Mario; Ledgerwood, Julie; Hill, Adrian V S; Ballou, W Ripley; Sullivan, Nancy; Graham, Barney; Levine, Myron M

2016-01-01

The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo). In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian). Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 10(10) pu, 35 [38%] to 2·5 × 10(10) pu, 35 [38%] to 5 × 10(10) pu, and 11 [12%] to 1 × 10(11) pu) and 20 in the USA (ten [50%] to 1 × 10(10) pu and ten [50%] to 1 × 10(11) pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 10(10) and two [2%] received 1 × 10(11) pu) and four (20%) of 20 in the USA (all received 1 × 10(11) pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness. 1 × 10(11) pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers). Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases. Copyright © 2016 Tapia et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.

PubMed

Shaw, Alice T; Felip, Enriqueta; Bauer, Todd M; Besse, Benjamin; Navarro, Alejandro; Postel-Vinay, Sophie; Gainor, Justin F; Johnson, Melissa; Dietrich, Jorg; James, Leonard P; Clancy, Jill S; Chen, Joseph; Martini, Jean-François; Abbattista, Antonello; Solomon, Benjamin J

2017-12-01

Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC. In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Pfizer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Westover, Kenneth D.; Loo, Billy W.; Gerber, David E.

2015-09-01

Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC. Methods and Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiationmore » therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy. Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59). Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.« less

Oseltamivir Pharmacokinetics, Dosing, and Resistance Among Children Aged <2 Years With Influenza

PubMed Central

Kimberlin, David W.; Acosta, Edward P.; Prichard, Mark N.; Sánchez, Pablo J.; Ampofo, Krow; Lang, David; Ashouri, Negar; Vanchiere, John A.; Abzug, Mark J.; Abughali, Nazha; Caserta, Mary T.; Englund, Janet A.; Sood, Sunil K.; Spigarelli, Michael G.; Bradley, John S.; Lew, Judy; Michaels, Marian G.; Wan, Wen; Cloud, Gretchen; Jester, Penelope; Lakeman, Fred D.; Whitley, Richard J.; Giles, Dusty; Cotton, Bari; Judy, Sharon; Cowie, Margaret; Francis, Jeanne; Evans, Candice; O'Donnell, Nan; Shiraishi, Ofelia Vargas; Latiolais, Lisa; Aymami, Valeri; Dole, Ken; Gaultier, Julie; Lofthus, Gerry; Kinnunen, Diane; Lacombe, Kirsten; Stellato, Nancy; Denlinger, Julie; Hingtgen, Sara; Mason, Christina; Jeffrey, Noreen

2013-01-01

Background. Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. Methods. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age–de-escalation, adaptive design with a targeted systemic exposure. Results. From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0–8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9–11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12–23 months receiving the Food and Drug Administration–approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. Conclusions. The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9–11 months old is 3.5 mg/kg. Clinical Trials Registration. NCT00391768. PMID:23230059

Low-dose priming before vaccination with the phase I chloroform-methanol residue vaccine against Q fever enhances humoral and cellular immune responses to Coxiella burnetii.

PubMed

Waag, David M; England, Marilyn J; Bolt, Christopher R; Williams, Jim C

2008-10-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 microg, followed by a booster dose of 30 microg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection.

Low-Dose Priming before Vaccination with the Phase I Chloroform-Methanol Residue Vaccine against Q Fever Enhances Humoral and Cellular Immune Responses to Coxiella burnetii▿

PubMed Central

Waag, David M.; England, Marilyn J.; Bolt, Christopher R.; Williams, Jim C.

2008-01-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 μg, followed by a booster dose of 30 μg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection. PMID:18701647

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

PubMed Central

Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

2016-01-01

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

PubMed

Thakur, Manish K; Heilbrun, Lance; Dobson, Kimberlee; Boerner, Julie; Stark, Karri; Li, Jing; Smith, Daryn; Heath, Elisabeth; Fontana, Joseph; Vaishampayan, Ulka

2018-06-01

Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. Chemotherapy naive mCRPC patients received docetaxel 75 mg/m 2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen. Copyright © 2018 Elsevier Inc. All rights reserved.

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients.

PubMed

Zweifel, Martin; Thürlimann, Beat; Riniker, Salome; Weder, Patrik; von Moos, Roger; Pagani, Olivia; Bigler, Martin; Rothgiesser, Karin M; Pilop, Christiane; Hawle, Hanne; Brauchli, Peter; Tapia, Coya; Schoenfeld, Wolfgang; Sessa, Cristiana

2017-10-01

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. © 2017 The authors.

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

PubMed Central

Tshilolo, Léon; Santos, Brigida; Tomlinson, George A.; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K.; Olupot‐Olupot, Peter; Williams, Thomas N.; Odame, Isaac; Ware, Russell E.

2015-01-01

Background Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers. Procedure A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. Conclusions REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. PMID:26275071

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.

PubMed

McGann, Patrick T; Tshilolo, Léon; Santos, Brigida; Tomlinson, George A; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K; Olupot-Olupot, Peter; Williams, Thomas N; Odame, Isaac; Ware, Russell E

2016-01-01

Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers. A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of four different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. © 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

PubMed

Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

2015-06-01

To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. NCT01023256. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

Total marrow irradiation using Helical TomoTherapy

NASA Astrophysics Data System (ADS)

Garcia-Fernandez, Lourdes Maria

Clinical dose response data of human tumours are limited or restricted to a radiation dose range determined by the level of toxicity to the normal tissues. This is the case for the most common disseminated plasma cell neoplasm, multiple myeloma, where the maximum dose deliverable to the entire bony skeleton using a standard total body irradiation (TBI) technique is limited to about 12 Gy. This study is part of scientific background of a phase I/II dose escalation clinical trial for multiple myeloma using image-guided intensity modulated radiotherapy (IG-IMRT) to deliver high dose to the entire volume of bone marrow with Helical TomoTherapy (HT). This relatively new technology can deliver highly conformal dose distributions to complex target shapes while reducing the dose to critical normal tissues. In this study tools for comparing and predicting the effectiveness of different approaches to total marrow irradiation (TMI) using HT were provided. The expected dose response for plasma cell neoplasms was computed and a radiobiological evaluation of different treatment cohorts in a dose escalating study was performed. Normal tissue complication probability (NTCP) and tumour control probability (TCP) models were applied to an actual TMI treatment plan for a patient and the implications of using different longitudinal field widths were assessed. The optimum dose was ˜39 Gy for which a predicted tumour control of 95% (+/-3%) was obtained, with a predicted 3% (0, 8%) occurrence of radiation pneumonitis. Tissue sparing was seen by using smaller field widths only in the organs of the head. This suggests it would be beneficial to use the small fields in the head only since using small fields for the whole treatment would lead to long treatment times. In TMI it may be necessary to junction two longitudinally adjacent treatment volumes to form a contiguous planning target volume PTV. For instance, this is the case when a different SUP-INF spatial resolution is required or when the PTV length exceeds the bed travel distance. In this work, the dosimetric challenges associated with junctioning longitudinally adjacent PTVs with HT were analyzed and the feasibility of PTV junctioning was demonstrated. The benefits of spatially dividing or splitting the treatment into a few sub-treatments along the longitudinal direction were also investigated.

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

PubMed

Gainor, Justin F; Chi, Andrew S; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S; Brastianos, Priscilla K; Shih, Helen A; Shaw, Alice T

2016-02-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

PubMed

Perl, Alexander E; Altman, Jessica K; Cortes, Jorge; Smith, Catherine; Litzow, Mark; Baer, Maria R; Claxton, David; Erba, Harry P; Gill, Stan; Goldberg, Stuart; Jurcic, Joseph G; Larson, Richard A; Liu, Chaofeng; Ritchie, Ellen; Schiller, Gary; Spira, Alexander I; Strickland, Stephen A; Tibes, Raoul; Ustun, Celalettin; Wang, Eunice S; Stuart, Robert; Röllig, Christoph; Neubauer, Andreas; Martinelli, Giovanni; Bahceci, Erkut; Levis, Mark

2017-08-01

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Quigley, Charmian A; Wan, Xiaohai; Garg, Sipi; Kowal, Karen; Cutler, Gordon B; Ross, Judith L

2014-09-01

The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined. The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years. This study was a prospective, randomized, double-blind, placebo-controlled clinical trial. The study was conducted at two US pediatric endocrine centers. Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset. Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age. The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed. Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not. In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.

A randomized, first-in-human, healthy volunteer trial of BIVV009, a humanized antibody for the specific inhibition of the classical complement pathway.

PubMed

Bartko, Johann; Schoergenhofer, Christian; Schwameis, Michael; Firbas, Christa; Beliveau, Martin; Chang, Colin; Marier, Jean-Francois; Nix, Darrell; Gilbert, James C; Panicker, Sandip; Jilma, Bernd

2018-05-08

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune haemolytic anaemia. Therapeutic options for these complement-mediated disorders are limited and BIVV009, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase-1, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single and multiple doses of BIVV009 or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of BIVV009 were well tolerated without any safety concerns. BIVV009 exhibited a steep concentration-effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 µg/mL. This study establishes the foundation for using BIVV009 as a highly selective inhibitor of the classical complement pathway in different diseases. This article is protected by copyright. All rights reserved. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Intra-Arterial Chemotherapy with Osmotic Blood-Brain Barrier Disruption for Aggressive Oligodendroglial tumors: Results of a Phase I Study

PubMed Central

Guillaume, Daniel J.; Doolittle, Nancy D.; Gahramanov, Seymur; Hedrick, Nancy A.; Delashaw, Johnny B.; Neuwelt, Edward A.

2009-01-01

Objective Refractory anaplastic oligodendroglioma (AO) and oligoastrocytoma (OA) tumors are challenging to treat. This trial primarily evaluated toxicity and estimated the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan, IA carboplatin and intravenous (IV) etoposide phosphate in conjunction with blood-brain barrier disruption (BBBD) in these tumors. The secondary measure was efficacy. Methods Thirteen subjects with temozolomide (TMZ) - refractory AO (11) or OA (2) underwent BBBD with carboplatin (IA, 200 mg/m2/day), etoposide phosphate (IV, 200 mg/m2/day), and melphalan (IA, dose escalation) every 4 weeks, for up to 1 year. Subjects underwent melphalan dose escalation (4, 8, 12, 16, and 20 mg/m2/day) until the MTD (one level below that producing grade 4 toxicity) was determined. Toxicity and efficacy were assessed. Results Two of four subjects receiving IA melphalan at 8 mg/m2/day developed grade 4 thrombocytopenia, thus the melphalan MTD was 4 mg/m2/day. Adverse events included asymptomatic subintimal tear (1 subject) and grade 4 thrombocytopenia (3 subjects). Two subjects demonstrated complete response, 3 had partial responses, 5 demonstrated stable disease and 3 progressed. Median overall PFS was 11 months. Subjects with complete or partial response demonstrated deletion of chromosomes 1p and 19q. In the 5 subjects with stable disease, 2 demonstrated 1p and 19q deletion and 3 demonstrated 19q deletion only. Conclusion In these patients with AO or OA tumors who failed TMZ, osmotic BBBD with IA carboplatin, IV etoposide phosphate, and IA melphalan (4mg/m2/day for 2 days) shows acceptable toxicity and encouraging efficacy, especially in subjects demonstrating 1p and/or 19q deletion. PMID:20023537

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takam, Rungdham; Bezak, Eva; Yeoh, Eric E.

2010-09-15

Purpose: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences inmore » radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.« less

Phase 1 Study of Preoperative Chemoradiation Therapy With Temozolomide and Capecitabine in Patients With Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeong, Jae Ho; Hong, Yong Sang; Park, Yangsoon

Purpose: Preoperative chemoradiation therapy (CRT) with capecitabine is a standard treatment strategy in patients with locally advanced rectal cancer (LARC). Temozolomide improves the survival of patients with glioblastoma with hypermethylated O{sup 6}-methylguanine DNA methyltransferase (MGMT); MGMT hypermethylation is one of the colorectal carcinogenesis pathways. We aimed to determine the dose-limiting toxicity (DLT) and recommended dose (RD) of temolozomide in combination with capecitabine-based preoperative CRT for LARC. Methods and Materials: Radiation therapy was delivered with 45 Gy/25 daily fractions with coned-down boost of 5.4 Gy/3 fractions. Concurrent chemotherapy comprised fixed and escalated doses of capecitabine and temozolomide, respectively. The MGMT hypermethylation was evaluatedmore » in pretreatment tumor samples. This trial is registered with (ClinicalTrials.gov) with the number (NCT01781403). Results: Twenty-two patients with LARC of cT3-4N0 or cT{sub any}N1-2 were accrued. Dose level 3 was chosen as the RD because DLT was noticeably absent in 10 patients treated up to dose level 3. An additional 12 patients were recruited in this group. Grade III adverse events were noted, and pathologic complete response (pCR) was observed in 7 patients (31.8%); MGMT hypermethylation was detected in 16. The pCR rate was 37.5% and 16.7% in the hypermethylated and unmethylated MGMT groups, respectively (P=.616). Conclusions: There was a tendency toward higher pCR rates in patients with hypermethylated MGMT. Future randomized studies are therefore warranted.« less

Clinical impact of IMPORT HIGH trial (CRUK/06/003) on breast radiotherapy practices in the United Kingdom

PubMed Central

Ciurlionis, Laura; Kirby, Anna M; Locke, Imogen; Venables, Karen; Yarnold, John R; Titley, Jenny; Bliss, Judith; Coles, Charlotte E

2015-01-01

Objective: IMPORT HIGH is a multicentre randomized UK trial testing dose-escalated intensity-modulated radiotherapy (IMRT) after tumour excision in females with early breast cancer and higher than average local recurrence risk. A survey was carried out to investigate the impact of this trial on the adoption of advanced breast radiotherapy (RT) techniques in the UK. Methods: A questionnaire was sent to all 26 IMPORT HIGH recruiting RT centres to determine whether the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. In order to compare the clinical practice of breast RT between IMPORT HIGH and non–IMPORT HIGH centres, parts of the Royal College of Radiologists (RCR) breast RT audit result were used in this study. Results: 26/26 participating centres completed the questionnaire. After joining the trial, the number of centres routinely using tumour bed clips to guide whole-breast RT rose from 5 (19%) to 21 (81%). 20/26 (77%) centres now contour target volumes and organs at risk (OARs) in some or all patients compared with 14 (54%) before the trial. 14/26 (54%) centres offer inverse-planned IMRT for selected non-trial patients with breast cancer, and 10/14 (71%) have adopted the IMPORT HIGH trial protocol for target volume and OARs dose constraints. Only 2/26 (8%) centres used clip information routinely for breast treatment verification prior to IMPORT HIGH, a minority that has since risen to 7/26 (27%). Data on 1386 patients was included from the RCR audit. This suggested that more cases from IMPORT HIGH centres had surgical clips implanted (83 vs 67%), were treated using CT guided planning with full three-dimensional dose compensation (100 vs 75%), and were treated with photon boost RT (30 vs 8%). Conclusion: The study suggests that participation in the IMPORT HIGH trial has played an important part in providing the guidance and support networks needed for the safe integration of advanced RT techniques, where appropriate, as a standard of care for breast cancer patients treated at participating cancer centres. Advances in knowledge: We investigated the impact of the IMPORT HIGH trial on the adoption of advanced breast RT techniques in the UK and the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. PMID:26492402

Clinical impact of IMPORT HIGH trial (CRUK/06/003) on breast radiotherapy practices in the United Kingdom.

PubMed

Tsang, Yat; Ciurlionis, Laura; Kirby, Anna M; Locke, Imogen; Venables, Karen; Yarnold, John R; Titley, Jenny; Bliss, Judith; Coles, Charlotte E

2015-01-01

IMPORT HIGH is a multicentre randomized UK trial testing dose-escalated intensity-modulated radiotherapy (IMRT) after tumour excision in females with early breast cancer and higher than average local recurrence risk. A survey was carried out to investigate the impact of this trial on the adoption of advanced breast radiotherapy (RT) techniques in the UK. A questionnaire was sent to all 26 IMPORT HIGH recruiting RT centres to determine whether the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. In order to compare the clinical practice of breast RT between IMPORT HIGH and non-IMPORT HIGH centres, parts of the Royal College of Radiologists (RCR) breast RT audit result were used in this study. 26/26 participating centres completed the questionnaire. After joining the trial, the number of centres routinely using tumour bed clips to guide whole-breast RT rose from 5 (19%) to 21 (81%). 20/26 (77%) centres now contour target volumes and organs at risk (OARs) in some or all patients compared with 14 (54%) before the trial. 14/26 (54%) centres offer inverse-planned IMRT for selected non-trial patients with breast cancer, and 10/14 (71%) have adopted the IMPORT HIGH trial protocol for target volume and OARs dose constraints. Only 2/26 (8%) centres used clip information routinely for breast treatment verification prior to IMPORT HIGH, a minority that has since risen to 7/26 (27%). Data on 1386 patients was included from the RCR audit. This suggested that more cases from IMPORT HIGH centres had surgical clips implanted (83 vs 67%), were treated using CT guided planning with full three-dimensional dose compensation (100 vs 75%), and were treated with photon boost RT (30 vs 8%). The study suggests that participation in the IMPORT HIGH trial has played an important part in providing the guidance and support networks needed for the safe integration of advanced RT techniques, where appropriate, as a standard of care for breast cancer patients treated at participating cancer centres. We investigated the impact of the IMPORT HIGH trial on the adoption of advanced breast RT techniques in the UK and the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

PubMed

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-12-01

The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. © 2014 The British Pharmacological Society.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects

PubMed Central

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-01-01

Aim The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. Methods This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. Results All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. Conclusion A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. PMID:25039273

Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175

PubMed Central

Chitnis, Chetan E.; Mukherjee, Paushali; Mehta, Shantanu; Yazdani, Syed Shams; Dhawan, Shikha; Shakri, Ahmad Rushdi; Bharadwaj, Rukmini; Gupta, Puneet Kumar; Hans, Dhiraj; Mazumdar, Suman; Singh, Bijender; Kumar, Sanjeev; Pandey, Gaurav; Parulekar, Varsha; Imbault, Nathalie; Shivyogi, Preethi; Godbole, Girish; Mohan, Krishna; Leroy, Odile; Singh, Kavita; Chauhan, Virander S.

2015-01-01

Background A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. Method Healthy malaria naïve Indian male subjects aged 18–45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. Results JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-119. Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. Conclusion Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-119 construct needs to be optimised to improve its immunogenicity. Trial Registration Clinical Trial Registry, India CTRI/2010/091/000301 PMID:25927360

A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).

PubMed

Kim, Se Hyun; Shim, Hyo Sup; Cho, Jaeho; Jeong, Jae Heon; Kim, Sun Mi; Hong, Yun Kyoung; Sung, Ji Hee; Ha, Sang-Jun; Kim, Hye Ryun; Chang, Hyun; Kim, Joo Hang; Tania, Crombet; Cho, Byoung Chul

2013-03-01

Nimotuzumab (TheraCIM®) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100mg or 200mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples. A total of 16 patients were enrolled (3 in 100mg cohort, 13 in 200mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100mg cohorts, 3 in 200mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

PubMed

Humphreys, A C; Dent, J; Rodwell, S; Crawford, S M; Joffe, J K; Bradley, C; Dodwell, D; Perren, T J

2004-06-01

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study.

PubMed

Elliott, Julian H; McMahon, James H; Chang, Christina C; Lee, Sulggi A; Hartogensis, Wendy; Bumpus, Namandje; Savic, Rada; Roney, Janine; Hoh, Rebecca; Solomon, Ajantha; Piatak, Michael; Gorelick, Robert J; Lifson, Jeff; Bacchetti, Peter; Deeks, Steven G; Lewin, Sharon R

2015-12-01

In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study. In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371. Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3-2·2; p<0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5-2·9; p<0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6-2·4; p<0·0001) and 2·5 (1·9-3·3; p<0·0001) in the 1000 mg group; and 1·6 (1·2-2·1; p=0·0026) and 2·1 (1·5-3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses. Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV. The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pugh, Thomas J.; Chen Changhu; Rabinovitch, Rachel

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m{sup 2}, 1.3 mg/m{sup 2}, and 1.6 mg/m{sup 2}/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, definedmore » as any grade 4 hematologic toxicity, any grade {>=}3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for {>=}2 weeks. Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m{sup 2}. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m{sup 2} is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m{sup 2}.« less

Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.

PubMed

Furman, Wayne L; Crews, Kristine R; Billups, Catherine; Wu, Jianrong; Gajjar, Amar J; Daw, Najat C; Patrick, Christian C; Rodriguez-Galindo, Carlos; Stewart, Clinton F; Dome, Jeffrey S; Panetta, John C; Houghton, Peter J; Santana, Victor M

2006-02-01

Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PubMed

Myers, Michael A; Hagan, Michael P; Todor, Dorin; Gilbert, Lynn; Mukhopadhyay, Nitai; Randolf, Jessica; Heimiller, Jeffrey; Anscher, Mitchell S

2012-01-01

A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/β=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer. Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Intrathecal Hydromorphone and Bupivacaine Combination Therapy for Post-Laminectomy Syndrome Optimized with Patient-Activated Bolus Device.

PubMed

Hayek, Salim M; Veizi, Elias; Hanes, Michael

2016-03-01

Intrathecal (IT) pumps have become a valuable tool in managing intractable non-cancer pain. The purpose of this study was to evaluate the efficacy of using a rigorous treatment algorithm for trialing and implanting IT pumps with hydromorphone and bupivacaine in managing a more homogeneous population of post-laminectomy syndrome or failed back surgery syndrome (FBSS) patients. This is a retrospective analysis of FBSS patients with chronic intractable back pain implanted with IT pumps delivering hydromorphone and bupivacaine. A cohort of 57 (26 males, 31 females) consecutively implanted FBSS patients was analyzed. The average age at implant was 65.4 years. Average pain scores were 8.4 ± 0.2 (pre-implant), 4.9 ± 0.4 (6 months), 5.2 ± 0.5 (12 months), and 4.3 ± 0.5 (24 months). Average oral opioid doses in morphine equivalents were 56 ± 10 mg/day (pre-implant), 12.0 ± 3.5 mg/day (12 months), 15 ± 6 mg/day (24 months). Average IT hydromorphone doses were 79 ± 6.8 mcg/day (at implant), 184 ± 22 mcg/day (6 months), 329 ± 48 mcg/day (12 months), and 487 ± 80 mcg (24 months). IT hydromorphone dose escalation from baseline was 133% (6 months vs baseline), 78% (12 months vs 6 months), and 48% from 12 months to 24 months. Average IT bupivacaine doses were 5.8 ± 0.3 mg/day (implant), 9.5 ± 0.6 mg/day (6 months), 12.2 ± 0.7 mg/day (12 months), and 12.6 ± 0.9 mg/day (24 months). IT hydromorphone and bupivacaine are effective in treating chronic pain of FBSS, as demonstrated by the reduction of pain intensity and oral opioid consumption. However, an IT dose escalation phenomenon was observed, although at a reduced rate compared with what had been previously reported in the literature. It is possible that the local anesthetic combination delivered via a patient-activaed bolus device is an important factor. Despite demonstrating effectiveness, the clinical utility of myPTM-optimized IT therapy remains limited by a lack of prospective, placebo-controlled trials and comparative effectiveness research. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Treat-early and treat-mild: role of fast vs. slow escalation of headaches.

PubMed

Ng-Mak, D S; Ma, L; Hu, X H; Chen, Y-T

2009-04-01

This prospective, multi-center, observational study aimed to examine patients' early treatment decision process. Specifically, we assessed if the association between mild headache pain at treatment initiation and early treatment differed by the speed of headache escalation. Patients (n = 168) were instructed to collect information on their headache experience during the study period via an electronic diary over 30 consecutive days after enrollment. At the time of treatment, patients who treated early were 2.3 times as likely to experience mild headache pain as those who treated late. Controlling for the effect of escalation of headache, patients who treated early were three times as likely to report mild headache pain at dosing as those who treated late. The interaction between fast escalation of headache and mild pain was not statistically significant. Early treatment is associated with mild pain, regardless of the speed of headache escalation.

A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction with High-Dose Melphalan as a Conditioning Regimen for Salvage Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

PubMed

Biran, Noa; Rowley, Scott D; Vesole, David H; Zhang, Shijia; Donato, Michele L; Richter, Joshua; Skarbnik, Alan P; Pecora, Andrew; Siegel, David S

2016-12-01

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m 2 (3 × 3 design) on days -4 and -1 before transplantation with melphalan 200 mg/m 2 given on day -2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.

PubMed

Pressler, Ronit M; Boylan, Geraldine B; Marlow, Neil; Blennow, Mats; Chiron, Catherine; Cross, J Helen; de Vries, Linda S; Hallberg, Boubou; Hellström-Westas, Lena; Jullien, Vincent; Livingstone, Vicki; Mangum, Barry; Murphy, Brendan; Murray, Deirdre; Pons, Gerard; Rennie, Janet; Swarte, Renate; Toet, Mona C; Vanhatalo, Sampsa; Zohar, Sarah

2015-05-01

Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. European Community's Seventh Framework Programme. Copyright © 2015 Elsevier Ltd. All rights reserved.

Phase I Study of SU5416, a Small Molecule Inhibitor of the Vascular Endothelial Growth Factor Receptor (VEGFR) in Refractory Pediatric Central Nervous System Tumors

PubMed Central

Kieran, Mark W.; Supko, Jeffrey G.; Wallace, Dana; Fruscio, Robert; Poussaint, Tina Young; Phillips, Peter; Pollack, Ian; Packer, Roger; Boyett, James M.; Blaney, Susan; Prados, Michael; Geyer, Russ; Friedman, Henry; Goldman, Stewart; Kun, Larry E.; MacDonald, Tobey

2009-01-01

SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (Stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110mg/m2 while stratum II started at 48mg/m2. Thirty-three eligible patients were treated on stratum I (n=23) and stratum II (n=10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas and 2 choroid plexus carcinomas. The MTD in Stratum I was initially estimated to be 110mg/m2. The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145mg/m2 dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in Stratum I were 26.1 ± 12.5 liter/h/m2, 41.9 ± 21.4 liter/m2, and 1.11 ± 0.41 h, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum 1 patients. PMID:19065567

A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy.

PubMed

Wood, R A; Sicherer, S H; Burks, A W; Grishin, A; Henning, A K; Lindblad, R; Stablein, D; Sampson, H A

2013-06-01

Immunotherapy for peanut allergy may be limited by the risk of adverse reactions. To investigate the safety and immunologic effects of a vaccine containing modified peanut proteins. This was a phase 1 trial of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2, and Ara h 3, modified by amino acid substitutions at major IgE-binding epitopes, encapsulated in heat/phenol-killed E. coli. Five healthy adults were treated with 4 weekly escalating doses after which 10 peanut-allergic adults received weekly dose escalations over 10 weeks from 10 mcg to 3063 mcg, followed by three biweekly doses of 3063 mcg. There were no significant adverse effects in the healthy volunteers. Of the 10 peanut-allergic subjects [4 with intermittent asthma, median peanut IgE 33.3 kUA /l (7.2-120.2), and median peanut skin prick test wheal 11.3 mm (6.5-18)]; four experienced no symptoms; one had mild rectal symptoms; and the remaining five experienced adverse reactions preventing completion of dosing. Two were categorized as mild, but the remaining three were more severe, including one moderate reaction and two anaphylactic reactions. Baseline peanut IgE was significantly higher in the five reactive subjects (median 82.4 vs 17.2 kUA /l, P = 0.032), as was baseline anti-Ara h 2 IgE (43.3 versus 8.3, P = 0.036). Peanut skin test titration and basophil activation (at a single dilution) were significantly reduced after treatment, but no significant changes were detected for total IgE, peanut IgE, or peanut IgG4. Rectal administration of EMP-123 resulted in frequent adverse reactions, including severe allergic reactions in 20%. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

PubMed Central

Buggy, Joseph J.; Sharman, Jeff P.; Smith, Sonali M.; Boyd, Thomas E.; Grant, Barbara; Kolibaba, Kathryn S.; Furman, Richard R.; Rodriguez, Sara; Chang, Betty Y.; Sukbuntherng, Juthamas; Izumi, Raquel; Hamdy, Ahmed; Hedrick, Eric; Fowler, Nathan H.

2013-01-01

Purpose Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies. PMID:23045577

Real-World Treatment Patterns for Golimumab and Concomitant Medications in Japanese Rheumatoid Arthritis Patients.

PubMed

Okazaki, Masateru; Kobayashi, Hisanori; Ishii, Yutaka; Kanbori, Masayoshi; Yajima, Tsutomu

2018-06-01

The aim of this study was to investigate real-world treatment patterns for use of golimumab and concomitant medications in Japanese patients with rheumatoid arthritis. This study was a post hoc retrospective analysis from post-marketing surveillance data on 2350 Japanese patients with moderate/severe rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided based on initiation treatment or dose adjustment patterns with golimumab, methotrexate, or oral glucocorticoids. Logistic regression analysis revealed that the baseline factors associated with administration of golimumab (100 mg) were higher body weight, failure of prior biological therapy (bio-failure), no previous methotrexate use, and respiratory disease, while previous methotrexate use and absence of renal impairment or respiratory disease were associated with concomitant methotrexate therapy, and previous glucocorticoid use was associated with concomitant glucocorticoid therapy. The following associations were identified with regard to dose adjustment during treatment: bio-failure, no previous methotrexate use, previous csDMARDs use, presence of respiratory disease, allergy history, and higher CRP for golimumab dose escalation; shorter disease duration, previous GC, and no previous methotrexate use for methotrexate dose escalation; no prior biological therapy and renal impairment for methotrexate dose reduction; no previous GC use for glucocorticoid dose escalation; and absence of Steinbrocker's stage II/III/IV, absence of Steinbrocker's class II, no bio-failure, and no previous csDMARDs use for glucocorticoid dose reduction. This study revealed that various baseline factors were associated with initiation of treatment and dose adjustment of golimumab, methotrexate, or oral glucocorticoids, reflecting both the treatment strategies of physicians for improving RA symptoms and/or reducing adverse events. Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.

PubMed

Advani, Ranjana H; Buggy, Joseph J; Sharman, Jeff P; Smith, Sonali M; Boyd, Thomas E; Grant, Barbara; Kolibaba, Kathryn S; Furman, Richard R; Rodriguez, Sara; Chang, Betty Y; Sukbuntherng, Juthamas; Izumi, Raquel; Hamdy, Ahmed; Hedrick, Eric; Fowler, Nathan H

2013-01-01

Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics.

PubMed

Prado, Carla M M; Maia, Yara L M; Ormsbee, Michael; Sawyer, Michael B; Baracos, Vickie E

2013-10-01

Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

A Dosing/Cross-Development Study of the Multikinase Inhibitor Sorafenib in Patients With Pulmonary Arterial Hypertension

PubMed Central

Gomberg-Maitland, M; Maitland, ML; Barst, RJ; Sugeng, L; Coslet, S; Perrino, TJ; Bond, L; LaCouture, ME; Archer, SL; Ratain, MJ

2012-01-01

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients. PMID:20010555

WE-G-BRB-04: Leveraging Innovation to Design Future Clinical Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michalski, J.

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

WE-G-BRB-00: NIH-Funded Research: Instrumental in the Pursuit of Clinical Trials and Technological Innovations

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Mild neonatal hyperthyrotrophinaemia: 10-year experience suggests the condition is increasingly common but often transient.

PubMed

Oren, Asaf; Wang, Michael K; Brnjac, Lori; Mahmud, Farid H; Palmert, Mark R

2013-12-01

To examine a large population of infants with mild neonatal hyperthyrotrophinaemia (MNH) and determine prevalence, clinical characteristics and treatment history. Retrospective study of infants with MNH followed at The Hospital for Sick Children between 2000 and 2011. MNH was defined by an abnormal newborn screen followed by thyroid-stimulating hormone (TSH) between 5 and 30 mU/l and normal free T4 (FT4) on confirmatory tests. Mild neonatal hyperthyrotrophinaemia represented 22·3% of patients (103/462; 60 boys, 43 girls) within our clinic. Incidence increased from two of 20 in 2000 to 31 of 74 cases in 2010. Seventy eight percent of patients started L-thyroxine (initial dose: 8·3 ± 2·5 mcg/kg). The treated group had higher confirmatory TSH levels (P = 0·001) and had undergone thyroid scintigraphy more often (P = 0·0001) compared with the nontreated group. Evidence of overtreatment was detected in 45% of thyroid function tests obtained during treatment. Among the treated infants who had reached 3 years of age, 45% (N = 14) underwent a trial-off medication. Compared with those not trialled-off therapy, these infants were less likely to have had dose escalations during treatment (P = 0·001). The trial-off treatment was successful in 50% of cases. In the subset of infants with confirmatory TSH >10 mU/l, trial-off therapy was successful in 40%. None of the assessed variables predicted success of trial-off therapy. Mild neonatal hyperthyrotrophinaemia is an increasingly common diagnosis. It is more common in males and is often transient, but predictors of success of trial-off therapy were not identified. Further studies are needed to determine optimum L-thyroxine dosing and to determine whether treatment improves neurocognitive outcomes. © 2013 John Wiley & Sons Ltd.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

PubMed Central

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O’Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-01-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ. PMID:24991840

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

PubMed

Rosenfeld, Myrna R; Ye, Xiaobu; Supko, Jeffrey G; Desideri, Serena; Grossman, Stuart A; Brem, Steven; Mikkelson, Tom; Wang, Daniel; Chang, Yunyoung C; Hu, Janice; McAfee, Quentin; Fisher, Joy; Troxel, Andrea B; Piao, Shengfu; Heitjan, Daniel F; Tan, Kay-See; Pontiggia, Laura; O'Dwyer, Peter J; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azria, David, E-mail: david.azria@icm.unicancer.fr; INSERM, U896, IRCM, Montpellier; Riou, Olivier

2014-03-15

Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabinemore » twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.« less

The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial.

PubMed

Pancioli, Arthur M; Broderick, Joseph; Brott, Thomas; Tomsick, Thomas; Khoury, Jane; Bean, Judy; del Zoppo, Gregory; Kleindorfer, Dawn; Woo, Daniel; Khatri, Pooja; Castaldo, John; Frey, James; Gebel, James; Kasner, Scott; Kidwell, Chelsea; Kwiatkowski, Thomas; Libman, Richard; Mackenzie, Richard; Scott, Phillip; Starkman, Sidney; Thurman, R Jason

2008-12-01

Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination. The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy. Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group. The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial.

PubMed

Ren, Xiao-Cang; Wang, Quan-Yu; Zhang, Rui; Chen, Xue-Ji; Wang, Na; Liu, Yue-E; Zong, Jie; Guo, Zhi-Jun; Wang, Dong-Ying; Lin, Qiang

2016-04-23

Increasing the biological effective dose (BED) of radiotherapy for non-small cell lung cancer (NSCLC) can increase local control rates and improve overall survival. Compared with conventional fractionated radiotherapy, accelerated hypofractionated radiotherapy can yield higher BED, shorten the total treatment time, and theoretically obtain better efficacy. However, currently, there is no optimal hypofractionated radiotherapy regimen. Based on phase I trial results, we performed this phase II trial to further evaluate the safety and preliminary efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy(3-DCRT) combined with concurrent chemotherapy for patients with unresectable stage III NSCLC. Patients with previously untreated unresectable stage III NSCLC received 3-DCRT with a total dose of 69 Gy, delivered at 3 Gy per fraction, once daily, five fractions per week, completed within 4.6 weeks. At the same time, platinum doublet chemotherapy was applied. After 12 patients were enrolled in the group, the trial was terminated early. There were five cases of grade III radiation esophagitis, of which four cases completed the radiation doses of 51 Gy, 51 Gy, 54 Gy, and 66 Gy, and one case had 16 days of radiation interruption. The incidence of grade III acute esophagitis in patients receiving an irradiation dose per fraction ≥2.7 Gy on the esophagus was 83.3% (5/6). The incidence of symptomatic grade III radiation pneumonitis among the seven patients who completed 69 Gy according to the plan was 28.6% (2/7). The median local control (LC) and overall survival (OS) were not achieved; the 1-year LC rate was 59.3%, and the 1-year OS rate was 78.6%. For unresectable stage III NSCLC, the accelerated hypofractionated radiotherapy with a total dose of 69 Gy (3 Gy/f) combined with concurrent chemotherapy might result in severe radiation esophagitis and pneumonitis to severely affect the completion of the radiotherapy. Therefore, we considered that this regimen was infeasible. During the hypofractionated radiotherapy with concurrent chemotherapy, the irradiation dose per fraction to esophagus should be lower than 2.7 Gy. Further studies should be performed using esophageal tolerance as a metric in dose escalation protocols. NCT02720614, the date of registration: March 23, 2016.

Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

PubMed

Clark, Robert E; Kuczenski, Ronald; Segal, David S

2007-07-01

Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors.

PubMed

Aghajanian, Carol; Bell-McGuinn, Katherine M; Burris, Howard A; Siu, Lillian L; Stayner, Lee-Ann; Wheler, Jennifer J; Hong, David S; Kurkjian, Carla; Pant, Shubham; Santiago-Walker, Ademi; Gauvin, Jennifer L; Antal, Joyce M; Opalinska, Joanna B; Morris, Shannon R; Infante, Jeffrey R

2018-04-03

Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.

The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

PubMed

Wu, Runhui; Luke, Koon Hung

2017-11-01

Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

EXTENDED ACCESS TO METHAMPHETAMINE SELF-ADMINISTRATION AFFECTS SENSORIMOTOR GATING IN RATS

PubMed Central

Hadamitzky, Martin; Markou, Athina; Kuczenski, Ronald

2010-01-01

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher-dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6-h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6-h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher-dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits. PMID:21070821

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer.

PubMed

Uwagawa, Tadashi; Sakamoto, Taro; Abe, Kyohei; Okui, Norimitsu; Hata, Daigo; Shiba, Hiroaki; Futagawa, Yasuro; Aiba, Keisuke; Yanaga, Katsuhiko

2015-01-01

To date, gemcitabine-based or fluoropyrimidine-based regimens are recommended for unresectable advanced biliary tract cancer. Then, we conducted a phase I study of gemcitabine/cisplatin and S-1 that is an oral fluoropyrimidine. The aim of this study was to determine the dose-limiting toxicity (DLT), maximum-tolerated dose, and a recommended phase II dose of S-1. Response was assessed as a secondary endpoint. Patients who have been diagnosed with unresectable or postoperative recurrent biliary tract cancer received cisplatin (25 mg/m² i.v. for 120 min) followed by gemcitabine (1,000 mg/m² i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days; this regimen was repeated at 21-day intervals. A standard '3 + 3' phase I dose-escalation design was adopted. This study was registered with University hospital Medical Information Network (UMIN) Center in Japan, number UMIN000008415. Twelve patients were evaluable in this study. No patients developed DLTs. Recommended dose of S-1 was 80 (<1.25 m²), 100 (1.25 ≤ 1.5 m²), and 120 mg (1.5 m²≥) per day. One patient could achieve conversion to curative surgery. This phase I study was performed safely and demonstrated encouraging response.

17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.

PubMed

Martins, Reinaldo M; Maia, Maria de Lourdes S; Farias, Roberto Henrique G; Camacho, Luiz Antonio B; Freire, Marcos S; Galler, Ricardo; Yamamura, Anna Maya Yoshida; Almeida, Luiz Fernando C; Lima, Sheila Maria B; Nogueira, Rita Maria R; Sá, Gloria Regina S; Hokama, Darcy A; de Carvalho, Ricardo; Freire, Ricardo Aguiar V; Pereira Filho, Edson; Leal, Maria da Luz Fernandes; Homma, Akira

2013-04-01

To verify if the Bio-Manguinhos 17DD yellow fever vaccine (17DD-YFV) used in lower doses is as immunogenic and safe as the current formulation. Doses from 27,476 IU to 587 IU induced similar seroconversion rates and neutralizing antibodies geometric mean titers (GMTs). Immunity of those who seroconverted to YF was maintained for 10 mo. Reactogenicity was low for all groups. Young and healthy adult males (n = 900) were recruited and randomized into 6 groups, to receive de-escalating doses of 17DD-YFV, from 27,476 IU to 31 IU. Blood samples were collected before vaccination (for neutralization tests to yellow fever, serology for dengue and clinical chemistry), 3 to 7 d after vaccination (for viremia and clinical chemistry) and 30 d after vaccination (for new yellow fever serology and clinical chemistry). Adverse events diaries were filled out by volunteers during 10 d after vaccination. Volunteers were retested for yellow fever and dengue antibodies 10 mo later. Seropositivity for dengue was found in 87.6% of volunteers before vaccination, but this had no significant influence on conclusions. In young healthy adults Bio-Manguinhos/Fiocruz yellow fever vaccine can be used in much lower doses than usual. INTERNATIONAL REGISTER: ISRCTN 38082350.

An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease.

PubMed

Chen, Justin R; Buchmiller, Brett L; Khan, David A

2015-01-01

Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

SU-C-BRA-01: 18F-NaF PET/CT-Directed Dose Escalation in Stereotactic Body Radiotherapy for Spine Oligometastases From Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, L; University of Nevada, Las Vegas, Las Vegas, NV; Zhang, W

2015-06-15

Purpose: To investigate the technical feasibility of SBRT dose painting using {sup 18}F-NaF positron emission tomography (PET) scans guidance in patients with spine oligometastases from prostate cancer. Methods: As a proof of concept, six patients with 14 spine oligometastatic lesions from prostate cancer who had {sup 18}F-NaF PET/CT scan prior to treatment were retrospectively included. GTV{sub reg} was delineated according to the regular tumor boundary shown on PET and/or CT images; and GTV{sub MATV} was contoured based on a net metabolically active tumor volume (MATV) defined by 60% of the SUV{sub max} values on {sup 18}F-NaF PET images. The PTVsmore » (PTV{sub reg} and PTV{sub MATV}) were defined as respective GTVs (plus involved entire vertebral body for PTV{sub reg}) with a 3-mm isotropic expansion margin. Three 1-fraction SBRT plans using VMAT technique along with 10 MV FFF beams (Plan{sub 24Gy}, Plan{sub 24–27Gy}, and Plan{sub 24–30Gy}) were generated for each patient. All plans included a dose of 24 Gy prescribed to PTV{sub reg}. The Plan{sub 24–27Gy} and Plan{sub 24–30Gy} also included a simultaneous boost dose of 27 Gy or 30 Gy prescribed to the PTV{sub MATV}, respectively. The feasibility of 18F-NaF PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The normal tissue complication probabilities (NTCP) calculated by radiological models were also compared between the plans. Results: In all 33 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 24–27Gy} and Plan{sub 24–30Gy} had a significantly higher dose in PTV{sub MATV} than Plan{sub 24Gy} (p < 0.05), respectively, while maintaining a similar OAR sparing profile and NTCP values. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-NaF PET-guided radiation boost dose up to 30 Gy into a SBRT plan is technically feasible. The relationship between local control and normal tissue toxicity in SBRT dose painting should be validated in clinical trials.« less

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

PubMed

Martin, David E; Blum, Robert; Wilton, John; Doto, Judy; Galbraith, Hal; Burgess, Gina L; Smith, Philip C; Ballow, Charles

2007-09-01

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.

The broken escalator phenomenon. Aftereffect of walking onto a moving platform.

PubMed

Reynolds, R F; Bronstein, A M

2003-08-01

We investigated the physiological basis of the 'broken escalator phenomenon', namely the sensation that when walking onto an escalator which is stationary one experiences an odd sensation of imbalance, despite full awareness that the escalator is not going to move. The experimental moving surface was provided by a linear motor-powered sled, moving at 1.2 m/s. Sled velocity, trunk position, trunk angular velocity, EMG of the ankle flexors-extensors and foot-contact signals were recorded in 14 normal subjects. The experiments involved, initially, walking onto the stationary sled (condition Before). Then, subjects walked 20 times onto the moving sled (condition Moving), and it was noted that they increased their walking velocity from a baseline of 0.60 m/s to 0.90 m/s. After the moving trials, subjects were unequivocally warned that the platform would no longer move and asked to walk onto the stationary sled again (condition After). It was found that, despite this warning, subjects walked onto the stationary platform inappropriately fast (0.71 m/s), experienced a large overshoot of the trunk and displayed increased leg electromyographic (EMG) activity. Subjects were surprised by their own behaviour and subjectively reported that the 'broken escalator phenomenon', as experienced in urban life, felt similar to the experiment. By the second trial, most movement parameters had returned to baseline values. The findings represent a motor aftereffect of walking onto a moving platform that occurs despite full knowledge of the changing context. As such, it demonstrates dissociation between the declarative and procedural systems in the CNS. Since gait velocity was raised before foot-sled contact, the findings are at least partly explained by open-loop, predictive behaviour. A cautious strategy of limb stiffness was not responsible for the aftereffect, as revealed by no increase in muscle cocontraction. The observed aftereffect is unlike others previously reported in the literature, which occur only after prolonged continuous exposure to a sensory mismatch, large numbers of learning trials or unpredictable catch trials. The relative ease with which the aftereffect was induced suggests that locomotor adaptation may be more impervious to cognitive control than other types of motor learning.

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PubMed

Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

2016-01-01

The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. NCT01149343, Results.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.

PubMed

Holdcroft, Anita; Maze, Mervyn; Doré, Caroline; Tebbs, Susan; Thompson, Simon

2006-05-01

Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain. Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose. Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5-3.1) and 1.3 (95% confidence interval, 1.1-1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg. These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.

Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

PubMed

Dósa, Edit; Heltai, Krisztina; Radovits, Tamás; Molnár, Gabriella; Kapocsi, Judit; Merkely, Béla; Fu, Rongwei; Doolittle, Nancy D; Tóth, Gerda B; Urdang, Zachary; Neuwelt, Edward A

2017-10-03

Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PubMed

Masters, G A; Mauer, A M; Hoffman, P C; Wyka, D; Samuels, B L; Krauss, S A; Watson, S; Golomb, H; Vokes, E E

1998-06-01

We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Systemic SMAD7 Gene Therapy Increases Striated Muscle Mass and Enhances Exercise Capacity in a Dose-Dependent Manner.

PubMed

Maricelli, Joseph W; Bishaw, Yemeserach M; Wang, Bo; Du, Min; Rodgers, Buel D

2018-03-01

Striated muscle wasting occurs with a variety of disease indications, contributing to mortality and compromising life quality. Recent studies indicate that the recombinant adeno-associated virus (serotype 6) Smad7 gene therapeutic, AVGN7, enhances skeletal and cardiac muscle mass and prevents cancer-induced wasting of both tissues. This is accomplished by attenuating ActRIIb intracellular signaling and, as a result, the physiological actions of myostatin and other ActRIIb ligands. AVGN7 also enhances isolated skeletal muscle twitch force, but is unknown to improve systemic muscle function similarly, especially exercise capacity. A 2-month-long dose-escalation study was therefore conducted using 5 × 10 11 , 1 × 10 12 , and 5 × 10 12 vg/mouse and different tests of systemic muscle function. Body mass, skeletal muscle mass, heart mass, and forelimb grip strength were all increased in a dose-dependent manner, as was the fiber cross-sectional area of tibialis anterior muscles. Maximal oxygen consumption (VO 2 max), a measure of metabolic rate, was similarly enhanced during forced treadmill running, and although the total distance traveled was only elevated by the highest dose, all doses reduced the energy expenditure rate compared to control mice injected with an empty vector. Such improvements in VO 2 max are consistent with physiological cardiac hypertrophy, which is highly beneficial and a normal adaptive response to exercise. This was particularly evident at the lowest dose tested, which had minimal significant effects on skeletal muscle mass and/or function, but increased heart weight and exercise capacity. These results together suggest that AVGN7 enhances striated muscle mass and systemic muscle function. They also define minimally effective and optimal doses for future preclinical trials and toxicology studies and in turn will aid in establishing dose ranges for clinical trials.

Intra-tumoral gene delivery of feIL-2, feIFN-gamma and feGM-CSF using magnetofection as a neoadjuvant treatment option for feline fibrosarcomas: a phase-I study.

PubMed

Jahnke, A; Hirschberger, J; Fischer, C; Brill, T; Köstlin, R; Plank, C; Küchenhoff, H; Krieger, S; Kamenica, K; Schillinger, U

2007-12-01

Despite aggressive pre- or postoperative treatment, feline fibrosarcomas have a high relapse rate. In this study, a new treatment option based on immune stimulation by intra-tumoral delivery of three feline cytokine genes was performed. The objective of this phase-I dose-escalation study was to determine a safe dose for further evaluation in a subsequent phase-II trial. Twenty-five client-owned cats with clinical diagnosis of fibrosarcoma - primary tumours as well as recurrences - entered the study. Four increasing doses of plasmids coding for feIL-2, feIFN-gamma or feGM-CSF, respectively, were previously defined. In groups I, II, III and IV these doses were 15, 50, 150 and 450 microg per plasmid and a corresponding amount of magnetic nanoparticles. Two preoperative intra-tumoral injections of the magnetic DNA solution were followed by magnetofection. A group of four control cats received only surgical treatment. Side effects were registered and graded according to the VCOG-CTCAE scale and correlated to treatment. Statistical analyses included one-way anova, post hoc and Kruskal-Wallis tests. ELISA tests detecting plasma feIFN-gamma and plasma feGM-CSF were performed. One cat out of group IV (450 microg per plasmid) showed adverse events probably related to gene delivery. As these side effects were self-limiting and occurred only in one of eight cats in group IV, this dose was determined to be well tolerable. Altogether six cats developed local recurrences during a 1-year observation period. Four of these cats had been treated with dose IV. Regarding these observations, a subsequent phase-II trial including a representative amount of cats should be tested for the efficacy of dose IV as well as dose III.

Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial.

PubMed

Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Benevolo, Giulia; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Masini, Luciano; Iacobelli, Massimo; Gaidano, Gianluca; Mitsiades, Constantine; Anderson, Kenneth; Boccadoro, Mario; Richardson, Paul

2010-07-01

Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35. Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

PubMed

Feldman, Brian M; Rivard, Georges E; Babyn, Paul; Wu, John K M; Steele, MacGregor; Poon, Man-Chiu; Card, Robert T; Israels, Sara J; Laferriere, Nicole; Gill, Kulwant; Chan, Anthony K; Carcao, Manuel; Klaassen, Robert J; Cloutier, Stephanie; Price, Victoria E; Dover, Saunya; Blanchette, Victor S

2018-06-01

Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia. In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344. Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point during the study. Tailored frequency-escalated prophylaxis leads to very little arthropathy and very good health outcomes within the WHO-ICF domains, and only uses a moderate amount of expensive clotting factor as compared with standard prophylaxis protocols. Some sequelae of bleeding were observed in our cohort, and future studies should consider a more stringent protocol of escalation. This study was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund. Subsequent renewals were funded by Bayer. Copyright © 2018 Elsevier Ltd. All rights reserved.

Deep reinforcement learning for automated radiation adaptation in lung cancer.

PubMed

Tseng, Huan-Hsin; Luo, Yi; Cui, Sunan; Chien, Jen-Tzung; Ten Haken, Randall K; Naqa, Issam El

2017-12-01

To investigate deep reinforcement learning (DRL) based on historical treatment plans for developing automated radiation adaptation protocols for nonsmall cell lung cancer (NSCLC) patients that aim to maximize tumor local control at reduced rates of radiation pneumonitis grade 2 (RP2). In a retrospective population of 114 NSCLC patients who received radiotherapy, a three-component neural networks framework was developed for deep reinforcement learning (DRL) of dose fractionation adaptation. Large-scale patient characteristics included clinical, genetic, and imaging radiomics features in addition to tumor and lung dosimetric variables. First, a generative adversarial network (GAN) was employed to learn patient population characteristics necessary for DRL training from a relatively limited sample size. Second, a radiotherapy artificial environment (RAE) was reconstructed by a deep neural network (DNN) utilizing both original and synthetic data (by GAN) to estimate the transition probabilities for adaptation of personalized radiotherapy patients' treatment courses. Third, a deep Q-network (DQN) was applied to the RAE for choosing the optimal dose in a response-adapted treatment setting. This multicomponent reinforcement learning approach was benchmarked against real clinical decisions that were applied in an adaptive dose escalation clinical protocol. In which, 34 patients were treated based on avid PET signal in the tumor and constrained by a 17.2% normal tissue complication probability (NTCP) limit for RP2. The uncomplicated cure probability (P+) was used as a baseline reward function in the DRL. Taking our adaptive dose escalation protocol as a blueprint for the proposed DRL (GAN + RAE + DQN) architecture, we obtained an automated dose adaptation estimate for use at ∼2/3 of the way into the radiotherapy treatment course. By letting the DQN component freely control the estimated adaptive dose per fraction (ranging from 1-5 Gy), the DRL automatically favored dose escalation/de-escalation between 1.5 and 3.8 Gy, a range similar to that used in the clinical protocol. The same DQN yielded two patterns of dose escalation for the 34 test patients, but with different reward variants. First, using the baseline P+ reward function, individual adaptive fraction doses of the DQN had similar tendencies to the clinical data with an RMSE = 0.76 Gy; but adaptations suggested by the DQN were generally lower in magnitude (less aggressive). Second, by adjusting the P+ reward function with higher emphasis on mitigating local failure, better matching of doses between the DQN and the clinical protocol was achieved with an RMSE = 0.5 Gy. Moreover, the decisions selected by the DQN seemed to have better concordance with patients eventual outcomes. In comparison, the traditional temporal difference (TD) algorithm for reinforcement learning yielded an RMSE = 3.3 Gy due to numerical instabilities and lack of sufficient learning. We demonstrated that automated dose adaptation by DRL is a feasible and a promising approach for achieving similar results to those chosen by clinicians. The process may require customization of the reward function if individual cases were to be considered. However, development of this framework into a fully credible autonomous system for clinical decision support would require further validation on larger multi-institutional datasets. © 2017 American Association of Physicists in Medicine.

A phase I, dose-finding study of sorafenib in combination with gemcitabine and radiation therapy in patients with unresectable pancreatic adenocarcinoma: a Grupo Español Multidisciplinario en Cáncer Digestivo (GEMCAD) study.

PubMed

Aparicio, Jorge; García-Mora, Carmen; Martín, Marta; Petriz, Ma Lourdes; Feliu, Jaime; Sánchez-Santos, Ma Elena; Ayuso, Juan Ramón; Fuster, David; Conill, Carlos; Maurel, Joan

2014-01-01

Sorafenib, an oral inhibitor of B-raf, VEGFR2, and PDGFR2-beta, acts against pancreatic cancer in preclinical models. Due to the radio-sensitization activity of both sorafenib and gemcitabine, we designed a multicenter, phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy. Patients with biopsy-proven, unresectable pancreatic adenocarcinoma (based on vascular invasion detected by computed tomography) were treated with gemcitabine (300 mg/m2 i.v. weekly ×5 weeks) concurrently with radiation therapy (45 Gy in 25 fractions) and sorafenib (escalated doses in a 3+3 design, from 200 to 800 mg/day). Radiation portals included the primary tumor but not the regional lymph nodes. Patients with planning target volumes (PTV) over 500 cc were excluded. Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression. Twelve patients were included. Three patients received 200 mg/day, 6 received 400 mg/day, and 3 received 800 mg/day; PTVs ranged from 105 to 500 cc. No dose-limiting toxicities occurred. The most common grade 2 toxicities were fatigue, neutropenia, nausea, and raised serum transaminases. Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy. There were no treatment-related deaths. The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma. A dose of 800 mg/day is recommended for phase II evaluation. EudraCT 2007-003211-31 ClinicalTrials.gov 00789763.

A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.

PubMed

Hong, David S; Kurzrock, Razelle; Supko, Jeffrey G; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J; Ferguson, Deborah A; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I; Dezube, Bruce J

2012-06-15

Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2-related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. ©2012 AACR.

A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

PubMed Central

Hong, David S.; Kurzrock, Razelle; Supko, Jeffrey G.; He, Xiaoying; Naing, Aung; Wheler, Jennifer; Lawrence, Donald; Eder, Joseph Paul; Meyer, Colin J.; Ferguson, Deborah A.; Mier, James; Konopleva, Marina; Konoplev, Sergej; Andreeff, Michael; Kufe, Donald; Lazarus, Hillard; Shapiro, Geoffrey I.; Dezube, Bruce J.

2015-01-01

Purpose Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. PMID:22634319

Stereotactic ablative radiotherapy after concomitant chemoradiotherapy in non-small cell lung cancer: A TITE-CRM phase 1 trial.

PubMed

Doyen, Jérôme; Poudenx, Michel; Gal, Jocelyn; Otto, Josiane; Guerder, Caroline; Naghavi, Arash O; Gérard, Anais; Leysalle, Axel; Cohen, Charlotte; Padovani, Bernard; Ianessi, Antoine; Schiappa, Renaud; Chamorey, Emmanuel; Bondiau, Pierre-Yves

2018-05-01

Platinum based chemoradiotherapy is the standard of care for inoperable non-small cell lung cancer (NSCLC). With evidence that NSCLC can have a dose dependent response with stereotactic ablative radiotherapy (SABR), we hypothesize that a SABR boost on residual tumor treated with chemoradiotherapy could increase treatment efficacy. The purpose of this study was to determine feasibility of such an approach. A prospective phase I trial was performed including 26 patients. Time-to-event continual reassessment method (TITE-CRM) was used for dose escalation which ranged from 3 × 7 to 3 × 12 Gy for the stereotactic boost, after 46 Gy (2 Gy per day) of chemoradiotherapy. Median follow-up was of 37.1 months (1.7-60.7), and 3, 4, 3, 3, 9 and 4 patients were included at the dose levels 1, 2, 3, 4, 5 and 6, respectively. During chemoradiotherapy, 9 patients experienced grade 3 toxicity. After stereotactic radiotherapy, 1 patient experienced an esophageal fistula (with local relapse) at the 3 × 11 Gy level, and 1 patient died from hemoptysis at the 3 × 12 Gy level. The 2-year rate of local control, locoregional free survival, metastasis-free survival, and overall survival was 70.3%, 55.5%, 44.5% and 50.8%, respectively. In the treatment of NSCLC with chemoradiotherapy followed by a stereotactic boost, the safe recommended dose in our protocol was a boost dose of 3 × 11 Gy. Copyright © 2018 Elsevier B.V. All rights reserved.

In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial.

PubMed

Adotevi, O; Godet, Y; Galaine, J; Lakkis, Z; Idirene, I; Certoux, J M; Jary, M; Loyon, R; Laheurte, C; Kim, S; Dormoy, A; Pouthier, F; Barisien, C; Fein, F; Tiberghien, P; Pivot, X; Valmary-Degano, S; Ferrand, C; Morel, P; Delabrousse, E; Borg, C

2018-01-01

Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.10 6 , 8.10 6 and 12.10 6 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3 + regulatory T cells and PD-1 + T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1

PubMed Central

Ziegler, David S.; Cohn, Richard J.; McCowage, Geoffrey; Alvaro, Frank; Oswald, Cecilia; Mrongovius, Robert; White, Les

2006-01-01

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children’s Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen. PMID:16443948

Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

PubMed

Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

2007-07-01

Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy.

PubMed

Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc; Brennen, W Nathaniel; Dalrymple, Susan; Dach, Ingrid; Olesen, Claus; Gurel, Bora; Demarzo, Angelo M; Wilding, George; Carducci, Michael A; Dionne, Craig A; Møller, Jesper V; Nissen, Poul; Christensen, S Brøgger; Isaacs, John T

2012-06-27

Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis.

PubMed

Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

2010-11-01

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥ 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase > 3 × baseline and greater than the upper limit of normal range, and eight patients had serum creatinine > 33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to < 250 ng/mL. Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.

A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis

PubMed Central

Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

2010-01-01

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase >3× baseline and greater than the upper limit of normal range, and eight patients had serum creatinine >33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to <250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population. (Hepatology 2010) PMID:20814896

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.

PubMed

LoRusso, Patricia M; Infante, Jeffrey R; Kim, Kevin B; Burris, Howard A; Curt, Gregory; Emeribe, Ugochi; Clemett, Delyth; Tomkinson, Helen K; Cohen, Roger B

2017-03-06

The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors. This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m 2 or dacarbazine 1000 mg/m 2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A. A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine. The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors. ClinicalTrials.gov NCT00600496; registered 8 July 2009.

Simulated Online Adaptive MR-Guided SBRT for the Treatment of Oligometastatic Disease of the Abdomen and Central Thorax: Characterization of Potential Advantages

PubMed Central

Henke, Lauren; Kashani, Rojano; Yang, Deshan; Zhao, Tianyu; Green, Olga; Olsen, Lindsey; Rodriguez, Vivian; Wooten, H. Omar; Li, H. Harold; Hu, Yanle; Bradley, Jeffrey; Robinson, Clifford; Parikh, Parag; Michalski, Jeff; Mutic, Sasa; Olsen, Jeffrey

2017-01-01

Purpose/Objectives Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastatic or unresectable primary malignancy, although proximity of organs-at-risk (OAR) may limit delivery of sufficiently ablative dose. Magnetic resonance (MR)-based online-adaptive radiotherapy (ART) has potential to improve SBRT’s therapeutic ratio. This study characterizes potential advantages of online-adaptive MR-guided SBRT to treat oligometastatic disease of the non-liver abdomen and central thorax. Materials/Methods Ten patients treated with RT for unresectable primary or oligometastatic disease of the non-liver abdomen (n=5) or central thorax (n=5) underwent imaging throughout treatment on a clinical MR-IGRT system. SBRT plans were created based on tumor/OAR anatomy at initial CT simulation (PI) and simulated adaptive plans were created based on observed MR-image set tumor/OAR “anatomy-of-the-day” (PA). Each PA was planned under workflow constraints to simulate online-ART. Prescribed dose was 50Gy/5fractions with goal coverage of 95% PTV by 95% of the prescription, subject to hard OAR constraints. PI was applied to each MR dataset and compared to PA to evaluate changes in dose delivered to tumor/OARs, with dose escalation when possible. Results Hard OAR constraints were met for all PI based on anatomy from initial CT simulation, and all PA based on anatomy from each daily MR-image set. Application of the PI to anatomy-of-the-day caused OAR constraint violation in 19/30 cases. Adaptive planning increased PTV coverage in 21/30 cases, including 14 cases where hard OAR constraints were violated by the non-adaptive plan. For 9 PA cases, decreased PTV coverage was required to meet hard OAR constraints that would have been violated in a non-adaptive setting. Conclusions Online-adaptive MRI-guided SBRT may allow PTV dose escalation and/or simultaneous OAR sparing compared to non-adaptive SBRT. A prospective clinical trial is underway at our institution to evaluate clinical outcomes of this technique. PMID:27742541

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload.

PubMed

Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L; Tapper, Amy; Kramer, William; Porter, John B; Neufeld, Ellis J

2011-04-01

There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (C(max)) was reached within 60-90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t(1/2)) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419).

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

PubMed

Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

2013-11-19

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial.

PubMed

Wayne, Alan S; Kreitman, Robert J; Findley, Harry W; Lew, Glen; Delbrook, Cynthia; Steinberg, Seth M; Stetler-Stevenson, Maryalice; Fitzgerald, David J; Pastan, Ira

2010-03-15

Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting. Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non-Hodgkin lymphoma. All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC(50), 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 microg/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects. CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood.

Combination immunotherapy with prostate GVAX and ipilimumab: safety and toxicity.

PubMed

Karan, Dev; Van Veldhuizen, Peter

2012-06-01

Evaluation of: van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 13(5), 509 – 517 (2012). A significant interest in the development of therapeutic cancer vaccines over the last decade has led to an improvement in overall survival of cancer patients in several clinical trials. As a result, two active immunotherapy agents, sipuleucel-T and ipilimumab, have been approved by the US FDA for the treatment of prostate cancer and melanoma, respectively. GVAX(®) cellular vaccine (Cell Genesysis, Inc., CA, USA) is another active immunotherapy agent targeting prostate cancer and it has been well studied in various clinical trials. The current publication, by van den Eertwegh et al., demonstrated a combination of two active immunotherapy approaches, using GVAX and ipilimumab for the treatment of metastatic castration-resistant prostate cancer. While GVAX is designed to amplify the antitumor response specific to prostate cancer cells, ipilimumab contributes to T-cell activation. Thus, the authors presented the possibility of augmenting antitumor T-cell activity in two different ways. They successfully demonstrated a tolerable dose and safety profile of ipilimumab in combination with GVAX for patients with metastatic castration-resistant prostate cancer. However, further studies of such immunotherapy combinations and detailed analysis of their immunological effects are needed to observe clinical benefit.

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma.

PubMed

Barnard, Rebecca A; Wittenburg, Luke A; Amaravadi, Ravi K; Gustafson, Daniel L; Thorburn, Andrew; Thamm, Douglas H

2014-08-01

Autophagy is a lysosomal degradation process that may act as a mechanism of survival in a variety of cancers. While pharmacologic inhibition of autophagy with hydroxychloroquine (HCQ) is currently being explored in human clinical trials, it has never been evaluated in canine cancers. Non-Hodgkin lymphoma (NHL) is one of the most prevalent tumor types in dogs and has similar pathogenesis and response to treatment as human NHL. Clinical trials in canine patients are conducted in the same way as in human patients, thus, to determine a maximum dose of HCQ that can be combined with a standard chemotherapy, a Phase I, single arm, dose escalation trial was conducted in dogs with spontaneous NHL presenting as patients to an academic, tertiary-care veterinary teaching hospital. HCQ was administered daily by mouth throughout the trial, beginning 72 h prior to doxorubicin (DOX), which was given intravenously on a 21-d cycle. Peripheral blood mononuclear cells and biopsies were collected before and 3 d after HCQ treatment and assessed for autophagy inhibition and HCQ concentration. A total of 30 patients were enrolled in the trial. HCQ alone was well tolerated with only mild lethargy and gastrointestinal-related adverse events. The overall response rate (ORR) for dogs with lymphoma was 93.3%, with median progression-free interval (PFI) of 5 mo. Pharmacokinetic analysis revealed a 100-fold increase in HCQ in tumors compared with plasma. There was a trend that supported therapy-induced increase in LC3-II (the cleaved and lipidated form of microtubule-associated protein 1 light chain 3/LC3, which serves as a maker for autophagosomes) and SQSTM1/p62 (sequestosome 1) after treatment. The superior ORR and comparable PFI to single-agent DOX provide strong support for further evaluation via randomized, placebo-controlled trials in canine and human NHL.

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

PubMed Central

Barnard, Rebecca A; Wittenburg, Luke A; Amaravadi, Ravi K; Gustafson, Daniel L; Thorburn, Andrew; Thamm, Douglas H

2014-01-01

Autophagy is a lysosomal degradation process that may act as a mechanism of survival in a variety of cancers. While pharmacologic inhibition of autophagy with hydroxychloroquine (HCQ) is currently being explored in human clinical trials, it has never been evaluated in canine cancers. Non-Hodgkin lymphoma (NHL) is one of the most prevalent tumor types in dogs and has similar pathogenesis and response to treatment as human NHL. Clinical trials in canine patients are conducted in the same way as in human patients, thus, to determine a maximum dose of HCQ that can be combined with a standard chemotherapy, a Phase I, single arm, dose escalation trial was conducted in dogs with spontaneous NHL presenting as patients to an academic, tertiary-care veterinary teaching hospital. HCQ was administered daily by mouth throughout the trial, beginning 72 h prior to doxorubicin (DOX), which was given intravenously on a 21-d cycle. Peripheral blood mononuclear cells and biopsies were collected before and 3 d after HCQ treatment and assessed for autophagy inhibition and HCQ concentration. A total of 30 patients were enrolled in the trial. HCQ alone was well tolerated with only mild lethargy and gastrointestinal-related adverse events. The overall response rate (ORR) for dogs with lymphoma was 93.3%, with median progression-free interval (PFI) of 5 mo. Pharmacokinetic analysis revealed a 100-fold increase in HCQ in tumors compared with plasma. There was a trend that supported therapy-induced increase in LC3-II (the cleaved and lipidated form of microtubule-associated protein 1 light chain 3/LC3, which serves as a maker for autophagosomes) and SQSTM1/p62 (sequestosome 1) after treatment. The superior ORR and comparable PFI to single-agent DOX provide strong support for further evaluation via randomized, placebo-controlled trials in canine and human NHL. PMID:24991836

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours.

PubMed

Weihrauch, Martin R; Richly, Heike; von Bergwelt-Baildon, Michael S; Becker, Hans Jiro; Schmidt, Manuel; Hacker, Ulrich T; Shimabukuro-Vornhagen, Alexander; Holtick, Udo; Nokay, Bahar; Schroff, Matthias; Wittig, Burghardt; Scheulen, Max E

2015-01-01

This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

PubMed Central

Fouladi, Maryam; Park, Julie R.; Stewart, Clinton F.; Gilbertson, Richard J.; Schaiquevich, Paula; Sun, Junfeng; Reid, Joel M.; Ames, Matthew M.; Speights, Roseanne; Ingle, Ashish M.; Zwiebel, James; Blaney, Susan M.; Adamson, Peter C.

2010-01-01

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults. PMID:20606092

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI‐1 study

PubMed Central

Ring, Arne; Morris, Tom; Wozniak, Marcin; Sullo, Nikol; Dott, William; Verheyden, Veerle; Kumar, Tracy; Brunskill, Nigel; Vaja, Rakesh

2016-01-01

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, C max 189.4 ng ml−1 and t 1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID:27779776

Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

PubMed

Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

2013-09-01

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.

Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dosemore » at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.« less

Combined MTOR and autophagy inhibition

PubMed Central

Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O’Dwyer, Peter J; Amaravadi, Ravi K

2014-01-01

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted. PMID:24991838

SU-D-BRB-06: Treating Glioblastoma Multiforme (GBM) as a Chronic Disease: Implication of Temporal-Spatial Dose Fractionation Optimization Including Cancer Stem Cell Dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, V; Nguyen, D; Pajonk, F

Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to exploremore » the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work is supported by the NSF Graduate Research Fellowship (DGE-1144087)« less

TH-CD-207A-12: Impacts of Inter- and Intra-Fractional Organ Motion for High-Risk Prostate Cancer Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hassan Rezaeian, N; Chi, Y; Zhou, Y

2016-06-15

Purpose: We are conducting a clinical trial on stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. Doses to three targets, prostate, intra-prostatic lesion, and pelvic lymph node (PLN) region, are escalated to three different levels via simultaneous integrated boost technique. Inter-/intra-fractional organ motions deteriorate planned dose distribution. This study aims at developing a dose reconstruction system to comprehensively understand the impacts of organ motion in our clinical trial. Methods: A 4D dose reconstruction system has been developed for this study. Using a GPU-based Monte-Carlo dose engine and delivery log file, the system is able to reconstruct dose on staticmore » or dynamic anatomy. For prostate and intra-prostatic targets, intra-fractional motion is the main concern. Motion trajectory acquired from Calypso in previously treated SBRT patients were used to perform 4D dose reconstructions. For pelvic target, inter-fractional motion is one concern. Eight patients, each with four cone beam CTs, were used to derive fractional motion. The delivered dose was reconstructed on the deformed anatomy. Dosimetric parameters for delivered dose distributions of the three targets were extracted and compared with planned levels. Results: For prostate intra-fractional motion, the mean 3D motion amplitude during beam delivery ranged from 1.5mm to 5.0mm and the average among all patients was 2.61mm. Inter-fractional motion for the PLN target was more significant. The average amplitude among patients was 4mm with the largest amplitude up to 9.6mm. The D95% deviation from planned level for prostate PTVs and GTVs are on average less than<0.1% and this deviation for intra-prostatic lesion PTVs and GTVs were more prominent. The dose at PLN was significantly affected with D{sub 95}% reduced by up to 44%. Conclusion: Intra-/inter-fractional organ motion is a concern for high-risk prostate SBRT, particularly for the PLN target. Our dose reconstruction approach can also serve as the basis to guide treatment adaptation.« less

Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies.

PubMed

Boyle, John; Craciunescu, Oana; Steffey, Beverly; Cai, Jing; Chino, Junzo

2014-11-01

To evaluate the safety of dose escalated radiotherapy using a simultaneous integrated boost technique in patients with locally advanced gynecological malignancies. Thirty-nine women with locally advanced gynecological malignancies were treated with intensity modulated radiation therapy utilizing a simultaneous integrated boost (SIB) technique for gross disease in the para-aortic and/or pelvic nodal basins, sidewall extension, or residual primary disease. Women were treated to 45Gy in 1.8Gy fractions to elective nodal regions. Gross disease was simultaneously treated to 55Gy in 2.2Gy fractions (n=44 sites). An additional sequential boost of 10Gy in 2Gy fractions was delivered if deemed appropriate (n=29 sites). Acute and late toxicity, local control in the treated volumes (LC), overall survival (OS), and distant metastases (DM) were assessed. All were treated with a SIB to a dose of 55Gy. Twenty-four patients were subsequently treated with a sequential boost to a median dose of 65Gy. Median follow-up was 18months. Rates of acute>grade 2 gastrointestinal (GI), genitourinary (GU), and hematologic (heme) toxicities were 2.5%, 0%, and 30%, respectively. There were no grade 4 acute toxicities. At one year, grade 1-2 late GI toxicities were 24.5%. There were no grade 3 or 4 late GI toxicities. Rates of grade 1-2 late GU toxicities were 12.7%. There were no grade 3 or 4 late GU toxicities. Dose escalated radiotherapy using a SIB results in acceptable rates of acute toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Vaginal dose de-escalation in image guided adaptive brachytherapy for locally advanced cervical cancer.

PubMed

Mohamed, Sandy; Lindegaard, Jacob Christian; de Leeuw, Astrid A C; Jürgenliemk-Schulz, Ina; Kirchheiner, Kathrin; Kirisits, Christian; Pötter, Richard; Tanderup, Kari

2016-09-01

Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD). Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV⩾85Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85Gy. The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points (p<0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4±4Gy EQD2 (p<0.001), while doses to bladder and rectum (D 2cm 3 ) were reduced by 2±2Gy and 3±2Gy, respectively (p<0.001). VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials.

PubMed

Glass, Jonathan D; Hertzberg, Vicki S; Boulis, Nicholas M; Riley, Jonathan; Federici, Thais; Polak, Meraida; Bordeau, Jane; Fournier, Christina; Johe, Karl; Hazel, Tom; Cudkowicz, Merit; Atassi, Nazem; Borges, Lawrence F; Rutkove, Seward B; Duell, Jayna; Patil, Parag G; Goutman, Stephen A; Feldman, Eva L

2016-07-26

To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Intraspinal transplantation of human spinal cord-derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues. © 2016 American Academy of Neurology.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients.

PubMed

Marvaso, Giulia; Jereczek-Fossa, Barbara A; Vischioni, Barbara; Ciardo, Delia; Giandini, Tommaso; Hasegawa, Azusa; Cattani, Federica; Carrara, Mauro; Ciocca, Mario; Bedini, Nice; Villa, Sergio; Morlino, Sara; Russo, Stefania; Zerini, Dario; Colangione, Sarah Pia; Panaino, Costanza Maria Vittoria; Fodor, Cristiana; Santoro, Luigi; Pignoli, Emanuele; Valvo, Francesca; Valdagni, Riccardo; De Cobelli, Ottavio; Orecchia, Roberto

2017-05-12

Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study.

PubMed

Thomas, A L; Cox, G; Sharma, R A; Steward, W P; Shields, F; Jeyapalan, K; Muller, S; O'Byrne, K J

2000-12-01

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis.

Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.

PubMed

Howlett, Christina; Snedecor, Sonya J; Landsburg, Daniel J; Svoboda, Jakub; Chong, Elise A; Schuster, Stephen J; Nasta, Sunita Dwivedy; Feldman, Tatyana; Rago, Allison; Walsh, Kristy M; Weber, Scott; Goy, Andre; Mato, Anthony

2015-08-01

'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary. © 2015 John Wiley & Sons Ltd.

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

PubMed

Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-hour Infusion With and Without G-CSF in a 14-day Cycle in Patients with Advanced Solid Tumors

PubMed Central

Cohen, Roger B.; Jones, Suzanne F.; Aggarwal, Charu; von Mehren, Margaret; Cheng, Jonathan; Spigel, David R.; Greco, F. Anthony; Mariani, Mariangela; Rocchetti, Maurizio; Ceruti, Roberta; Comis, Silvia; Laffranchi, Bernard; Moll, Jurgen; Burris, Howard A.

2009-01-01

Purpose This study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the intravenous pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors. Experimental Design In Part 1, patients received escalating doses of danusertib (24-h infusion every 14 days) without filgrastim (G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was performed in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3). Results Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose limiting toxicity in Part 1 without G-CSF. Most other adverse events were grade 1–2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The MTD without G-CSF is 500 mg/m2. The recommended phase 2 dose (RP2D) in Part 2 with G-CSF is 750 mg/m2. Danusertib demonstrated dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18–26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline. Conclusions Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of anti-tumor activity, including a PR and several occurrences of prolonged stable disease (SD), was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. PMID:19825950

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

PubMed

Yoh, Kiyotaka; Doi, Toshihiko; Ohmatsu, Hironobu; Kojima, Takashi; Takahashi, Hideaki; Zenke, Yoshitaka; Wacheck, Volker; Enatsu, Sotaro; Nakamura, Takashi; Turner, Kellie; Uenaka, Kazunori

2016-10-01

Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

PubMed

Walsh, Stephen R; Wilck, Marissa B; Dominguez, David J; Zablowsky, Elise; Bajimaya, Shringkhala; Gagne, Lisa S; Verrill, Kelly A; Kleinjan, Jane A; Patel, Alka; Zhang, Ying; Hill, Heather; Acharyya, Aruna; Fisher, David C; Antin, Joseph H; Seaman, Michael S; Dolin, Raphael; Baden, Lindsey R

2013-06-15

Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. NCT00565929.

Phase I Study of Preoperative Chemoradiation With S-1 and Oxaliplatin in Patients With Locally Advanced Resectable Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Yong Sang; Lee, Jae-Lyun; Park, Jin Hong

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m{sup 2}/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1-14 and 22-35. The initial dose of S-1 was 50 mg/m{supmore » 2}/day, gradually increasing to 60, 70, and 80 mg/m{sup 2}/day. Surgery was performed within 6 {+-} 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m{sup 2}/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m{sup 2}/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing.« less

The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills?

PubMed

Sridharan, Prasanna; Chamberlain, Ronald S

2013-12-01

Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the context of an underlying infectious process, and is associated with high rates of morbidity and mortality, particularly when initial therapy is delayed. Numerous biomarkers, including but not limited to cytokines (interleukins-2 and -6 [IL-2, IL-6] and tumor necrosis factor-α [TNF-α]), leukotrienes, acute-phase proteins (C-reactive protein [CRP]), and adhesion molecules, have been evaluated and rejected as unsuitable for the diagnosis of sepsis, predicting its severity, and guiding its treatment. Most recently, procalcitonin (PCT) has been suggested as a novel biomarker that may be useful in guiding therapeutic decision making in the management of sepsis. This article assesses critically the published literature on the clinical utility of PCT concentrations for guiding the treatment of sepsis in adult patients. A comprehensive search of all published studies of the use of serum concentrations of PCT to guide the treatment of sepsis in adult patients (1996 to 2011) was conducted with PubMed and Google Scholar. The search focused on the value of PCT concentrations to guide the diagnosis, prognosis, monitoring, and escalation and de-escalation of antbiotic therapy in these patients. Keywords searched included "procalcitonin," "sepsis," "sepsis biomarker," "sepsis diagnosis," "sepsis prognosis," "sepsis mortality," "antibiotic escalation," "antibiotic de-escalation," "antibiotic duration," and "antimicrobial stewardship." Forty-six trials evaluating the efficacy of PCT concentrations in diagnosing sepsis have been published, with 39 of these trials yielding positive results and 7 yielding negative results. Wanner et al. published the largest study (n=405) demonstrating that peak PCT concentrations occur early after injury in both patients with sepsis and those with multiple organ dysfunction syndrome (MODS). Among 17 trials assessing the prognostic value of PCT concentrations with regard to clinical outcome and morbidity, 12 trials yielded positive results and five showed negative or equivocal results. Reith et al. published the largest study of the prognostic use of PCT concentrations (n=246), demonstrating that median PCT values on post-operative days (POD) one, four, and 10 were predictive of mortality in patients with abdominal sepsis (p<0.01). Among 14 trials of the utility of PCT concentrations for establishing an infectious cause of sepsis, 13 yielded positive results and only one yielded negative results. The largest study of this use of PCT concentrations, conducted by Baykut et al. (n=400), evaluated these concentrations in post-operative patients with infection, and demonstrated that concentrations of PCT remained elevated until POD 4, with a second increase observed between POD 4 and POD 6. In uninfected patients, PCT concentrations began to decrease on POD 2. Only a single study has assessed the utility of PCT concentrations in guiding the escalation of antibiotic therapy, and its results were negative. Specifically, Jensen et al. (n=1,200) compared a PCT-guided antibiotic escalation strategy with the standard of care for sepsis and found no difference in outcomes. They also found that the PCT group had a longer average stay in the intensive care unit (ICU), greater rates of mechanical ventilation, and a decreased estimated glomerular filtration rate (eGFR). Among four trials focusing on PCT concentrations and antibiotic de-escalation, all showed positive results with the measurement of PCT concentrations. The largest such study, by Bouadma et al. (n=621), demonstrated a four-day decrease in antibiotic duration when PCT concentrations were used to guide therapy relative to the study arm given the standard of care, with no increase in mortality (p=0.003). The diagnostic value of serum PCT concentrations for discriminating among SIRS, sepsis, severe sepsis, and septic shock remains to be established. Although higher PCT concentrations suggest a systemic bacterial infection as opposed to a viral, fungal, or inflammatory etiology of sepsis, serum PCT concentrations do not correlate with the severity of sepsis or with mortality. At present, PCT concentrations are solely investigational with regard to determining the timing and appropriateness of escalation of antimicrobial therapy in sepsis. Nevertheless, serum PCT concentrations have established utility in monitoring the clinical response to medical and surgical therapy for sepsis, and in surveillance for the development of sepsis in burn and ICU patients, and may have a role in guiding the de-escalation of antibiotic therapy.

Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.

PubMed

Nakamura, Toshimichi; Toshimoto, Kota; Lee, Wooin; Imamura, Chiyo K; Tanigawara, Yusuke; Sugiyama, Yuichi

2018-06-19

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET-1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

PubMed

Takahashi, Aki; Lee, Ray X; Iwasato, Takuji; Itohara, Shigeyoshi; Arima, Hiroshi; Bettler, Bernhard; Miczek, Klaus A; Koide, Tsuyoshi

2015-04-22

Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons. Copyright © 2015 the authors 0270-6474/15/356452-12$15.00/0.

High-dose octreotide acetate for management of gastroenteropancreatic neuroendocrine tumors.

PubMed

Chadha, Manpreet K; Lombardo, Jeffrey; Mashtare, Terry; Wilding, Gregory E; Litwin, Alan; Raczyk, Cheryl; Gibbs, John F; Kuvshinoff, Boris; Javle, Milind M; Iyer, Renuka V

2009-10-01

Long-acting sandostatin (S-LAR; octreotide acetate) is well tolerated and effective for symptom control and possibly disease control in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We undertook a retrospective analysis to study the efficacy and tolerability of higher doses (more than 20-30 mg/month) of S-LAR in GEP-NETs. With IRB approval, charts of all patients with GEP-NET who received S-LAR between June 2002 to September 2007 at Roswell Park Cancer Institute were reviewed and their data analyzed. Fifty-four patients with GEP-NET received S-LAR; thirty required dose escalation. Patients received a median of 5 doses of S-LAR at conventional dose followed by up-titration of the dose for symptom control (20) and radiological progression (17). Median high dose of S-LAR was 40 mg (range: 40-90 mg) with a median of 8.5 high doses received. No treatment related toxicities were seen. The estimated 1-year survival for patients on conventional dose alone was 0.77 (95% CI of 0.50 to 0.91) and those on high-dose was 0.88 (95% CI of 0.68 to 0.96) (p=0.4777) while median time to any other intervention was 2.9 months versus 17.7 months (p=0.12). Dose escalation of S-LAR is well tolerated and may provide longer disease control.

WE-G-BRB-01: The Importance of NIH Funding in Innovation in Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deye, J.

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

WE-G-BRB-03: Innovating the Delivery of Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bortfeld, T.

2015-06-15

Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview willmore » be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH.« less

Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer.

PubMed

Shinoto, Makoto; Yamada, Shigeru; Yasuda, Shigeo; Imada, Hiroshi; Shioyama, Yoshiyuki; Honda, Hiroshi; Kamada, Tadashi; Tsujii, Hirohiko; Saisho, Hiromitsu

2013-01-01

The authors evaluated the tolerance and efficacy of carbon-ion radiotherapy (CIRT) as a short-course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue. Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short-course, dose-escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT. The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty-one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5-year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively. Preoperative, short-course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity. Copyright © 2012 American Cancer Society.

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

What is the added value of ultrasound joint examination for monitoring synovitis in rheumatoid arthritis and can it be used to guide treatment decisions? A systematic review and cost-effectiveness analysis.

PubMed

Simpson, Emma; Hock, Emma; Stevenson, Matt; Wong, Ruth; Dracup, Naila; Wailoo, Allan; Conaghan, Philip; Estrach, Cristina; Edwards, Christopher; Wakefield, Richard

2018-04-01

Synovitis (inflamed joint synovial lining) in rheumatoid arthritis (RA) can be assessed by clinical examination (CE) or ultrasound (US). To investigate the added value of US, compared with CE alone, in RA synovitis in terms of clinical effectiveness and cost-effectiveness. Electronic databases including MEDLINE, EMBASE and the Cochrane databases were searched from inception to October 2015. A systematic review sought RA studies that compared additional US with CE. Heterogeneity of the studies with regard to interventions, comparators and outcomes precluded meta-analyses. Systematic searches for studies of cost-effectiveness and US and treatment-tapering studies (not necessarily including US) were undertaken. A model was constructed that estimated, for patients in whom drug tapering was considered, the reduction in costs of disease-modifying anti-rheumatic drugs (DMARDs) and serious infections at which the addition of US had a cost per quality-adjusted life-year (QALY) gained of £20,000 and £30,000. Furthermore, the reduction in the costs of DMARDs at which US becomes cost neutral was also estimated. For patients in whom dose escalation was being considered, the reduction in number of patients escalating treatment and in serious infections at which the addition of US had a cost per QALY gained of £20,000 and £30,000 was estimated. The reduction in number of patients escalating treatment for US to become cost neutral was also estimated. Fifty-eight studies were included. Two randomised controlled trials compared adding US to a Disease Activity Score (DAS)-based treat-to-target strategy for early RA patients. The addition of power Doppler ultrasound (PDUS) to a Disease Activity Score 28 joints-based treat-to-target strategy in the Targeting Synovitis in Early Rheumatoid Arthritis (TaSER) trial resulted in no significant between-group difference for change in Disease Activity Score 44 joints (DAS44). This study found that significantly more patients in the PDUS group attained DAS44 remission ( p  = 0.03). The Aiming for Remission in Rheumatoid Arthritis (ARCTIC) trial found that the addition of PDUS and grey-scale ultrasound (GSUS) to a DAS-based strategy did not produce a significant between-group difference in the primary end point: composite DAS of < 1.6, no swollen joints and no progression in van der Heijde-modified total Sharp score (vdHSS). The ARCTIC trial did find that the erosion score of the vdHS had a significant advantage for the US group ( p  = 0.04). In the TaSER trial there was no significant group difference for erosion. Other studies suggested that PDUS was significantly associated with radiographic progression and that US had added value for wrist and hand joints rather than foot and ankle joints. Heterogeneity between trials made conclusions uncertain. No studies were identified that reported the cost-effectiveness of US in monitoring synovitis. The model estimated that an average reduction of 2.5% in the costs of biological DMARDs would be sufficient to offset the costs of 3-monthly US. The money could not be recouped if oral methotrexate was the only drug used. Heterogeneity of the trials precluded meta-analysis. Therefore, no summary estimates of effect were available. Additional costs and health-related quality of life decrements, relating to a flare following tapering or disease progression, have not been included. The feasibility of increased US monitoring has not been assessed. Limited evidence suggests that US monitoring of synovitis could provide a cost-effective approach to selecting RA patients for treatment tapering or escalation avoidance. Considerable uncertainty exists for all conclusions. Future research priorities include evaluating US monitoring of RA synovitis in longitudinal clinical studies. This study is registered as PROSPERO CRD42015017216. The National Institute for Health Research Health Technology Assessment programme.

Safety, tolerability, and immunogenicity of a recombinant toxic shock syndrome toxin (rTSST)-1 variant vaccine: a randomised, double-blind, adjuvant-controlled, dose escalation first-in-man trial.

PubMed

Schwameis, Michael; Roppenser, Bernhard; Firbas, Christa; Gruener, Corina S; Model, Nina; Stich, Norbert; Roetzer, Andreas; Buchtele, Nina; Jilma, Bernd; Eibl, Martha M

2016-09-01

Staphylococcal toxic shock syndrome is a superantigen-driven potentially life-threatening disease affecting mainly young and otherwise healthy individuals. Currently, no specific treatment or preventive measure is available. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers. In this randomised, double-blind, adjuvant-controlled, dose-escalation first-in-human trial, healthy adults aged 18-64 years were enrolled from the Medical University of Vienna, Austria. Participants were randomly assigned (2:1 and 3:1) by block randomisation (block sizes of three and 12) to receive increasing doses of rTSST-1v (100 ng to 30 μg) or the adjuvant comparator aluminium hydroxide (Al(OH)3) (200 μg, 600 μg, or 1 mg). Investigators and participants were masked to group allocation. The per-protocol population received a booster immunisation 42 days after the first vaccination. The primary endpoint was safety and tolerability of rTSST-1v. The per-protocol population included all participants who had adhered to the study protocol without any major protocol deviations. The per-protocol population was the primary analysis population for immunogenicity. The trial is registered with EudraCT, number 2013-003716-50, and ClinicalTrials.gov, number NCT02340338. Between Aug 19, 2014, and April 14, 2015, 46 participants were enrolled (safety population), of whom three were assigned to cohort 1 (two to receive 100 ng rTSST-1v and one to receive 200 μg Al(OH)3), three to cohort 2 (two to receive 300 ng rTSST-1v and one to receive 600 μg Al(OH)3), four to cohort 3 (three to receive 1 μg rTSST-1v and one to receive 1 mg Al(OH)3), 12 to cohort 4 (nine to receive 3 μg rTSST-1v and three to receive 1 mg Al(OH)3), 12 to cohort 5 (nine to receive 10 μg rTSST-1v and three to receive 1 mg Al(OH)3), and 12 to cohort 6 (nine to receive 300 μg rTSST-1v and three to receive 1 mg Al(OH)3). 45 participants (98%) were included in the per-protocol population. rTSST-1v had a good safety profile, and no vaccination-related severe or serious adverse events occurred. Adverse event rates were similar between participants who received rTSST-1v and those who received placebo (26 [76%] vs 10 [83%]; p=0·62) independent of pre-existing TSST-1 immunity. rTSST-1v was safe, well-tolerated, and immunogenic. This study represents an important step in vaccine development to prevent or treat a potentially lethal disease. Biomedizinische Forschungs GmbH. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

PubMed Central

Lee, Nancy Y.; Mechalakos, James G.; Nehmeh, Sadek; Lin, Zhixiong; Squire, Olivia D.; Cai, Shangde; Chan, Kelvin; Zanzonico, Pasquale B.; Greco, Carlo; Ling, Clifton C.; Humm, John L.; Schöder, Heiko

2010-01-01

Purpose Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTVh) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTVh increases the tumor control probability. This study examined the feasibility of fluorine-18–labeled fluoromisonidazole positron emission tomography/computed tomography (18F-FMISO PET/CT)–guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. Methods and Materials 18F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate 18F-FMISO PET/CT-guided IMRT plans. Results The heterogeneous distribution of 18F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18F-FMISO PET/CT–guided IMRT for 10 HNC patients achieved 84 Gy to the GTVh and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTVh for 2 patients and were successful in 1, with normal tissue sparing. Conclusion It was feasible to dose escalate the GTVh to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients. PMID:17869020

Safety and Immunogenicity of Heterologous Prime-Boost Immunisation with Plasmodium falciparum Malaria Candidate Vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in Healthy Gambian and Kenyan Adults

PubMed Central

Kimani, Domtila; Jagne, Ya Jankey; Sheehy, Susanne H.; Bliss, Carly M.; Duncan, Christopher J. A.; Collins, Katharine A.; Garcia Knight, Miguel A.; Kimani, Eva; Anagnostou, Nicholas A.; Berrie, Eleanor; Moyle, Sarah; Gilbert, Sarah C.; Spencer, Alexandra J.; Soipei, Peninah; Mueller, Jenny; Okebe, Joseph; Colloca, Stefano; Cortese, Riccardo; Viebig, Nicola K.; Roberts, Rachel; Gantlett, Katherine; Lawrie, Alison M.; Nicosia, Alfredo; Imoukhuede, Egeruan B.; Bejon, Philip; Urban, Britta C.; Flanagan, Katie L.; Ewer, Katie J.; Chilengi, Roma; Hill, Adrian V. S.; Bojang, Kalifa

2013-01-01

Background Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI). Methodology We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns. Results ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC). Conclusions ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted. Trial Registration Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430 PMID:23526949

First-in-human testing of a wirelessly controlled drug delivery microchip.

PubMed

Farra, Robert; Sheppard, Norman F; McCabe, Laura; Neer, Robert M; Anderson, James M; Santini, John T; Cima, Michael J; Langer, Robert

2012-02-22

The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222