Patient-reported outcomes to assess the efficacy of extended-release guaifenesin for the treatment of acute respiratory tract infection symptoms.

PubMed

Albrecht, Helmut; Vernon, Margaret; Solomon, Gail

2012-12-27

Guaifenesin is a component of medicines used to improve symptoms associated with upper respiratory tract infections. Patient-reported outcome instruments are valuable for evaluating symptom improvements; however, a validated tool to assess efficacy of mucoactive drugs does not exist. We compared the efficacy of extended-release guaifenesin with placebo for treatment of symptoms of upper respiratory tract infection using subjective efficacy assessments in a pilot study and confirmed precision of assessments in a validation study. The pilot study was a randomized, double-blind study where patients were dosed with either 1200 mg extended-release guaifenesin (n = 188) or placebo (n = 190), every 12 hours for 7 days. Efficacy was assessed using subjective measures including the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and the Wisconsin Upper Respiratory Symptom Survey. End-of-study assessments were completed by patients and investigator. The validation study consisted of two phases. In Phase I, subjects completed interviews to gather evidence to support the content validity of the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and Patient's End-of-Treatment Assessment. Phase II examined the psychometric properties of assessments evaluated in Phase I of the validation study using data from the pilot study. Subjective measures of efficacy at Day 4 showed the most prominent difference between treatment groups, in favor of guaifenesin. The 8-symptom related questions (SUM8) in the Daily Cough and Phlegm Diary, analyzed as a composite score appeared to be the strongest candidate endpoint for further evaluation. Results from the interviews in Phase I supported the content of the assessments which were validated during Phase II. Treatments were well tolerated. Results from the clinical pilot and validation studies showed that the SUM8 diary scores were robust and reliable for use as efficacy endpoints in studies of mucoactive drugs. The study was registered with clinicaltrials.gov (NCT01046136).

Patient-reported outcomes to assess the efficacy of extended-release guaifenesin for the treatment of acute respiratory tract infection symptoms

PubMed Central

2012-01-01

Background Guaifenesin is a component of medicines used to improve symptoms associated with upper respiratory tract infections. Patient-reported outcome instruments are valuable for evaluating symptom improvements; however, a validated tool to assess efficacy of mucoactive drugs does not exist. We compared the efficacy of extended-release guaifenesin with placebo for treatment of symptoms of upper respiratory tract infection using subjective efficacy assessments in a pilot study and confirmed precision of assessments in a validation study. Methods The pilot study was a randomized, double-blind study where patients were dosed with either 1200 mg extended-release guaifenesin (n = 188) or placebo (n = 190), every 12 hours for 7 days. Efficacy was assessed using subjective measures including the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and the Wisconsin Upper Respiratory Symptom Survey. End-of-study assessments were completed by patients and investigator. The validation study consisted of two phases. In Phase I, subjects completed interviews to gather evidence to support the content validity of the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and Patient’s End-of-Treatment Assessment. Phase II examined the psychometric properties of assessments evaluated in Phase I of the validation study using data from the pilot study. Results Subjective measures of efficacy at Day 4 showed the most prominent difference between treatment groups, in favor of guaifenesin. The 8-symptom related questions (SUM8) in the Daily Cough and Phlegm Diary, analyzed as a composite score appeared to be the strongest candidate endpoint for further evaluation. Results from the interviews in Phase I supported the content of the assessments which were validated during Phase II. Treatments were well tolerated. Conclusions Results from the clinical pilot and validation studies showed that the SUM8 diary scores were robust and reliable for use as efficacy endpoints in studies of mucoactive drugs. Trial registration The study was registered with clinicaltrials.gov (NCT01046136). PMID:23270519

Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.

PubMed

Boonstra, P S; Braun, T M; Taylor, J M G; Kidwell, K M; Bellile, E L; Daignault, S; Zhao, L; Griffith, K A; Lawrence, T S; Kalemkerian, G P; Schipper, M J

2017-07-01

Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping. © The Author 2017. 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.

Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.

PubMed

Overman, Michael J; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D; Kopetz, Scott

2016-10-11

Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy.

PubMed

Awada, A; Dirix, L; Manso Sanchez, L; Xu, B; Luu, T; Diéras, V; Hershman, D L; Agrapart, V; Ananthakrishnan, R; Staroslawska, E

2013-01-01

Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

S-1 chemotherapy and intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with node-positive gastric cancer: a phase I/II study.

PubMed

Wang, X; Zhao, D B; Yang, L; Chi, Y; Tang, Y; Li, N; Wang, S L; Song, Y W; Liu, Y P; Liu, W Y; Ren, H; Zhang, T; Wang, J Y; Chen, X S; Fang, H; Wang, W H; Li, Y X; Jin, J

2018-02-06

This phase I/II clinical trial investigated S-1 administered with intensity-modulated radiotherapy (IMRT) as adjuvant therapy for node-positive gastric cancer. Patients had undergone radical resection and D1/D2 lymph node dissection. In phase I, patients received adjuvant chemoradiotherapy of IMRT (45 Gy in 25 fractions) with concurrent S-1 administered on a dose-escalation schedule to determine the recommended dose (RD). In phase II, the safety and efficacy of the RD of S-1 combined with IMRT were assessed. We consecutively enrolled 73 patients (56 men; median age, 53 years; range, 29-73 years) and the phase I portion of the study included 27 patients. The RD of S-1 administered concomitantly with IMRT was 80 mg m -2  day -1 orally, twice daily. The phase II analysis included 52 patients (46 new patients plus 6 from phase I). 8 patients (15.4%) developed grade 3 or 4 toxicities. There were 21 recurrence events and 15 deaths (1 bowel obstruction, 14 gastric cancer). Three-year disease-free survival and overall survival were 62.2% (95% confidence interval (CI), 48.5-75.9) and 70.0% (95% CI, 56.3-83.7), respectively. The median time to recurrence was 17.5 months (range, 3.8-42.0). The median time from recurrence to death was 7.0 months (range, 1.5-28.7). S-1 combined with IMRT adjuvant chemoradiotherapy is safe and efficacious for advanced gastric cancer.

Phase II Clinical Trial of Intraoral Grafting of Human Tissue Engineered Oral Mucosa

DTIC Science & Technology

2017-10-01

experimental arm subject in the small defect study. A protocol amendment in early 2017revised the study inclusionary criteria to include all non ...construed as an official Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE...group phase II study to assess the safety and efficacy for use of human EVPOME for soft tissue intraoral grafting procedures compared to the “gold

Sphingosine 1-phosphate receptor modulators in multiple sclerosis.

PubMed

Subei, Adnan M; Cohen, Jeffrey A

2015-07-01

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.

Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin

PubMed Central

Overman, Michael J.; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S.; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T.; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D.; Kopetz, Scott

2016-01-01

Purpose Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Conclusions Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker. PMID:27542211

Long-Term Safety and Efficacy of Fulranumab in Patients With Moderate-to-Severe Osteoarthritis Pain: A Phase II Randomized, Double-Blind, Placebo-Controlled Extension Study.

PubMed

Sanga, Panna; Katz, Nathaniel; Polverejan, Elena; Wang, Steven; Kelly, Kathleen M; Haeussler, Juergen; Thipphawong, John

2017-04-01

To evaluate the long-term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate-to-severe chronic osteoarthritis (OA). In this phase II double-blind, placebo-controlled extension study, patients who were randomized in equal proportions to receive subcutaneous doses of either placebo or fulranumab (1 mg every 4 weeks, 3 mg every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks) in the 12-week double-blind efficacy phase and who completed this double-blind efficacy phase were eligible to continue the dosage throughout a 92-week double-blind extension phase, followed by a 24-week posttreatment follow-up period. Safety assessments included evaluation of treatment-emergent adverse events (TEAEs), pre-identified AEs of interest, and joint replacements. Efficacy assessments included changes from baseline to the end of the double-blind extension phase in scores on the patient's global assessment and the pain and physical function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index. Overall, 401 of the 423 patients who completed the 12-week double-blind efficacy phase entered the extension study. Long-term sustained improvements were observed in all efficacy parameters following fulranumab treatment (1 mg every 4 weeks, 3 mg every 4 weeks, and 10 mg every 8 weeks) as compared with placebo. Similar percentages of patients in both groups experienced TEAEs (88% taking placebo and 91% taking fulranumab; all phases). Across all fulranumab groups, arthralgia (21%) and OA (18%) (e.g., exacerbation of OA pain) were the most common TEAEs. The most common serious TEAEs were the requirement for knee (10%) and hip (7%) arthroplasty, with 80% occurring during the posttreatment follow-up period. Neurologic-related TEAEs (28%; all phases) were generally mild-to-moderate. Overall, 81 joint replacements were performed in 71 patients (8 [11%] receiving placebo and 63 [89%] receiving fulranumab); 15 patients (21%) had rapid progression of OA (RPOA). All cases of RPOA occurred in fulranumab-treated patients who were concurrently receiving nonsteroidal antiinflammatory drugs and occurred in joints with preexisting OA. Long-term treatment with fulranumab was generally well-tolerated and efficacious. RPOA was observed as a safety signal. Future studies are warranted to demonstrate whether the risk of RPOA can be reduced in patients taking fulranumab. © 2016, American College of Rheumatology.

Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

NASA Technical Reports Server (NTRS)

Das, H.; Daniels, V. R.; Vaksman, Z.; Boyd, J. L.; Buckey, J. C.; Locke, J. P.; Putcha, L.

2007-01-01

Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training, selection of clinical research operations contractor, data capturing and management, and annual reporting of results to FDA were successfully completed. Protocol 002-A was completed and sample and data analysis is currently in progress. Protocol 002-B is currently in progress at Dartmouth Hitchcock Medical Center and Protocol 002-C has been submitted to the FDA and will be implemented at the same contractor site as 002-A. An annual report was filed as required by FDA on the results of Protocol 002-A. Once all the three Phase II protocols are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be identified for this phase. This is critical for making this available for treatment of SMS in astronauts and military personnel on duty. Once approved by FDA, INSCOP can be also used by civilian population for motion sickness associated with recreational travel and other ailments that require treatment with anticholinergic drugs.

SimCenter Hawaii Technology Enabled Learning and Intervention Systems

DTIC Science & Technology

2008-01-01

manikin training in acquiring triage skills and self -efficacy. Phase II includes the development of the VR training scenarios, which includes iterative...Task A5. Skills acquisition relative to self -efficacy study See Appendix F, Mass Casualty Triage Training using Human Patient Simulators Improves...relative to self -efficacy study • See Appendix F, Mass Casualty Triage Training using Human Patient Simulators Improves Speed and Accuracy of First

Treatment rationale and design of the RAMNITA study: A phase II study of the efficacy of docetaxel + ramucirumab for non-small cell lung cancer with brain metastasis.

PubMed

Tanimura, Keiko; Uchino, Junji; Tamiya, Nobuyo; Kaneko, Yoshiko; Yamada, Tadaaki; Yoshimura, Kenichi; Takayama, Koichi

2018-06-01

We described the treatment rationale and procedure for a phase II study of docetaxel plus ramucirumab for non-small cell lung cancer (NSCLC) patients with brain metastasis (RAMNITA study: University Information Network Clinical Trials Registry identification no. [UMIN]: 000024551). Combination therapy of angiogenetic inhibitor with chemotherapy improved the outcome of patients with brain metastasis in previous reports; however, the efficacy of ramucirumab, a vascular endothelial growth factor receptor-2 monoclonal antibody, for brain metastasis has not been shown. This RAMNITA study is a prospective, multicenter, open-label, single-arm phase II study designed to evaluate efficacy and safety of docetaxel and ramucirumab for advanced NSCLC patients with brain metastasis. Eligible patients will receive docetaxel (60 mg/m) and ramucirumab (10 mg/kg) every 21 days until disease progression. The primary endpoint is progression-free survival (PFS), and secondary endpoints are overall survival, intracranial PFS, response rate, and safety. Sixty-five participants will be recruited from September 2017 to December 2019 and followed up for 1 year after final registration. The results from this study may suggest a treatment option for brain metastasis in NSCLC. The protocol was approved by the institutional review board of each study center. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki.

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

Long-acting rilpivirine for HIV prevention.

PubMed

Jackson, Akil; McGowan, Ian

2015-07-01

Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.

A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma.

PubMed

Markovic, Svetomir N; Suman, Vera J; Rao, Ravi A; Ingle, James N; Kaur, Judith S; Erickson, Lori A; Pitot, Henry C; Croghan, Gary A; McWilliams, Robert R; Merchan, Jaime; Kottschade, Lisa A; Nevala, Wendy K; Uhl, Cindy B; Allred, Jacob; Creagan, Edward T

2007-06-01

Thrombospondins are natural inhibitors of angiogenesis, tumor metastases, and tumor growth (melanoma). ABT-510 is a synthetic analog of thrombospondin-1, well tolerated in phase I studies. We conducted a phase II trial evaluating the clinical efficacy of ABT-510 and its effects on biomarkers of angiogenesis and immunity in patients with metastatic melanoma (MM). A 2-stage phase II clinical trial was conducted to assess the clinical efficacy, safety, and pharmacodynamic effects (angiogenesis and immunity) of ABT-510 in patients with stage IV melanoma. The primary endpoint was 18-week treatment failure rate. Patients self-administered 100 mg of ABT-510 subcutaneously twice daily. Blood samples were collected at baseline and every 3 weeks while on therapy. Eligible patients demonstrated measurable disease, good performance status and no evidence of intracranial metastases. Correlative laboratory studies evaluated biomarkers of angiogenesis and immunity. Twenty-one patients were enrolled. Most patients were stage M1c (71%) and all had prior therapy for MM. Only 3 of the first 20 patients enrolled were progression free and on treatment at 18 weeks resulting in early termination of the study. Decreases in peripheral blood VEGF-A levels and VEGF-C levels, and CD146 and CD34/133 counts relative to pretreatment were detected. Limited changes in antitumor T cell immunity were observed. ABT-510 therapy administered at 100 mg twice/day in patients with MM did not demonstrate definite clinical efficacy. Further dose escalation or combination with cytotoxic therapy may be more effective therapeutically.

A randomized, multicenter, phase II/III study to determine the optimal dose and to evaluate the efficacy and safety of pegteograstim (GCPGC) on chemotherapy-induced neutropenia compared to pegfilgrastim in breast cancer patients: KCSG PC10-09.

PubMed

Lee, Ki Hyeong; Kim, Ji-Yeon; Lee, Moon Hee; Han, Hye Sook; Lim, Joo Han; Park, Keon Uk; Park, In Hae; Cho, Eun Kyung; Yoon, So Young; Kim, Jee Hyun; Choi, In Sil; Park, Jae Hoo; Choi, Young Jin; Kim, Hee-Jun; Jung, Kyung Hae; Kim, Si-Young; Oh, Do-Youn; Im, Seock-Ah

2016-04-01

Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/μL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.

A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor

ClinicalTrials.gov

2017-06-13

Related Donors Donating PBSC to a Family Member; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Chronic Myelogenous Leukemia; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Chronic Lymphocytic Leukemia

Using Data Augmentation to Facilitate Conduct of Phase I–II Clinical Trials with Delayed Outcomes

PubMed Central

Jin, Ick Hoon; Liu, Suyu; Thall, Peter F.; Yuan, Ying

2014-01-01

A practical impediment in adaptive clinical trials is that outcomes must be observed soon enough to apply decision rules to choose treatments for new patients. For example, if outcomes take up to six weeks to evaluate and the accrual rate is one patient per week, on average three new patients will be accrued while waiting to evaluate the outcomes of the previous three patients. The question is how to treat the new patients. This logistical problem persists throughout the trial. Various ad hoc practical solutions are used, none entirely satisfactory. We focus on this problem in phase I–II clinical trials that use binary toxicity and efficacy, defined in terms of event times, to choose doses adaptively for successive cohorts. We propose a general approach to this problem that treats late-onset outcomes as missing data, uses data augmentation to impute missing outcomes from posterior predictive distributions computed from partial follow-up times and complete outcome data, and applies the design’s decision rules using the completed data. We illustrate the method with two cancer trials conducted using a phase I–II design based on efficacy-toxicity trade-offs, including a computer stimulation study. PMID:25382884

Bayesian adaptive phase II screening design for combination trials.

PubMed

Cai, Chunyan; Yuan, Ying; Johnson, Valen E

2013-01-01

Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial.

Motivation and participation in a phase III cardiac rehabilitation programme: an application of the health action process approach.

PubMed

Dohnke, Birte; Nowossadeck, Enno; Müller-Fahrnow, Werner

2010-10-01

This longitudinal study extends the previous research on low participation rates and high dropout rates in phase III cardiac rehabilitation (CR) exercise programmes. It examines the correlates of motivation and participation 6 months after inpatient phase II CR (T1) and the predictors of dropout 6 months later (T2) using the health action process approach (HAPA). Risk perception, outcome expectancies, self-efficacy, intention (at T1), and participation (at T1 and T2) in relation to phase III CR programmes was assessed in 456 patients. Based on intention and participation at T1, patients were classified as nonintenders (56%), intenders (13%), or actors (31%). Group differences were confirmed in outcome expectancies and self-efficacy. By T2, 21% of T1 actors had dropped out. Dropouts and maintainers differed in intention and self-efficacy (at T1). Results are in line with the HAPA and suggest a perspective for tailoring motivational counselling to improve participation in phase III CR programmes.

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients.

PubMed

Ahmadi, Hossein; Jamshidi, Ahmad Reza; Gharibdoost, Farhad; Mahmoudi, Mahdi; Rastkari, Noushin; Mostafaei, Shayan; Fattahi, Mohammad Javad; Vojdanian, Mahdi; Cuzzocrea, Salvatore; Rehm, Bernd H A; Matsuo, Hidenori; Hosseini, Mostafa; Aghazadeh, Zahra; Mortazavi-Jahromi, Seyed Shahabeddin; Mirshafiey, Abbas

2018-06-01

Following the potent efficacy of β-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

Safety and efficacy of a nurse-led clinic for post-operative coronary artery bypass grafting patients.

PubMed

Broers, Carla; Hogeling-Koopman, Jeanne; Burgersdijk, Cees; Cornel, Jan H; van der Ploeg, J; Umans, Victor A

2006-01-04

New opportunities are emerging for nurses as sovereign health care specialists. In accordance with British and American experience, several universities on the European Continent started Advance Nursing Practice programs for nurses to become certified nurse specialists, functioning as intermediates between the consultant, the ward nurse and the patient. This observational study was conducted to evaluate safety and efficacy of a nurse-led clinic for patients recovering after a successful coronary artery bypass grafting operation. From April 1999 to June 2002, 584 consecutive patients underwent a coronary artery bypass graft operation after which they were admitted to the cardiology ward. Subsequently, these patients were treated either by a certified nurse practitioner or by a resident. Both were supervised by an attending cardiologist. The study elapses three time phases: phase I (1999) first control period, phase II (2000-2002) the nurse practitioner was in charge, and phase III (2002) the second control period. A total of 584 patients were admitted at a mean of 5.5 and 6.3 days after the operation (phase II vs I+III, respectively). Typically these patients were men (79%) with a mean age of 67+/-11 years. During the observation period, 349 patients were treated by the nurse practitioner and 235 by a resident (89 in phase I and 146 in phase III). Two patients suddenly died while admitted. All other patients recovered and were discharged. The nurse-treated patients (phase II) were discharged significantly sooner than those treated by the regular staff (11.5 vs 14.7 days; p<0.001, respectively). The 30-day mortality rate was 0.4% and did not differ between the respective patient or time-phase groups. A nurse-led clinic for patients recovering from a coronary artery bypass graft operation was safely and efficaciously introduced in a large Dutch non-cardiac surgery hospital. This study protocol may serve as a preamble for upcoming nurse-led programs to developed and implement the sovereign care by nurse practitioners for various diseases and in different settings.

Evaluating Adaptation of a Cancer Clinical Trial Decision Aid for Rural Cancer Patients: A Mixed-Methods Approach.

PubMed

Pathak, Swati; George, Nerissa; Monti, Denise; Robinson, Kathy; Politi, Mary C

2018-06-03

Rural-residing cancer patients often do not participate in clinical trials. Many patients misunderstand cancer clinical trials and their rights as participant. The purpose of this study is to modify a previously developed cancer clinical trials decision aid (DA), incorporating the unique needs of rural populations, and test its impact on knowledge and decision outcomes. The study was conducted in two phases. Phase I recruited 15 rural-residing cancer survivors in a qualitative usability study. Participants navigated the original DA and provided feedback regarding usability and implementation in rural settings. Phase II recruited 31 newly diagnosed rural-residing cancer patients. Patients completed a survey before and after using the revised DA, R-CHOICES. Primary outcomes included decisional conflict, decision self-efficacy, knowledge, communication self-efficacy, and attitudes towards and willingness to consider joining a trial. In phase I, the DA was viewed positively by rural-residing cancer survivors. Participants provided important feedback about factors rural-residing patients consider when thinking about trial participation. In phase II, after using R-CHOICES, participants had higher certainty about their choice (mean post-test = 3.10 vs. pre-test = 2.67; P = 0.025) and higher trial knowledge (mean percentage correct at post-test = 73.58 vs. pre-test = 57.77; P < 0.001). There was no significant change in decision self-efficacy, communication self-efficacy, and attitudes towards or willingness to join trials. The R-CHOICES improved rural-residing patients' knowledge of cancer clinical trials and reduced conflict about making a trial decision. More research is needed on ways to further support decisions about trial participation among this population.

Odanacatib, a New Drug for the Treatment of Osteoporosis: Review of the Results in Postmenopausal Women

PubMed Central

Pérez-Castrillón, José Luis; Pinacho, Florentino; De Luis, Daniel; Lopez-Menendez, María; Dueñas Laita, Antonio

2010-01-01

Osteoclasts are specialized cells that initiate the process of bone resorption, which has two phases, dissolution of the mineral component and degradation of the organic matrix, in which cathepsin K plays a key role. Cathepsin K inhibitors, which block the activity of cathepsin on bone resorption lacunae, may be a new therapeutic option in osteoporosis. Odanacatib is a nonpeptidic biaryl inhibitor of cathepsin K. Two studies have evaluated the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study of safety and efficacy. Due to the long half-life of odanacatib and the similar effects of different doses on bone remodeling markers, a weekly dosage was chosen for the phase II trail, with the best results being obtained with a dose of 50 mg. At 36 months, increases in bone mineral density similar to those produced by other powerful antiresorptive drugs (zoledronate and denosumab) were observed but there were differences in the behaviour of bone remodeling markers. Data on fractures from the phase III trial currently in development are required to confirm these possible advantages. PMID:20948576

Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials.

PubMed

Schadendorf, Dirk; Wolchok, Jedd D; Hodi, F Stephen; Chiarion-Sileni, Vanna; Gonzalez, Rene; Rutkowski, Piotr; Grob, Jean-Jacques; Cowey, C Lance; Lao, Christopher D; Chesney, Jason; Robert, Caroline; Grossmann, Kenneth; McDermott, David; Walker, Dana; Bhore, Rafia; Larkin, James; Postow, Michael A

2017-12-01

Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials

PubMed Central

Schadendorf, Dirk; Wolchok, Jedd D.; Hodi, F. Stephen; Chiarion-Sileni, Vanna; Gonzalez, Rene; Rutkowski, Piotr; Grob, Jean-Jacques; Cowey, C. Lance; Lao, Christopher D.; Chesney, Jason; Robert, Caroline; Grossmann, Kenneth; McDermott, David; Walker, Dana; Bhore, Rafia; Larkin, James

2017-01-01

Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs (P = .97). Median overall survival had not been reached in either group (P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy. PMID:28841387

Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials.

PubMed

D'Amico, Ferdinando; Fiorino, Gionata; Furfaro, Federica; Allocca, Mariangela; Danese, Silvio

2018-06-23

A new pharmacological class, janus kinases (JAK) inhibitors, has been shown to be effective and safe for the treatment of inflammatory bowel diseases (IBD). The aim of this review is to provide an overview of the JAK inhibitors currently under investigation in phase I and II clinical trials for patients with Crohn's disease (CD) and ulcerative colitis (UC), and the possible future perspectives for the treatment of IBD patients with this class of drugs. Areas covered: This review describes the JAK-STAT pathway and analyzes the efficacy and safety of new small molecules such as filgotinib, upadacitinib, TD-1473, peficitinib and Pf-06651600/Pf-06700841, showing data from phase I and II trials. Expert Opinion: JAK inhibitors, if approved by the regulatory authorities, could represent a novel and intriguing drug class. In the next years the approach to patients with IBD will become increasingly personalized.

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies.

PubMed

Luo, Xiaoping; Hou, Ling; Liang, Li; Dong, Guanping; Shen, Shuixian; Zhao, Zhuhui; Gong, Chun Xiu; Li, Yuchuan; Du, Min-Lian; Su, Zhe; Du, Hongwei; Yan, Chaoying

2017-08-01

We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). Phase II and III, multicenter, open-label, randomized controlled trials. 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment ( P  < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment ( P  < 0.05). Adverse event rates and treatment compliance were comparable between the two groups. Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH. © 2017 The authors.

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

PubMed Central

Hou, Ling; Liang, Li; Dong, Guanping; Shen, Shuixian; Zhao, Zhuhui; Gong, Chun Xiu; Li, Yuchuan; Du, Min-lian; Su, Zhe; Du, Hongwei; Yan, Chaoying

2017-01-01

Objective We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). Design Phase II and III, multicenter, open-label, randomized controlled trials. Methods 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. Results The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment (P < 0.05). Additionally, significantly greater improvement in the height standard deviation scores was associated with Jintrolong throughout the treatment (P < 0.05). Adverse event rates and treatment compliance were comparable between the two groups. Conclusion Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH. PMID:28566441

A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

ClinicalTrials.gov

2017-07-24

Primary Myelofibrosis; Thrombocythemia, Essential; Thrombocytosis; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Blood Coagulation Disorders; Blood Platelet Disorders; Hemorrhagic Disorders

Feasibility and Efficacy of the Nintendo Wii Gaming System to Improve Balance Performance Post-Stroke: Protocol of a Phase II Randomized Controlled Trial in an Inpatient Rehabilitation Setting.

PubMed

Bower, Kelly J; Clark, Ross A; McGinley, Jennifer L; Martin, Clarissa L; Miller, Kimberly J

2013-04-01

Balance deficits following stroke are common and debilitating. Commercially available gaming systems, such as the Nintendo(®) (Kyoto, Japan) Wii™, have been widely adopted clinically; however, there is limited evidence supporting their feasibility and efficacy for improving balance performance following stroke. The aim of this trial is to investigate the clinical feasibility and efficacy of using the Nintendo Wii gaming system as an adjunct to standard care to improve balance performance following stroke in an inpatient rehabilitation setting. Thirty participants undergoing inpatient stroke rehabilitation will be recruited into this Phase II, single-blind, randomized controlled trial. Participants will be allocated into a Balance or Upper Limb Group, and both groups will perform activities using the Nintendo Wii in addition to their standard care. Participants will attend three 45-minute sessions per week, for a minimum of 2 and a maximum of 4 weeks. The main focus of the study is to investigate the feasibility of the intervention protocol. This will be evaluated through recruitment, retention, adherence, acceptability, and safety. The Step Test and Functional Reach Test will be the primary efficacy outcomes. Secondary outcomes will include force platform, mobility, and upper limb measures. Assessments will occur at baseline, 2 weeks, and 4 weeks after study entry. To the authors' knowledge, this will be the largest randomized clinical trial to investigate the feasibility and efficacy of the Nintendo Wii gaming system for improving balance performance in a stroke population. The results will inform the design of a Phase III multicenter trial.

Tumor shrinkage and objective response rates: gold standard for oncology efficacy screening trials, or an outdated end point?

PubMed

Bradbury, Penelope; Seymour, Lesley

2009-01-01

Phase II clinical trials have long been used to screen new cancer therapeutics for antitumor activity ("efficacy") worthy of further evaluation. Traditionally, the primary end point used in these screening trials has been objective response rate (RR), with the desired rate being arbitrarily set by the researchers before initiation of the trial. For cytotoxic agents, especially in common tumor types, response has been a reasonably robust and validated surrogate of benefit. Phase II trials with response as an end point have a modest sample size (15-40 patients) and are completed rapidly allowing early decisions regarding future development of a given agent. More recently, a number of new agents have proven successful in pivotal phase III studies, despite a low or very modest RR demonstrated in early clinical trials. Researchers have postulated that these novel agents, as a class, may not induce significant regression of tumors, and that the use of RR as an end point for phase II studies will result in false negative results, and point out that not all available data is used in making the decision. Others have pointed out that even novel agents have proven unsuccessful in pivotal trials if objective responses are not demonstrated in early clinical trials. We review here the historical and current information regarding objective tumor response.

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma

PubMed Central

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Ishizawa, Kenichi; Uike, Naokuni; Uchida, Toshiki; Suzuki, Tatsuya; Aoki, Tomohiro; Watanabe, Takashi; Maruyama, Dai; Yokoyama, Masahiro; Takubo, Takatoshi; Kagehara, Hideaki; Matsushima, Takafumi

2014-01-01

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650). This phase I/II study was to investigate the tolerability, safety and efficacy of brentuximab vedotin. This study indicates that 1.8 mg/kg brentuximab vedotin given every 3 weeks has a manageable safety profile and has high overall tumor response rate in Japanese patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. PMID:24814862

Chemoradiation in elderly esophageal cancer patients: rationale and design of a phase I/II multicenter study (OSAGE).

PubMed

Servagi-Vernat, Stéphanie; Créhange, Gilles; Bonnetain, Franck; Mertens, Cécile; Brain, Etienne; Bosset, Jean François

2017-07-13

The management of elderly patients with cancer is a therapeutic challenge and a public health problem. Definitive chemoradiotherapy (CRT) is an accepted standard treatment for patients with locally advanced esophageal cancer who cannot undergo surgery. However, there are few reports regarding tolerance to CRT in elderly patients. We previously reported results for CRT in patients aged ≥75 years. Following this first phase II trial, we propose to conduct a phase I/II study to evaluate the combination of carboplatin and paclitaxel, with concurrent RT in unresectable esophageal cancer patients aged 75 years or older. This prospective multicenter phase I/II study will include esophageal cancer in patients aged 75 years or older. Study procedures will consist to determinate the tolerated dose of chemotherapy (Carboplatin, paclitaxel) and of radiotherapy (41.4-45 and 50.4 Gy) in the phase I. Efficacy will be assessed using a co-primary endpoint encompassing health related quality of life and the progression-free survival in the phase II with the dose recommended of CRT in the phase I. This geriatric evaluation was defined by the French geriatric oncology group (GERICO). This trial has been designed to assess the tolerated dose of CRT in selected patient aged 75 years or older. Clinicaltrials.gov ID: NCT02735057 . Registered on 18 March 2016.

Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials

PubMed Central

Song, Gwan Gyu; Bae, Sang-Cheol

2014-01-01

Background/Aims The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). Methods A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. Results Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. Conclusions Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile. PMID:25228842

Bayesian adaptive phase II screening design for combination trials

PubMed Central

Cai, Chunyan; Yuan, Ying; Johnson, Valen E

2013-01-01

Background Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Methods Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Results Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. Limitations The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. Conclusions The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial. PMID:23359875

Early investigational tubulin inhibitors as novel cancer therapeutics.

PubMed

Nepali, Kunal; Ojha, Ritu; Lee, Hsueh-Yun; Liou, Jing-Ping

2016-08-01

Microtubules represent one of the most logical and strategic molecular targets amongst the current targets for chemotherapy, alongside DNA. In the past decade, tubulin inhibitors as cancer therapeutics have been an area of focus due to the improved understanding and biological relevance of microtubules in cellular functions. Fueled by the objective of developing novel chemotherapeutics and with the aim of establishing the benefits of tubulin inhibition, several clinical trials have been conducted with others ongoing. At present, the antitubulin development pipeline contains an armful of agents under clinical investigation. This review focuses on novel tubulin inhibitors as cancer therapeutics. The article covers the agents which have completed the phase II studies along with the agents demonstrating promising results in phase I studies. Countless clinical trials evaluating the efficacy, safety and pharmacokinetics of novel tubulin inhibitors highlights the scientific efforts being paid to establish their candidature as cancer therapeutics. Colchicine binding site inhibitors as vascular disrupting agents (VDAs) and new taxanes appear to be the most likely agents for future clinical interest. Numerous agents have demonstrated clinical benefits in terms of efficacy and survival in phase I and II studies. However conclusive benefits can only be ascertained on the basis of phase III studies.

Virtual reality bringing a new reality to postthoracotomy lung cancer patients via a home-based exercise intervention targeting fatigue while undergoing adjuvant treatment.

PubMed

Hoffman, Amy J; Brintnall, Ruth Ann; Brown, Jean K; von Eye, Alexander; Jones, Lee W; Alderink, Gordon; Ritz-Holland, Deborah; Enter, Mark; Patzelt, Lawrence H; VanOtteren, Glenn M

2014-01-01

Little is known about rehabilitation for postthoracotomy non-small cell lung cancer (NSCLC) patients. This research uses a perceived self-efficacy-enhancing light-intensity exercise intervention targeting a priority symptom, cancer-related fatigue (CRF), for postthoracotomy NSCLC patients. This article reports on phase II of a 2-phase study. Phase I focused on initiation and tolerance of exercise during the 6 weeks immediately after thoracotomy, whereas phase II addressed maintenance of exercise for an additional 10 weeks including participants initiating and completing chemotherapy and/or radiation therapy. The objective of this study was to investigate the feasibility, acceptability, and preliminary efficacy of an exercise intervention for postthoracotomy NSCLC patients to include those initiating and completing adjuvant therapy. A single-arm design composed of 7 participants postthoracotomy for NSCLC performed light-intensity exercises using an efficacy-enhancing virtual-reality approach using the Nintendo Wii Fit Plus. Despite most participants undergoing chemotherapy and/or radiation therapy, participants adhered to the intervention at a rate of 88% with no adverse events while giving the intervention high acceptability scores on conclusion. Likewise, participants' CRF scores improved from initiation through the conclusion of the intervention with perceived self-efficacy for walking at a light intensity continuously for 60 minutes, improving significantly upon conclusion over presurgery values. Postthoracotomy NSCLC patients maintained exercise for an additional 10 weeks while undergoing adjuvant therapy showing rehabilitation potential because the exercise intervention was feasible, safe, well tolerated, and highly acceptable showing positive changes in CRF self-management. A randomized controlled trial is needed to further investigate these relationships.

Phase II Trials for Heterogeneous Patient Populations with a Time-to-Event Endpoint.

PubMed

Jung, Sin-Ho

2017-07-01

In this paper, we consider a single-arm phase II trial with a time-to-event end-point. We assume that the study population has multiple subpopulations with different prognosis, but the study treatment is expected to be similarly efficacious across the subpopulations. We review a stratified one-sample log-rank test and present its sample size calculation method under some practical design settings. Our sample size method requires specification of the prevalence of subpopulations. We observe that the power of the resulting sample size is not very sensitive to misspecification of the prevalence.

The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing.

PubMed

Nieuwenhuizen, Natalie E; Kulkarni, Prasad S; Shaligram, Umesh; Cotton, Mark F; Rentsch, Cyrill A; Eisele, Bernd; Grode, Leander; Kaufmann, Stefan H E

2017-01-01

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes . Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔ ureC :: hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

Integrated safety and efficacy analysis of once-daily fluticasone furoate for the treatment of asthma.

PubMed

O'Byrne, Paul M; Jacques, Loretta; Goldfrad, Caroline; Kwon, Namhee; Perrio, Michael; Yates, Louisa J; Busse, William W

2016-11-24

Fluticasone furoate is a once-daily inhaled corticosteroid. This report provides an overview of safety and efficacy data that support the use of once-daily fluticasone furoate 100 μg or 200 μg in adult and adolescent asthma patients. Fourteen clinical studies (six Phase II and eight Phase III) were conducted as part of the fluticasone furoate global clinical development programme in asthma. Safety data from 10 parallel-group, randomised, double-blind Phase II and III studies (including 3345 patients who received at least one dose of fluticasone furoate) were integrated to provide information on adverse events, withdrawals, laboratory assessments, vital signs and hypothalamic-pituitary-adrenal axis function. The efficacy of once-daily fluticasone furoate was evaluated in all included studies. Once-daily fluticasone furoate 100 μg and 200 μg safety profiles were consistent with those reported for other inhaled corticosteroids, and both doses consistently demonstrated efficacy versus placebo. In the integrated analysis, no dose-response relationship was observed for the overall incidence of adverse events and there were no significant effects of fluticasone furoate on hypothalamic-pituitary-adrenal axis function. Once-daily fluticasone furoate 100 μg and 200 μg had acceptable safety profiles and was efficacious in adult and adolescent patients with asthma. There was no evidence of cortisol suppression at studied doses. GSK (NCT01499446/FFA20001, NCT00398645/FFA106783, NCT00766090/112202, NCT00603746/FFA109684, NCT00603278/FFA109685, NCT00603382/FFA109687, NCT01436071/115283, NCT01436110/115285, NCT01159912/112059, NCT01431950/114496, NCT01165138/HZA106827, NCT01086384/106837, NCT01134042/HZA106829 and NCT01244984/1139879).

Iron-Magnesium Hydroxycarbonate (Fermagate): A Novel Non-Calcium-Containing Phosphate Binder for the Treatment of Hyperphosphatemia in Chronic Hemodialysis Patients

PubMed Central

McIntyre, Christopher W.; Pai, Pearl; Warwick, Graham; Wilkie, Martin; Toft, Alex J.; Hutchison, Alastair J.

2009-01-01

Background and objectives: This phase II study tested the safety and efficacy of fermagate, a calcium-free iron and magnesium hydroxycarbonate binder, for treating hyperphosphatemia in hemodialysis patients. Design, setting, participants, & measurements: A randomized, double-blind, three-arm, parallel-group study compared two doses of fermagate (1 g three times daily or 2 g three times daily with placebo). Sixty-three patients who had been on a stable hemodialysis regimen for ≥3 mo were randomized to the treatment phase. Study medication was administered three times daily just before meals for 21 d. The primary endpoint was reduction in serum phosphate over this period. Results: In the intention-to-treat analysis, mean baseline serum phosphate was 2.16 mmol/L. The fermagate 1- and 2-g three-times-daily treatment arms were associated with statistical reductions in mean serum phosphate to 1.71 and 1.47 mmol/L, respectively. Adverse event (AE) incidence in the 1-g fermagate arm was statistically comparable to the placebo group. The 2-g arm was associated with a statistically higher number of patients reporting AEs than the 1-g arm, particularly gastrointestinal AEs, as well as a higher number of discontinuations, complicating interpretation of this dose's efficacy. Both doses were associated with elevations of prehemodialysis serum magnesium levels. Conclusions: The efficacy and tolerability of fermagate were dose dependent. Fermagate showed promising efficacy in the treatment of hyperphosphatemia in chronic hemodialysis patients as compared with placebo in this initial phase II study. The optimal balance between efficacy and tolerability needs to be determined from future dose-titration studies, or fixed-dose comparisons of more doses. PMID:19158369

Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward.

PubMed

Guy, Bruno; Briand, Olivier; Lang, Jean; Saville, Melanie; Jackson, Nicholas

2015-12-10

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Analysis of the Japanese subgroup in LEOPOLD II: a phase 2/3 study of BAY 81-8973, a new recombinant factor VIII product.

PubMed

Fujii, Teruhisa; Hanabusa, Hideji; Shima, Midori; Morinaga, Takeshi; Fukutake, Katsuyuki

2017-03-01

BAY 81-8973, a new full length recombinant FVIII product, has been developed for prophylaxis and on-demand therapy in patients with hemophilia A. LEOPOLD II was a phase 2/3 study comparing prophylaxis versus on-demand treatment with BAY 81-8973. The analysis herein evaluated the clinical profile in Japanese subjects enrolled in LEOPOLD II. The LEOPOLD II was an open-label randomized crossover study. Our analysis evaluated the efficacy using the annualized bleeding rate, safety, and pharmacokinetics in Japanese subjects with severe hemophilia A enrolled in LEOPOLD II. The median annualized bleeding rate was 59.9/year in the on-demand group and 1.9/year in the prophylaxis group for Japanese subjects. There were no study drug-related adverse events in the Japanese subjects. None of the subjects developed FVIII inhibitors. There were no apparent clinical differences in efficacy, safety, and pharmacokinetics between the Japanese and the non-Japanese subjects. Data for the Japanese subjects showed annualized bleeding rates to be remarkably lower in the prophylaxis group compared to the on-demand group and that BAY 81-8973 exhibited a good safety profile and tolerability. These results were similar for the non-Japanese subjects. The results support adoption of BAY 81-8973 for treatment of Japanese subjects with severe hemophilia A.

SAFETY AND ACTIVITY OF TEMSIROLIMUS AND BEVACIZUMAB IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA PREVIOUSLY TREATED WITH TYROSINE KINASE INHIBITORS: A PHASE 2 CONSORTIUM STUDY

PubMed Central

Merchan, Jaime R.; Qin, Rui; Pitot, Henry; Picus, Joel; Liu, Glenn; Fitch, Tom; Maples, William J.; Flynn, Patrick J.; Fruth, Briant F.; Erlichman, Charles

2015-01-01

Purpose Bevacizumab or Temsirolimus regimens have clinical activity in the first line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. Methods In the phase I portion, eligible patients were treated with Temsirolimus (25 mg IV weekly) and escalating doses of IV Bevacizumab (level 1=5mg/kg; level 2=10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression free rate. Secondary endpoints were response rate, toxicity evaluation, PFS and OS. Results MTD was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (Temsirolimus 25 mg IV weekly and Bevacizumab 10 mg/kg IV every two weeks). The 6-month progression free rate was 40% (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response/stable/progressive disease were seen in 23%/63%/14% of patients. Most common grade 3-4 AEs included fatigue (17.8%), hypertriglyceridemia (11.1%), stomatitis (8.9%), proteinuria (8.9%), abdominal pain (6.7%), and anemia (6.7%). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Conclusions Temsirolimus and Bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population. PMID:25556030

Fixed dose darunavir boosted with cobicistat combined with emtricitabine and tenofovir alafenamide fumarate.

PubMed

Cevik, Muge; Orkin, Chloe

2018-07-01

In an era when virological efficacy approaches 100%, novel antiretroviral (ARV) therapies must deliver better tolerability, safety, and convenient coformulated regimens. We review the phase II and III clinical data on the fixed dose combination (FDC) darunavir (DRV) 800mg / cobicistat (COBI/C) 150 mg / emtricitabine (F/FTC) 200 mg / tenofovir alafenamide fumarate (TAF) 10mg (D/C/F/TAF) for the treatment of HIV-1 infection. In an exploratory phase II study, D/C/F/TAF FDC demonstrated similar virological efficacy to darunavir/cobicistat FDC + F /tenofovir disoproxil fumarate (TDF) FDC in treatment-naive HIV-1-infected individuals with favorable bone and renal outcomes. These findings led to two subsequent international phase III double-blind randomized controlled trials; AMBER and EMERALD. In the (treatment naïve) AMBER study, D/C/F/TAF FDC was noninferior to component regimen F/TDF + darunavir/cobicistat with favorable bone and renal outcomes at week 48. In the EMERALD study (switch study for virologically suppressed patients), D/C/F/TAF showed noninferior efficacy to F/TDF and boosted protease inhibitor (bPI) regimen at week 48 also with favorable renal and bone outcomes. No virological failure was observed, and no resistance to TDF or darunavir emerged in either study. In clinical trials, D/C/F/TAF FDC demonstrated excellent, noninferior virological efficacy, maintained a high genetic barrier and conferred the additional safety benefits of TAF. As the first one pill, once daily, protease inhibitor-based regimen, D/C/F/TAF FDC offers a new option for the treatment of HIV infection.

A call for more transparency of registered clinical trials on endometriosis

PubMed Central

Guo, Sun-Wei; Hummelshoj, Lone; Olive, David L.; Bulun, Serdar E.; D'Hooghe, Thomas M.; Evers, Johannes L.H.

2009-01-01

In response to the pressing need for more efficacious and safer therapeutics for endometriosis, there have been numerous reports in the last decade of positive results from animal and in vitro studies of various compounds as potential therapeutics for endometriosis. A handful of these have undergone phase II/III clinical trials. Since the announcement of the International Committee of Medical Journal Editors that mandated registration as a prerequisite for publication, 57 endometriosis-related clinical trials have been registered at ClinicalTrials.gov, an Internet-based public depository for information on drug studies. Among them, 25 are listed as completed, and 2 as suspended. There are 15 completed phase II/III trials, which evaluated the efficacy of various promising compounds. Yet only three of the 15 trials (20%) have published their results. The remaining 12 (80%) studies so far have not published their findings. We argue that this apparent lack of transparency will actually not benefit the trial sponsors or the public, and will ultimately prove detrimental to research efforts attempting to develop more efficacious and safer therapeutics for endometriosis. Thus we call for more transparency of clinical trials on endometriosis. PMID:19264712

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

Noel, Donna

This project integrated state-of-the-art exploration technologies with a geologic framework and reservoir modeling to ultimately determine the efficacy of future geothermal production within the PLPT reservation. The information gained during this study should help the PLPT to make informed decisions regarding construction of a geothermal power plant. Additional benefits included the transfer of new technologies and geothermal data to the geothermal industry and it created and/or preserved nearly three dozen jobs accordance with the American Recovery and Reinvestment Act of 2009. A variety of tasks were conducted to achieve the above stated objectives. The following are the tasks completed withinmore » the project: 1. Permitting 2. Shallow temperature survey 3. Seismic data collection and analysis 4. Fracture stress analysis 5. Phase I reporting Permitting 7. Shallow temperature survey 8. Seismic data collection and analysis 9. Fracture stress analysis 10. Phase I reporting 11. Drilling two new wells 12. Borehole geophysics 13. Phase II reporting 14. Well testing and geochemical analysis 15. Three-dimensional geologic model 16. Three-dimensional reservoir analysis 17. Reservation wide geothermal potential analysis 18. Phase III reporting Phase I consisted of tasks 1 – 5, Phase II tasks 6 – 8, and Phase III tasks 9 – 13. This report details the results of Phase III tasks. Reports are available for Phase I, and II as separate documents.« less

Phase-II trials in osteosarcoma recurrences: A systematic review of past experience.

PubMed

Omer, Natacha; Le Deley, Marie-Cécile; Piperno-Neumann, Sophie; Marec-Berard, Perrine; Italiano, Antoine; Corradini, Nadège; Bellera, Carine; Brugières, Laurence; Gaspar, Nathalie

2017-04-01

The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point. Copyright © 2017 Elsevier Ltd. All rights reserved.

Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

ClinicalTrials.gov

2018-04-20

Leukemia; Leukemia,Pediatric; Leukemia, Myleiod; Leukemia, Mylegenous, Chronic; Leukemia, Mylegenous, Accelerated; BCR-ABL Positive; Myeloproliferative Disorder; Bone Marrow Disease; Hematologic Diseases; Neoplastic Processes; Imatinib; Dasatinib; Enzyme Inhibitor; Protein Kinase Inhibitor

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

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.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

PubMed

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non-Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group.

PubMed

Karampeazis, Athanasios; Vamvakas, Lambros; Kentepozidis, Nikolaos; Polyzos, Aris; Chandrinos, Vassilis; Rigas, Georgios; Christofyllakis, Charalambos; Kotsakis, Athanasios; Hatzidaki, Dora; Pallis, Athanasios G; Georgoulias, Vassilis

2016-11-01

The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non-small-cell lung cancer (NSCLC). Patients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m 2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m 2 ). The primary endpoint was the overall response rate. A total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. The biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.

PubMed

Sawada, Hideyuki

2017-05-01

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients. Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.

Update on the use of defibrotide.

PubMed

Guglielmelli, Tommasina; Bringhen, Sara; Palumbo, Antonio

2012-03-01

Defibrotide is a polydisperse oligonucleotide obtained from porcine intestinal mucosa and prepared by controlled depolymerization of DNA. It is a nucleic acid polymer, predominantly single-stranded, which has anti-ischemic and anti-thrombotic properties. The efficacy and safety of defibrotide in the treatment of veno-occlusive disease (VOD) occurring after high-dose chemotherapy and hematopoietic stem-cell transplantation is now well established in Phase II - III trials. A recent randomized, Phase III trial in pediatric patients has also demonstrated its role in the prevention of VOD. Preclinical studies reported the inhibitory effects of defibrotide on myeloma cells' growth through an antiangiogenic action and a regulation of the tumor-microenvironment interactions. A recent Phase II trial underlines the efficacy and safety of defibrotide-thalidomide-melphalan combination in the treatment of relapsed/refractory multiple myeloma. Defibrotide may be effective in the prophylaxis and the treatment of veno-occlusive disease. Recent experimental results suggest that defibrotide may belong to the new generation of anti-cancer drugs that can prevent tumor angiogenesis. In multiple myeloma, defibrotide may overcome the prothrombotic effect of thalidomide on endothelial cells. Further preclinical and clinical investigations are needed to assess the precise role of defibrotide in the treatment of patients with multiple myeloma.

Phase I/II evaluation of RV1001, a novel PI3Kδ inhibitor, in spontaneous canine lymphoma.

PubMed

Gardner, Heather L; Rippy, Sarah B; Bear, Misty D; Cronin, Kim L; Heeb, Heather; Burr, Holly; Cannon, Claire M; Penmetsa, Kumar V; Viswanadha, Srikant; Vakkalanka, Swaroop; London, Cheryl A

2018-01-01

RV1001 is a novel, potent, and selective PI3Kδ inhibitor. The purpose of this study was to evaluate the safety and efficacy of RV1001 in canine Non-Hodgkin lymphoma (NHL). Inhibition of endogenous pAKT by RV1001 in primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in 21 dogs with naïve and drug resistant T and B-cell NHL to assess safety, pharmacokinetic profile, and response to therapy. The objective response rate was 62% (complete response (CR) n = 3; partial response (PR) n = 10), and responses were observed in both naïve and chemotherapy-resistant B and T cell NHL. This study provided the recommended starting dose for a phase II, non-pivotal, exploratory, open label multi-centered clinical trial in 35 dogs with naïve and drug resistant T and B-cell NHL, to further define the efficacy and safety profile of RV1001. The objective response rate in the phase II study was 77% (CR n = 1; PR n = 26). Clinical toxicities were primarily hepatobiliary and gastrointestinal, and were responsive to dose modifications and/or temporary drug discontinuation. Hepatotoxicity was the primary dose limiting toxicity. RV1001 exhibits good oral bioavailability, an acceptable safety profile, and biologic activity with associated inhibition of pAKT in dogs with B and T cell NHL. Data from these studies can be leveraged to help inform the design of future studies involving isoform-selective PI3K inhibitors in humans.

Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer.

PubMed

Hu, Xichun; Zhang, Jian; Xu, Binghe; Jiang, Zefei; Ragaz, Joseph; Tong, Zhongsheng; Zhang, Qingyuan; Wang, Xiaojia; Feng, Jifeng; Pang, Danmei; Fan, Minhao; Li, Jin; Wang, Biyun; Wang, Zhonghua; Zhang, Qunling; Sun, Si; Liao, Chunmei

2014-10-15

Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4-week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression-free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand-foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7-5.0) and 10.6 (95% CI 5.6-15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS. © 2014 UICC.

Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies

PubMed Central

Feldstein, Leora R.; Matrajt, Laura; Halloran, M. Elizabeth; Keitel, Wendy A.; Longini, Ira M.

2016-01-01

Influenza A virus subtype H5N1 has been a public health concern for almost 20 years due to its potential ability to become transmissible among humans. Phase I and II clinical trials have assessed safety, reactogenicity and immunogenicity of inactivated influenza A/H5N1 virus vaccines. A shortage of vaccine is likely to occur during the first months of a pandemic. Hence, determining whether to give one dose to more people or two doses to fewer people to best protect the population is essential. We use hemagglutination-inhibition antibody titers as an immune correlate for avian influenza vaccines. Using an established relationship to obtain a theoretical vaccine efficacy from immunogenicity data from thirteen arms of six phase I and phase II clinical trials of inactivated influenza A/H5N1 virus vaccines, we assessed: 1) the proportion of theoretical vaccine efficacy achieved after a single dose (defined as primary response level), and 2) whether theoretical efficacy increases after a second dose, with and without adjuvant. Participants receiving vaccine with AS03 adjuvant had higher primary response levels (range: 0.48–0.57) compared to participants receiving vaccine with MF59 adjuvant (range: 0.32–0.47), with no observed trends in primary response levels by antigen dosage. After the first and second doses, vaccine with AS03 at dosage levels 3.75, 7.5 and 15 mcg had the highest estimated theoretical vaccine efficacy: Dose 1) 45% (95%CI: 36–57%), 53% (95%CI: 42–63%) and 55% (95%CI: 44–64%), respectively and Dose 2) 93% (95%CI: 89–96%), 97% (95%CI: 95–98%) and 97% (95%CI: 96–100%), respectively. On average, the estimated theoretical vaccine efficacy of lower dose adjuvanted vaccines (AS03 and MF59) was 17% higher than that of higher dose unadjuvanted vaccines, suggesting that including an adjuvant is dose-sparing. These data indicate adjuvanted inactivated influenza A/H5N1 virus vaccine produces high theoretical efficacy after two doses to protect individuals against a potential avian influenza pandemic. PMID:27268778

Reverse and Forward Translational Neuropharmacology in Psychiatric Drug Discovery.

PubMed

Shaffer, Christopher L

2018-02-01

The probability of achieving marketing approval of a novel therapeutic for psychiatric indications is extremely low due largely to the inability to demonstrate durable and reproducible efficacy in phase II trials and beyond. These failures are often attributed to the lack of translation of the underlying neuropharmacology from animal model(s) to the disease population. However, how assured is such a conclusion considering the clinical efficacy path rarely meticulously parallels the preclinical experiment(s) that underwrote it? © 2017 American Society for Clinical Pharmacology and Therapeutics.

Cysticidal Efficacy of Combined Treatment With Praziquantel and Albendazole for Parenchymal Brain Cysticercosis.

PubMed

Garcia, Hector H; Lescano, Andres G; Gonzales, Isidro; Bustos, Javier A; Pretell, E Javier; Horton, John; Saavedra, Herbert; Gonzalez, Armando E; Gilman, Robert H

2016-06-01

The efficacy of current antiparasitic treatment for cerebral Taenia solium cysticercosis with either albendazole (ABZ) or praziquantel (PZQ) is suboptimal. A recent study demonstrated that combining these 2 antiparasitic drugs improves antiparasitic efficacy. We present here the parasiticidal efficacy data obtained during a previous phase II pharmacokinetic study that compared combined ABZ plus PZQ with ABZ alone. The study was a randomized, double-blinded, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ (15 mg/k/d, for 10 days) and PZQ (50 mg/k/d, for 10 days) in intraparenchymal brain cysticercosis. Patients received the usual concomitant medications, including an antiepileptic drug (phenytoin or carbamazepine), dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug. Patients underwent safety laboratory evaluations at days 4, 7, and 11, as well as magnetic resonance (MR) imaging at 6 months to assess parasiticidal efficacy. Thirty-two patients were included, 16 in each arm. All of them completed antiparasitic treatment and underwent follow-up brain MR imaging. Cysticidal efficacy was strikingly higher in the combined ABZ-plus-PZQ group than in the ABZ-alone group (proportion of cysts resolved, 78 of 82 [95%] vs 23 of 77 [30%] [relative risk {RR}, 3.18; 95% confidence interval {CI}, 2.08-4.88; P < .001]; patients with complete cyst clearance, 12 of 16 [75%] vs 4 of 16 [25%] [RR, 3.00; 95% CI, 1.23-7.34; P = .005]). The combination of ABZ plus PZQ is more effective in destroying viable brain cysticercosis cysts than ABZ alone. NCT00441285. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Single-Dose Oritavancin Treatment of Acute Bacterial Skin and Skin Structure Infections: SOLO Trial Efficacy by Eron Severity and Management Setting.

PubMed

Deck, Daniel H; Jordan, Jennifer M; Holland, Thomas L; Fan, Weihong; Wikler, Matthew A; Sulham, Katherine A; Ralph Corey, G

2016-09-01

Introduction of new antibiotics enabling single-dose administration, such as oritavancin may significantly impact site of care decisions for patients with acute bacterial skin and skin structure infections (ABSSSI). This analysis compared the efficacy of single-dose oritavancin with multiple-dose vancomycin in patients categorized according to disease severity via modified Eron classification and management setting. SOLO I and II were phase 3 studies evaluating single-dose oritavancin versus 7-10 days of vancomycin for treatment of ABSSSI. Patient characteristics were collected at baseline and retrospectively analyzed. Study protocols were amended, allowing outpatient management at the discretion of investigators. In this post hoc analysis, patients were categorized according to a modified Eron severity classification and management setting (outpatient vs. inpatient) and the efficacy compared. Overall, 1910 patients in the SOLO trials were categorized into Class I (520, 26.5%), II (790, 40.3%), and III (600, 30.6%). Of the 767 patients (40%) in the SOLO trials who were managed entirely in the outpatient setting 40.3% were categorized as Class II and 30.6% were Class III. Clinical efficacy was similar between oritavancin and vancomycin treatment groups, regardless of severity classification and across inpatient and outpatient settings. Class III patients had lower response rates (oritavancin 73.3%, vancomycin 76.6%) at early clinical evaluation when compared to patients in Class I (82.6%) or II (86.1%); however, clinical cure rates at the post-therapy evaluation were similar for Class III patients (oritavancin 79.8%, vancomycin 79.9%) when compared to Class I and II patients (79.1-85.7%). Single-dose oritavancin therapy results in efficacy comparable to multiple-dose vancomycin in patients categorized according to modified Eron disease severity classification regardless of whether management occurred in the inpatient or outpatient setting. The Medicines Company, Parsippany, NJ, USA. ClinicalTrials.gov identifiers, NCT01252719 (SOLO I) and NCT01252732 (SOLO II).

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C.

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of non-small cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify two major lessons from the outcomes of these trials: 1) The antioxidant hypothesis was tested in wrong subjects or patient populations. 2) The selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to re-vitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials. PMID:26595411

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges.

PubMed

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.

Targeting mTOR pathway in gynecological malignancies: Biological rationale and systematic review of published data.

PubMed

Kassem, Loay; Abdel-Rahman, Omar

2016-12-01

mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers. A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results. A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed. mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bupropion-SR plus naltrexone-SR for the treatment of mild-to-moderate obesity.

PubMed

Ali, Khawla F; Shukla, Alpana P; Aronne, Louis J

2016-01-01

Naltrexone-bupropion is a recently approved drug combination for chronic weight management. In this article, we discuss the rationale for its use as a combination followed by a comprehensive review of safety and efficacy data from major preclinical, phase II and III clinical trials.

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study.

PubMed

Jankowitz, Rachel C; Abraham, Jame; Tan, Antoinette R; Limentani, Steven A; Tierno, Marni B; Adamson, Laura M; Buyse, Marc; Wolmark, Norman; Jacobs, Samuel A

2013-12-01

Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

Synthesis of a Dual Functional Anti-MDR Tumor Agent PH II-7 with Elucidations of Anti-Tumor Effects and Mechanisms

PubMed Central

Tan, Yaohong; Hu, Yunhui; Zhou, Yuan; Liu, Juanni; Xu, Yuanfu; Xie, Yinliang; Wang, Caiyun; Gao, Yingdai; Wang, Jianxiang; Cheng, Tao; Yang, Chunzheng; Xiong, Dongsheng; Miao, Hua

2012-01-01

Multidrug resistance mediated by P-glycoprotein in cancer cells has been a major issue that cripples the efficacy of chemotherapy agents. Aimed for improved efficacy against resistant cancer cells, we designed and synthesized 25 oxindole derivatives based on indirubin by structure-activity relationship analysis. The most potent one was named PH II-7, which was effective against 18 cancer cell lines and 5 resistant cell lines in MTT assay. It also significantly inhibited the resistant xenograft tumor growth in mouse model. In cell cycle assay and apoptosis assay conducted with flow cytometry, PH II-7 induced S phase cell cycle arrest and apoptosis even in resistant cells. Consistently revealed by real-time PCR, it modulates the expression of genes related to the cell cycle and apoptosis in these cells, which may contributes to its efficacy against them. By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells. Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators. Taken together, PH II-7 is a dual-functional compound that features both the cytotoxicity against cancer cells and the inhibitory effect on P-gp mediated drug efflux. PMID:22403708

Human Data Supporting Glyburide in Ischemic Stroke.

PubMed

Sheth, Kevin N; Simard, J Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. An early phase II study using magnetic resonance imaging and plasma biomarkers supports the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase II study and definitive efficacy studies are needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

PubMed

Moreno, Lucas; Casanova, Michela; Chisholm, Julia C; Berlanga, Pablo; Chastagner, Pascal B; Baruchel, Sylvain; Amoroso, Loredana; Melcón, Soledad Gallego; Gerber, Nicolas U; Bisogno, Gianni; Fagioli, Franca; Geoerger, Birgit; Glade Bender, Julia L; Aerts, Isabelle; Bergeron, Christophe; Hingorani, Pooja; Elias, Ileana; Simcock, Mathew; Ferrara, Stefano; Le Bruchec, Yvan; Slepetis, Ruta; Chen, Nianhang; Vassal, Gilles

2018-06-21

nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty.

PubMed

Golpanian, Samuel; DiFede, Darcy L; Pujol, Marietsy V; Lowery, Maureen H; Levis-Dusseau, Silvina; Goldstein, Bradley J; Schulman, Ivonne H; Longsomboon, Bangon; Wolf, Ariel; Khan, Aisha; Heldman, Alan W; Goldschmidt-Clermont, Pascal J; Hare, Joshua M

2016-03-15

Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.

The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes.

PubMed

Pafili, K; Maltezos, E; Papanas, N

2016-10-01

There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion. In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM. Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.

Decision-theoretic designs for a series of trials with correlated treatment effects using the Sarmanov multivariate beta-binomial distribution.

PubMed

Hee, Siew Wan; Parsons, Nicholas; Stallard, Nigel

2018-03-01

The motivation for the work in this article is the setting in which a number of treatments are available for evaluation in phase II clinical trials and where it may be infeasible to try them concurrently because the intended population is small. This paper introduces an extension of previous work on decision-theoretic designs for a series of phase II trials. The program encompasses a series of sequential phase II trials with interim decision making and a single two-arm phase III trial. The design is based on a hybrid approach where the final analysis of the phase III data is based on a classical frequentist hypothesis test, whereas the trials are designed using a Bayesian decision-theoretic approach in which the unknown treatment effect is assumed to follow a known prior distribution. In addition, as treatments are intended for the same population it is not unrealistic to consider treatment effects to be correlated. Thus, the prior distribution will reflect this. Data from a randomized trial of severe arthritis of the hip are used to test the application of the design. We show that the design on average requires fewer patients in phase II than when the correlation is ignored. Correspondingly, the time required to recommend an efficacious treatment for phase III is quicker. © 2017 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effectiveness of crisis resource management and team debriefing in resuscitation education of nursing students: A randomised controlled trial.

PubMed

Coppens, Imgard; Verhaeghe, Sofie; Van Hecke, Ann; Beeckman, Dimitri

2018-01-01

The aim of this study was to investigate (i) whether integrating a course on crisis resource management principles and team debriefings in simulation training, increases self-efficacy, team efficacy and technical skills of nursing students in resuscitation settings and (ii) which phases contribute the most to these outcomes. Crisis resource management principles have been introduced in health care to optimise teamwork. Simulation training offers patient safe training opportunities. There is evidence that simulation training increases self-efficacy and team efficacy but the contribution of the different phases like crisis resource management principles, simulation training and debriefing on self-efficacy, team efficacy and technical skills is not clear. Randomised controlled trial in a convenience sample (n = 116) in Belgium. Data were collected between February 2015-April 2015. Participants in the intervention group (n = 60) completed a course on crisis resource management principles, followed by a simulation training session, a team debriefing and a second simulation training session. Participants in the control group (n = 56) only completed two simulation training sessions. The outcomes self-efficacy, team efficacy and technical skills were assessed after each simulation training. An ancillary analysis of the learning effect was conducted. The intervention group increased on self-efficacy (2.13%, p = .02) and team efficacy (9.92%, p < .001); the control group only increased significantly on team efficacy (4.5%, p = .001). The intervention group scored significantly higher on team efficacy (8.49%, p < .001) compared to the control group. Combining crisis resource management principles and team debriefings in simulation training increases self-efficacy and team efficacy. The debriefing phase contributes the most to these effects. By partnering with healthcare settings, it becomes possible to offer interdisciplinary simulation training that can increase patient safety. © 2017 John Wiley & Sons Ltd.

Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine.

PubMed

Lee, Choong-kun; Jung, Minkyu; Choi, Hye Jin; Kim, Hye Ryun; Kim, Hyo Song; Roh, Mi Ryung; Ahn, Joong Bae; Chung, Hyun Cheol; Heo, Su Jin; Rha, Sun Young; Shin, Sang Joon

2015-10-01

There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m(2) on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR). Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per-protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine.

Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study.

PubMed

Merchan, Jaime R; Qin, Rui; Pitot, Henry; Picus, Joel; Liu, Glenn; Fitch, Tom; Maples, William J; Flynn, Patrick J; Fruth, Briant F; Erlichman, Charles

2015-03-01

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS. Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

Nurse Home Visits Improve Maternal-Infant Interaction and Decrease Severity of Postpartum Depression

PubMed Central

Horowitz, June Andrews; Murphy, Christine A.; Gregory, Katherine; Wojcik, Joanne; Pulcini, Joyce; Solon, Lori

2013-01-01

Objective To test the efficacy of the relationship-focused behavioral coaching intervention Communicating and Relating Effectively (CARE) in increasing maternal-infant relational effectiveness between depressed mothers and their infants during the first nine months postpartum. Design Randomized clinical trial (RCT) with three phases. Methods In this three-phase study, women were screened for postpartum depression (PPD) in Phase I at 6 weeks postpartum. In Phase II, women were randomly assigned to treatment or control conditions and maternal-infant interaction was video-recorded at four intervals postpartum: 6 weeks, 3 months, 6 months, and 9 months. Phase III involved focus group and individual interviews with study participants. Setting Phase I mothers were recruited from obstetric units of two major medical centers. Phase II involved the RCT, a series of nurse-led home visits beginning at 6 weeks and ending at 9 months postpartum. Phase III focus groups were conducted at the university and personal interviews were conducted by telephone or in participants’ homes. Participants Postpartum mother-infant dyads (134) representative of southeastern New England, United States participated in the RCT. One hundred and twenty-five mother-infant dyads were fully retained in the 9-month protocol. Results Treatment and control groups had significant increases in quality of mother-infant interaction and decreases in depression severity. Qualitative findings indicated presence of the nurse, empathic listening, focused attention and self-reflection during data collection, directions for video-recorded interaction, and assistance with referrals likely contributed to improvements for both groups. Conclusions Efficacy of the CARE intervention was only partially supported. Nurse attention given to the control group and the data collection process likely confounded results and constituted an unintentional treatment. Results suggest that nurse-led home visits had a positive effect on outcomes for all participants. PMID:23682696

A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II.

PubMed

del Carmen Cravioto, M; Alvarado, G; Canto-de-Cetina, T; Bassol, S; Oropeza, G; Santos-Yung, R; Valencia, J; Palma, Y; Fuziwara, J L; Navarrete, T; Garza-Flores, J; Pérez-Palacios, G

1997-06-01

In order to assess efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II in Mexican women, a comparative phase III clinical trial was undertaken in eight clinics across the country. The study involved 1052 women who were followed-up trimonthly for three years. Cumulative pregnancy rates were 0.29% and 0.34% for Norplant and Norplant-II implants, respectively. Similar overall cumulative discontinuation rates were observed at three years: 50.38% for Norplant capsules, and 50.44% for Norplant-II rods. The main method-related reason for termination was endometrial bleeding irregularity which led to discontinuation rates of 11.94% and 11.62% for Norplant and Norplant-II contraceptive systems, respectively. In 15,279 woman-months of experience accumulated with Norplant implants and 14,092 with Norplant-II implants, there were few adverse events reported. No difference was found between the two groups in either difficulty for implants placement and removal or women's discomfort, even though the time required for insertion and removal of Norplant capsules was longer than for Norplant-II rods. It is concluded that during the first three years of use, both implants systems are equally effective, safe, and acceptable.

Strategies that target leukocyte traffic in inflammatory bowel diseases: recent developments.

PubMed

Rivera-Nieves, Jesús

2015-11-01

We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of inflammatory bowel diseases (IBD). We discuss the most important findings of one published phase II trial that targeted the β7 integrin (etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: mucosal addressin cell adhesion molecule 1 (MAdCAM-1, PF-00547659), a phase II trial targeting the chemokine IP-10 (CXCL10) in Crohn's, and a phase II trial that targeted the sphingosine-1-phosphate receptor-1: ozanimod in patients with ulcerative colitis. Targeting molecules involved in leukocyte traffic has recently become an effective and well tolerated strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn's. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin: immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules.

New clinical trial explores precision treatment for advanced pancreatic cancer | Center for Cancer Research

Cancer.gov

A new phase II clinical trial to assess the safety and efficacy of a drug called selumetinib for treating patients with advanced pancreatic cancer whose tumors harbor a specific genetic marker has opened at the Center for Cancer Research and is currently recruiting participants. Read more...

A Safety Run-in and Randomized Phase II Study of Cilengitide Combined with Chemoradiation for Newly Diagnosed Glioblastoma (NABTT 0306)

PubMed Central

Nabors, L. Burt; Mikkelsen, Tom; Hegi, Monika E.; Ye, Xiaubu; Batchelor, Tracy; Lesser, Glenn; Peereboom, David; Rosenfeld, Myrna R.; Olsen, Jeff; Brem, Steve; Fisher, Joy D.; Grossman, Stuart A.

2012-01-01

Background Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biological activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase II trial were to determine safety and efficacy of cilengitide when combined with radiation and temozolomide for newly diagnosed glioblastoma (GBM) and to select a dose for comparative clinical testing. Methods A total of 112 patients were accrued. Eighteen patients received standard RT+TMZ with cilengitide in a safety run-in phase followed by a randomized phase II with ninety-four patients assigned to either 500 or 2000 mg dose groups. The trial was designed to estimate overall survival benefit when compared with the NABTT internal historical control or the published EORTC 26981 data. Results Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for those receiving the 500 mg dose, 20.8 months for those receiving the 2000mg dose, 30 months for patients with methylated MGMT promoters and 17.4 months for unmethylated patients. For patients ages 70 and younger, the median survival and survival at 24 months was superior to that observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27% (p=0.008) respectively). Conclusions Cilengitide is well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with GBM regardless of MGMT status. From an efficacy and safety standpoint, future trials of this agent in this population should utilize the 2000 mg dose. PMID:22517399

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer

PubMed Central

Cutsem, Eric Van; Eng, Cathy; Nowara, Elzbieta; Świeboda-Sadlej, Anna; Tebbutt, Niall C.; Mitchell, Edith; Davidenko, Irina; Stephenson, Joe; Elez, Elena; Prenen, Hans; Deng, Hongjie; Tang, Rui; McCaffery, Ian; Oliner, Kelly S.; Chen, Lisa; Gansert, Jennifer; Loh, Elwyn; Smethurst, Dominic; Tabernero, Josep

2015-01-01

Purpose Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8,10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. PMID:24919569

Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis

PubMed Central

Subei, Adnan M.

2015-01-01

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor’s function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the United States in 2010 for relapsing MS after two phase 3 trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience as well as a third phase 3 trial (FREEDOMS II) also showed favorable results. More selective S1P receptor agents: ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303 are still in relatively early stages of development, but phase 1 and 2 trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase 3 clinical trials. PMID:26239599

Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02

PubMed Central

Lee, Eudocia Q.; Kuhn, John; Lamborn, Kathleen R.; Abrey, Lauren; DeAngelis, Lisa M.; Lieberman, Frank; Robins, H. Ian; Chang, Susan M.; Yung, W. K. Alfred; Drappatz, Jan; Mehta, Minesh P.; Levin, Victor A.; Aldape, Kenneth; Dancey, Janet E.; Wright, John J.; Prados, Michael D.; Cloughesy, Timothy F.; Gilbert, Mark R.; Wen, Patrick Y.

2012-01-01

The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID:23099651

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice.

PubMed

Ravaud, Alain; Bello, Carlo L

2011-06-01

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-naïve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P < 0.001). Median overall survival was 26.4 versus 21.8 months, respectively (P = 0.0510). In preclinical and phase I/II studies, sunitinib inhibits tyrosine kinase inhibitors in a dose-dependent manner, suggesting a correlation between increasing exposure and greater response. A pharmacokinetics/pharmacodynamics meta-analysis investigating the relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.

Safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment.

PubMed

Goldstein, I; Newman, L; Baum, N; Brooks, M; Chaikin, L; Goldberg, K; McBride, A; Krane, R J

1997-03-01

We investigated safety and efficacy outcome pertaining to the Mentor Alpha-1, 3-piece inflatable penile prosthesis for impotence treatment. A 2-phase, multi-institutional, large scale retrospective study, with independently analyzed medical record (phase I) and questionnaire (phase II) data from consecutive eligible patients of 7 physician investigators was performed from March to October 1993. In phase I there were no morbidities of any type in 394 of the 434 patients (90.8%) (mean age 61 years, range 24 to 88) who underwent Alpha-1 implantation (mean followup 22.2 months, range 0.67 to 44.5). The risk of prosthesis malfunction (fluid leak and auto-inflation) was 2.5%. No cylinder aneurysms were reported. A total of 93.1% of Alpha-1 devices was free from explantation (4.4%) or revision surgery (2.5%) for approximately 2 years from the original implant date. Kaplan-Meier actuarial analyses revealed that cumulative survival of the Alpha-1 prostheses at 12, 24 and 36 months was 98 +/- 1%, 93 +/- 2% and 85 +/- 7% until device malfunction, and 91 +/- 2% 83 +/- 4% and 75 +/- 7% until surgical intervention (revision or explantation). In phase II 89% of the men claimed fulfilled expectations with the Alpha-1 prosthesis as impotence treatment. Satisfaction responses 80% or greater were noted with regard to intercourse ability and confidence, and device rigidity and function. Implantation did not result in greater than 80% satisfaction in partner relationships or feelings (as judged by the patient), social or work confidence, or intercourse frequency. Factors adversely affecting satisfaction included partner feelings of dissatisfaction (as judged by the patient), specific physician investigators and need for explantation/revision surgery. In 1 of the largest multi-institutional implant outcome studies thus far performed, safety and efficacy data concerning the Alpha-1 contemporary inflatable device were found markedly improved over earlier inflatable prostheses and now compare favorably with historical data from noninflatable rod type devices.

Insecticide resistance profile of Anopheles gambiae from a phase II field station in Cové, southern Benin: implications for the evaluation of novel vector control products.

PubMed

Ngufor, Corine; N'Guessan, Raphael; Fagbohoun, Josias; Subramaniam, Krishanthi; Odjo, Abibatou; Fongnikin, Augustin; Akogbeto, Martin; Weetman, David; Rowland, Mark

2015-11-18

Novel indoor residual spraying (IRS) and long-lasting insecticidal net (LLIN) products aimed at improving the control of pyrethroid-resistant malaria vectors have to be evaluated in Phase II semi-field experimental studies against highly pyrethroid-resistant mosquitoes. To better understand their performance it is necessary to fully characterize the species composition, resistance status and resistance mechanisms of the vector populations in the experimental hut sites. Bioassays were performed to assess phenotypic insecticide resistance in the malaria vector population at a newly constructed experimental hut site in Cové, a rice growing area in southern Benin, being used for WHOPES Phase II evaluation of newly developed LLIN and IRS products. The efficacy of standard WHOPES-approved pyrethroid LLIN and IRS products was also assessed in the experimental huts. Diagnostic genotyping techniques and microarray studies were performed to investigate the genetic basis of pyrethroid resistance in the Cové Anopheles gambiae population. The vector population at the Cové experimental hut site consisted of a mixture of Anopheles coluzzii and An. gambiae s.s. with the latter occurring at lower frequencies (23 %) and only in samples collected in the dry season. There was a high prevalence of resistance to pyrethroids and DDT (>90 % bioassay survival) with pyrethroid resistance intensity reaching 200-fold compared to the laboratory susceptible An. gambiae Kisumu strain. Standard WHOPES-approved pyrethroid IRS and LLIN products were ineffective in the experimental huts against this vector population (8-29 % mortality). The L1014F allele frequency was 89 %. CYP6P3, a cytochrome P450 validated as an efficient metabolizer of pyrethroids, was over-expressed. Characterizing pyrethroid resistance at Phase II field sites is crucial to the accurate interpretation of the performance of novel vector control products. The strong levels of pyrethroid resistance at the Cové experimental hut station make it a suitable site for Phase II experimental hut evaluations of novel vector control products, which aim for improved efficacy against pyrethroid-resistant malaria vectors to WHOPES standards. The resistance genes identified can be used as markers for further studies investigating the resistance management potential of novel mixture LLIN and IRS products tested at the site.

Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design.

PubMed

Trachtman, Howard; Vento, Suzanne; Gipson, Debbie; Wickman, Larysa; Gassman, Jennifer; Joy, Melanie; Savin, Virginia; Somers, Michael; Pinsk, Maury; Greene, Tom

2011-02-10

The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases.

Exploring the statistical and clinical impact of two interim analyses on the Phase II design with option for direct assignment.

PubMed

An, Ming-Wen; Mandrekar, Sumithra J; Edelman, Martin J; Sargent, Daniel J

2014-07-01

The primary goal of Phase II clinical trials is to understand better a treatment's safety and efficacy to inform a Phase III go/no-go decision. Many Phase II designs have been proposed, incorporating randomization, interim analyses, adaptation, and patient selection. The Phase II design with an option for direct assignment (i.e. stop randomization and assign all patients to the experimental arm based on a single interim analysis (IA) at 50% accrual) was recently proposed [An et al., 2012]. We discuss this design in the context of existing designs, and extend it from a single-IA to a two-IA design. We compared the statistical properties and clinical relevance of the direct assignment design with two IA (DAD-2) versus a balanced randomized design with two IA (BRD-2) and a direct assignment design with one IA (DAD-1), over a range of response rate ratios (2.0-3.0). The DAD-2 has minimal loss in power (<2.2%) and minimal increase in T1ER (<1.6%) compared to a BRD-2. As many as 80% more patients were treated with experimental vs. control in the DAD-2 than with the BRD-2 (experimental vs. control ratio: 1.8 vs. 1.0), and as many as 64% more in the DAD-2 than with the DAD-1 (1.8 vs. 1.1). We illustrate the DAD-2 using a case study in lung cancer. In the spectrum of Phase II designs, the direct assignment design, especially with two IA, provides a middle ground with desirable statistical properties and likely appeal to both clinicians and patients. Copyright © 2014 Elsevier Inc. All rights reserved.

A phase II flexible screening design allowing for interim analysis and comparison with historical control.

PubMed

Wu, Wenting; Bot, Brian; Hu, Yan; Geyer, Susan M; Sargent, Daniel J

2013-07-01

Sargent and Goldberg [1] proposed a randomized phase II flexible screening design (SG design) which took multiple characteristics of candidate regimens into consideration in selecting a regimen for further phase III testing. In this paper, we extend the SG design by including provisions for an interim analysis and/or a comparison to a historical control. By including a comparison with a historical control, a modified SG design not only identifies a more promising treatment but also assures that the regimen has a clinically meaningful level of efficacy as compared to a historical control. By including an interim analysis, a modified SG design could reduce the number of patients exposed to inferior treatment regimens. When compared to the original SG design, the modified designs increase the sample size moderately, but expand the utility of the flexible screening design substantially. Copyright © 2013 Elsevier Inc. All rights reserved.

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

PubMed Central

2012-01-01

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances. PMID:22587874

The Effect of a Multiple Treatment Program and Maintenance Procedures on Smoking Cessation.

ERIC Educational Resources Information Center

Powell, Don R.

The efficacy of a multiple treatment smoking cessation program and three maintenance strategies was evaluated. Phases I and II of the study involved 51 subjects who participated in a five-day smoking cessation project consisting of lectures, demonstrations, practice exercises, negative smoking, and the teaching of self-control procedures. At the…

Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial.

PubMed

Wong, Wai T; Kam, Waynekid; Cunningham, Denise; Harrington, Molly; Hammel, Keri; Meyerle, Catherine B; Cukras, Catherine; Chew, Emily Y; Sadda, Srinivas R; Ferris, Frederick L

2010-12-01

To investigate the safety and preliminary efficacy of OT-551, a disubstituted hydroxylamine with antioxidant properties, for the treatment of geographic atrophy (GA), the advanced atrophic form of age-related macular degeneration (AMD). The study was a single-center, open-label phase II trial, enrolling 10 participants with bilateral GA. Topical 0.45% OT-551 was administered in one randomly assigned eye three times daily for 2 years. Safety measures were assessed by complete ophthalmic examination, fundus photography, and review of symptoms. The primary efficacy outcome measure was the change in best corrected visual acuity at 24 months. Secondary efficacy measures included changes in area of GA, contrast sensitivity, microperimetry measurements, and total drusen area from baseline. Study drug was well tolerated and was associated with few adverse events. The mean change in BCVA at 2 years was +0.2 ± 13.3 letters in the study eyes and -11.3 ± 7.6 letters in fellow eyes (P = 0.0259). However, no statistically significant differences were found between the study and fellow eyes for all other secondary outcome measures. OT-551 was well tolerated by study participants and was not associated with any serious adverse effects. Efficacy measurements in this small study indicate a possible effect in maintaining visual acuity. However, the absence of significant effects on other outcomes measures in this study suggests that OT-551, in the current concentration and mode of delivery, may have limited or no benefit as a treatment for GA (ClinicalTrials.gov number, NCT00306488).

A study comparing centralized CD-ROM and decentralized intranet access to MEDLINE

PubMed Central

Darmoni, Stefan J.; Benichou, Jacques; Thirion, Benoit; Hellot, Marie France; Fuss, Jacques

2000-01-01

Objective: The purpose of this study was to evaluate the efficacy of a decentralized intranet access in each medical department as opposed to centralized unique MEDLINE access in the medical library. Design: A two-phase questionnaire to evaluate MEDLINE use was given to junior and senior physicians at Rouen University Hospital (RUH). Phase I (August–October 1996) corresponded to a time period when centralized access was the only means of access available and phase II (August–October 1997) to a time period following the introduction of decentralized intranet access. Results: A total of 168 physicians filled out at least one phase of the questionnaire, among whom 123 (73%) filled out both phases. Use of MEDLINE significantly increased in 1997 (average of 10.2 ± 1.1 searches in three months) versus 1996 (average of 4.9 ± 0.7 searches in three months, P < 0.0001). The aim of searches changed, becoming significantly more care oriented in phase II (P < 0.0001). The number of searches performed by the physicians alone increased (P < 0.0001) and searches performed by the librarian decreased (P < 0.0001) in phase II. The method of searches also changed, as searches by author (P < 0.0001), by journal (P = 0.0042), and by free word (P = 0.0027) increased in phase II. Knowledge of the following concepts of MEDLINE significantly increased: explosion (P < 0.0001), scope note (P < 0.0001), Abridged Index Medicus (AIM) journals (P < 0.0001), Medical Subject Headings (MeSH) qualifier (P < 0.0001), and focus (P < 0.0001). Conclusion: A decentralized intranet access to MEDLINE increased the number of searches and knowledge of this bibliographic database. MEDLINE intranet access modified the purpose and the methods of searching. PMID:10783970

Progress in HIV vaccine development

PubMed Central

Hsu, Denise C.; O'Connell, Robert J.

2017-01-01

ABSTRACT An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of protection is the induction of functional antibodies to V1V2 region of HIV envelope. The 2 main current approaches to the generation of protective immunity are through broadly neutralizing antibodies (bnAb) and induction of functional antibodies (non-neutralizing Abs with other potential anti-viral functions). Passive immunization using bnAb has advanced into phase II clinical trials. The induction of bnAb using mimics of the natural Env trimer or B-cell lineage vaccine design is still in pre-clinical phase. An attempt at optimization of protective functional antibodies will be assessed next with the efficacy trial (HVTN702) about to start. With on-going optimization of prime/boost strategies, the development of mosaic immunogens, replication competent vectors, and emergence of new strategies designed to induce bnAb, the prospects for a preventive HIV vaccine have never been more promising. PMID:28281871

Translating and testing the ENABLE: CHF-PC concurrent palliative care model for older adults with heart failure and their family caregivers.

PubMed

Dionne-Odom, J Nicholas; Kono, Alan; Frost, Jennifer; Jackson, Lisa; Ellis, Daphne; Ahmed, Ali; Azuero, Andres; Bakitas, Marie

2014-09-01

Heart failure (HF) and palliative care (PC) organizations recommend early PC to improve the quality of life of patients living with HF. We conducted a two-phase formative evaluation study to translate a cancer-focused concurrent PC intervention into one that would be appropriate for rural-dwelling adults with New York Heart Association Class III-IV HF and their primary caregivers. Phase I: We tailored the intervention for an HF population via literature review, expert consultation, and clinician (N=15) small group interviews. Phase II: We enrolled 11 patient/caregiver dyads to assess intervention feasibility and satisfaction. We assessed participants' experiences and satisfaction after session/week three and session/week six via digitally recorded interviews. Clinician and participant interviews were transcribed and content analyzed. Outcome measures were evaluated for completion rates and effect sizes. Phase I: Clinicians described barriers to initiating PC in HF, triggers for initiating PC, and suggestions for intervention improvement. Phase II: Participants were able to complete the majority of study sessions, measures, and interviews. Satisfaction interviews revealed the content to be relevant and comprehensive in addressing HF patient and caregiver primary concerns; however, participants unanimously suggested making the intervention available earlier in the illness trajectory. Efficacy measures demonstrated small to medium effect sizes. We tailored and demonstrated feasibility of providing an early, concurrent palliative care intervention to patients with advanced HF and their caregivers. Based on this experience we are now conducting an efficacy trial in a racially diverse sample.

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.

PubMed

Basarab, Gregory S; Kern, Gunther H; McNulty, John; Mueller, John P; Lawrence, Kenneth; Vishwanathan, Karthick; Alm, Richard A; Barvian, Kevin; Doig, Peter; Galullo, Vincent; Gardner, Humphrey; Gowravaram, Madhusudhan; Huband, Michael; Kimzey, Amy; Morningstar, Marshall; Kutschke, Amy; Lahiri, Sushmita D; Perros, Manos; Singh, Renu; Schuck, Virna J A; Tommasi, Ruben; Walkup, Grant; Newman, Joseph V

2015-07-14

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

PubMed Central

Basarab, Gregory S.; Kern, Gunther H.; McNulty, John; Mueller, John P.; Lawrence, Kenneth; Vishwanathan, Karthick; Alm, Richard A.; Barvian, Kevin; Doig, Peter; Galullo, Vincent; Gardner, Humphrey; Gowravaram, Madhusudhan; Huband, Michael; Kimzey, Amy; Morningstar, Marshall; Kutschke, Amy; Lahiri, Sushmita D.; Perros, Manos; Singh, Renu; Schuck, Virna J. A.; Tommasi, Ruben; Walkup, Grant; Newman, Joseph V.

2015-01-01

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy. PMID:26168713

A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.

PubMed

André, F E; Foulkes, M A

1998-01-01

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

PubMed Central

Hamilton, Betty K.; Rosen, Mark A.; Amaravadi, Ravi K.; Schuchter, Lynn M.; Gallagher, Maryann; Chen, Helen; Sehgal, Chandra; O’Dwyer, Peter J.

2015-01-01

Background. Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis. Patients and Methods. We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks. Results. A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors. Conclusion. Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients. Implications for Practice: Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a standalone therapy in renal cell carcinoma and glioblastoma multiforme. Also, enhancement of conventional cytotoxic chemotherapy efficacy has been observed in colorectal, non-small-cell lung, breast, and ovarian cancers. Optimal strategies to cotarget angiogenic cytokines combined with VEGF have not been defined. It was found that bevacizumab could be safely combined with imatinib, which was used as a platelet-derived growth factor receptor inhibitor in our study. High-dose imatinib-related edema was not observed when paired with bevacizumab. This regimen might be suitable for further investigation in other cancers but apparently not in melanoma. PMID:26084808

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma.

PubMed

Reardon, David A; Nabors, Louis B; Mason, Warren P; Perry, James R; Shapiro, William; Kavan, Petr; Mathieu, David; Phuphanich, Surasak; Cseh, Agnieszka; Fu, Yali; Cong, Julie; Wind, Sven; Eisenstat, David D

2015-03-01

This phase I/II trial evaluated the maximum tolerated dose (MTD) and pharmacokinetics of afatinib plus temozolomide as well as the efficacy and safety of afatinib as monotherapy (A) or with temozolomide (AT) vs temozolomide monotherapy (T) in patients with recurrent glioblastoma (GBM). Phase I followed a traditional 3 + 3 dose-escalation design to determine MTD. Treatment cohorts were: afatinib 20, 40, and 50 mg/day (plus temozolomide 75 mg/m(2)/day for 21 days per 28-day cycle). In phase II, participants were randomized (stratified by age and KPS) to receive A, T or AT; A was dosed at 40 mg/day and T at 75 mg/m(2) for 21 of 28 days. Primary endpoint was progression-free survival rate at 6 months (PFS-6). Participants were treated until intolerable adverse events (AEs) or disease progression. Recommended phase II dose was 40 mg/day (A) + T based on safety data from phase I (n = 32). Most frequent AEs in phase II (n = 119) were diarrhea (71% [A], 82% [AT]) and rash (71% [A] and 69% [AT]). Afatinib and temozolomide pharmacokinetics were unaffected by coadministration. Independently assessed PFS-6 rate was 3% (A), 10% (AT), and 23% (T). Median PFS was longer in afatinib-treated participants with epidermal growth factor receptor (EFGR) vIII-positive tumors versus EGFRvIII-negative tumors. Best overall response included partial response in 1 (A), 2 (AT), and 4 (T) participants and stable disease in 14 (A), 14 (AT), and 21 (T) participants. Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Strategies that Target Leukocyte Traffic in IBD: Recent Developments

PubMed Central

Rivera-Nieves, Jesús

2015-01-01

Purpose of review We review the most recent developments regarding the targeting of molecules involved in the traffic of leukocytes for the treatment of IBD. Recent Findings We discuss the most important findings of one published phase II trial that targeted the β7 integrin (Etrolizumab), two phase II trials that targeted the α4β7 integrin ligand: Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1, PF-00547659), a phase II targeting the chemokine IP-10 (CXCL10) in Crohn’s and a phase II trial that targeted the sphingosine-1-phosphate receptor-1 (S1P1): ozanimod in patients with ulcerative colitis (UC). Summary Targeting molecules involved in leukocyte traffic has recently become an effective and safe strategy for the treatment of IBD. Novel approaches now not only target the integrins on the lymphocyte surface, but also its endothelial ligand: MAdCAM-1. As with vedolizumab, antibodies against MAdCAM-1 appear most effective in ulcerative colitis rather than in Crohn’s. Targeting chemokines or their receptors does not appear to have the same efficacy as those that target the most stable integrin:immunoglobulin superfamily interactions between the lymphocyte and endothelium. Preliminary results also suggest that the sphingosine-1-phosphate pathway might also be targeted therapeutically in IBD, no longer with parenterally administered antibodies but with orally administered small molecules. PMID:26398681

Ebola virus vaccine: benefit and risks of adenovirus-based vectors.

PubMed

Mennechet, Franck J D; Tran, Thi Thu Phuong; Eichholz, Karsten; van de Perre, Philippe; Kremer, Eric J

2015-01-01

In 2014, an outbreak of Ebola virus spread rapidly in West Africa. The epidemic killed more than 10,000 people and resulted in transmissions outside the endemic countries. WHO hopes for effective vaccines by the end of 2015. Numerous vaccine candidates have been proposed, and several are currently being evaluated in humans. Among the vaccine candidates are vectors derived from adenovirus (Ad). Despite previous encouraging preclinical and Phase I/II trials, Ad vectors used in three Phase II trials targeting HIV were prematurely interrupted because of the lack of demonstrated efficacy. The vaccine was not only ineffective but also led to a higher rate of HIV acquisition. In this context, the authors discuss the potential benefits, risks and impact of using Ad-derived vaccines to control Ebola virus disease.

A Phase II Randomized Trial (GO27827) of First‐Line FOLFOX Plus Bevacizumab with or Without the MET Inhibitor Onartuzumab in Patients with Metastatic Colorectal Cancer

PubMed Central

Hochster, Howard; Hart, Lowell L.; Firdaus, Irfan; Mace, Joseph R.; McFarlane, Joshua J.; Kozloff, Mark; Catenacci, Daniel; Hsu, Jessie J.; Hack, Stephen P.; Shames, David S.; Phan, See‐Chun; Koeppen, Hartmut; Cohn, Allen L.

2017-01-01

Abstract Background. Dysregulated hepatocyte growth factor/mesenchymal‐epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double‐blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX‐6 and bevacizumab for mCRC (GO27827; NCT01418222). Materials and Methods. Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX‐6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8–12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression‐free survival (PFS) in the intent‐to‐treat (ITT) and MET immunohistochemistry (IHC) expression‐positive populations. Results. Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC‐positive populations. An improvement in PFS was noted in the MET IHC‐negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. Conclusion. Onartuzumab combined with mFOLFOX‐6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC‐positive populations. MET expression by IHC was not a predictive biomarker in this setting. Implications for Practice. The addition of onartuzumab to mFOLFOX‐6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard‐of‐care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal‐epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway. PMID:28209746

Efficacy and safety of Lian-Ju-Gan-Mao capsules for treating the common cold with wind-heat syndrome: study protocol for a randomized controlled trial.

PubMed

Wang, Shengjun; Jiang, Hongli; Yu, Qin; She, Bin; Mao, Bing

2017-01-05

The common cold is a common and frequent respiratory disease mainly caused by viral infection of the upper respiratory tract. Chinese herbal medicine has been increasingly prescribed to treat the common cold; however, there is a lack of evidence to support the wide utility of this regimen. This protocol describes an ongoing phase II randomized controlled clinical trial, based on the theory of traditional Chinese medicine (TCM), with the objective of evaluating the efficacy and safety of Lian-Ju-Gan-Mao capsules (LJGMC), a Chinese patent medicine, compared with placebo in patients suffering from the common cold with wind-heat syndrome (CCWHS). This is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. A total of 240 patients will be recruited and randomly assigned to a high-dose group, medium-dose group, low-dose group, and placebo-matched group in a 1:1:1:1 ratio. The treatment course is 3 consecutive days, with a 5-day follow-up. The primary outcome is time to all symptoms' clearance. Secondary outcomes include time to the disappearance of primary symptoms and each secondary symptom, time to fever relief, time to fever clearance, and change in TCM symptom and sign scores. This trial is a well-designed study according to principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high-quality evidence on the efficacy and safety of LJGMC in treating CCWHS and help to optimize the dose for the next phase III clinical trial. Moreover, the protocol presents a detailed and practical methodology for future clinical trials of drugs developed based on TCM. Chinese Clinical Trial Registry, ChiCTR-IPR-15006504 . Registered on 4 June 2015.

Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial

PubMed Central

Wasunna, Monique; Njenga, Simon; Balasegaram, Manica; Alexander, Neal; Omollo, Raymond; Edwards, Tansy; Dorlo, Thomas P. C.; Musa, Brima; Ali, Mohammed Hassan Sharaf; Elamin, Mohammed Yasein; Kirigi, George; Kip, Anke E.; Schoone, Gerard J.; Hailu, Asrat; Olobo, Joseph; Ellis, Sally; Kimutai, Robert; Wells, Susan; Khalil, Eltahir Awad Gasim; Strub Wourgaft, Nathalie; Alves, Fabiana; Musa, Ahmed

2016-01-01

Background SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. Methods A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. Results In sequential analyses with 49–51 patients per arm, initial cure was 85% (95% CI: 73–92) in all arms. At D210, definitive cure was 87% (95% CI: 77–97) for AmBisome + SSG, 77% (95% CI 64–90) for AmBisome + miltefosine and 72% (95% CI 60–85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. Conclusion No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. Trial Registration The study was registered with ClinicalTrials.gov, number NCT01067443 PMID:27627654

miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer.

PubMed

Tanaka, Hironori; Hazama, Shoichi; Iida, Michihisa; Tsunedomi, Ryouichi; Takenouchi, Hiroko; Nakajima, Masao; Tokumitsu, Yukio; Kanekiyo, Shinsuke; Shindo, Yoshitaro; Tomochika, Shinobu; Tokuhisa, Yoshihiro; Sakamoto, Kazuhiko; Suzuki, Nobuaki; Takeda, Shigeru; Yamamoto, Shigeru; Yoshino, Shigefumi; Ueno, Tomio; Hamamoto, Yoshihiko; Fujita, Yusuke; Tanaka, Hiroaki; Tahara, Ko; Shimizu, Ryoichi; Okuno, Kiyotaka; Fujita, Koji; Kuroda, Masahiko; Nakamura, Yusuke; Nagano, Hiroaki

2017-11-01

Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse-transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR-378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027-7.585; P = 0.044). In conclusion, miR-125b-1 and miR-378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PREVENT Cancer Preclinical Drug Development Program (PREVENT) | Division of Cancer Prevention

Cancer.gov

The PREVENT program provides a structure for the introduction of new agents, drugs and vaccines to inhibit, retard or reverse the cancer process. The program was designed to optimize translational opportunities from discovery to the clinic, and provide a mechanism to identify and study efficacy and pharmacodynamics biomarkers that will help in phase II trials to evaluate drug

A Phase II Study of the Central European Society of Anticancer-Drug Research (CESAR) Group: Results of an Open-Label Study of Gemcitabine plus Cisplatin with or without Concomitant or Sequential Gefitinib in Patients with Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium.

PubMed

Miller, Kurt; Morant, Rudolf; Stenzl, Arnulf; Zuna, Ivan; Wirth, Manfred

2016-01-01

This phase II trial evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, in combination with first-line chemotherapy in advanced urothelial cancer. Chemotherapy-naïve patients with advanced or metastatic urothelial carcinoma were randomized 1:1:1 to receive six cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1 of every cycle) concomitantly with gefitinib 250 mg/day (arm A); or with sequential gefitinib (arm B); or alone (arm C). The primary endpoint was the time to progression (TTP). A total of 105 patients received study treatment. Median TTP for arms A, B, and C were 6.1, 6.3, and 7.8 months, respectively. There were no significant differences between treatment arms for any outcomes measured. The most common adverse events were nausea and vomiting. Gefitinib in combination with chemotherapy did not improve efficacy in advanced urothelial cancer. © 2015 S. Karger AG, Basel.

Antibody for the prevention of neonatal noscocomial staphylococcal infection: a review of the literature.

PubMed

Weisman, L E

2007-09-01

Staphylococci, especially coagulase negative staphylococci (CONS), are responsible for over 75 % of late-onset infections in very low birth weight infants. These infections cause increased length of hospital stay, need for antibiotics, and cost of medical care. Several drug companies have developed and evaluated hyperimmune polyclonal and monoclonal antibodies for the prevention of neonatal staphylococcal infection including 1) Altastaph by North American Biologics Inc., 2) Veronate by Inhibitex Inc., and 3) Pagibaximab by Biosynexus Inc, and Glaxo Smith Kline Inc. We will review the development and status of these potential products. Altastaph is a S. aureus serotype 5 and 8 vaccine induced hyperimmune polyclonal antibody whose development has been placed on hold due to its failure to demonstrate any trend toward efficacy in a recently completed Phase II study. Veronate is a polyclonal antibody obtained by plasmapheresis from donors with high titers of MSCRAMM (microbial surface components recognizing adhesion matrix molecules) activity against CONS whose development has been placed on hold due to its failure to demonstrate effectiveness in a recently completed Phase III study. Pagibaximab is a humanized mouse chimeric monoclonal antibody (previously known as BSYX-A110) directed against lipoteichoic acid (LTA), a major cell wall component of gram-positive bacteria, that has recently completed a Phase II study suggesting efficacy and is being developed further for clinical investigation.

Innovations in Clinical Trial Design in the Era of Molecular Profiling.

PubMed

Wulfkuhle, Julia D; Spira, Alexander; Edmiston, Kirsten H; Petricoin, Emanuel F

2017-01-01

Historically, cancer has been studied, and therapeutic agents have been evaluated based on organ site, clinical staging, and histology. The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available, and this has necessitated an evolution in clinical trial design. The traditional, large phase II and phase III adjuvant trial models need to be replaced with smaller, shorter, and more focused trials. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames. New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need.

Apatinib for the treatment of gastric cancer.

PubMed

Roviello, Giandomenico; Ravelli, Andrea; Fiaschi, Anna Ida; Cappelletti, Maria Rosa; Gobbi, Angela; Senti, Chiara; Zanotti, Laura; Polom, Karol; Reynolds, Andrew R; Fox, Stephen B; Generali, Daniele

2016-08-01

Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models. Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer. Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cancer.

Bovine rotavirus pentavalent vaccine development in India.

PubMed

Zade, Jagdish K; Kulkarni, Prasad S; Desai, Sajjad A; Sabale, Rajendra N; Naik, Sameer P; Dhere, Rajeev M

2014-08-11

A bovine rotavirus pentavalent vaccine (BRV-PV) containing rotavirus human-bovine (UK) reassortant strains of serotype G1, G2, G3, G4 and G9 has been developed by the Serum Institute of India Ltd, in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), USA. The vaccine underwent animal toxicity studies and Phase I and II studies in adults, toddlers and infants. It has been found safe and immunogenic and will undergo a large Phase III study to assess efficacy against severe rotavirus gastroenteritis. Copyright © 2014. Published by Elsevier Ltd.

Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain.

PubMed

Ezzati, Mohammad; Carr, Bruce R

2015-01-01

Suppression of estrogen production and reduction of menstrual blood flow are the mainstays of medical treatment of endometriosis-related pain and have been traditionally achieved by methods such as combined hormonal contraception, progestins and GnRH analogs, all with comparable efficacies, though different side-effect profiles. Elagolix is the frontrunner among an emerging class of GnRH antagonists, which unlike their peptide predecessors has a nonpeptide structure resulting in its oral bioavailability. Phase I and II clinical trials have demonstrated safety of elagolix and its efficacy in partial and reversible suppression of ovarian estrogen production resulting in improvements in endometriosis-related pain. Phase III clinical trials are currently underway and elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension.

PubMed

Mende, Christian W; Giles, Thomas D; Bharucha, David B; Ferguson, William G; Mallick, Madhuja; Patel, Mehul D

2017-06-01

Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a β 1 -selective adrenergic blocker with vasodilatory properties via β 3 -agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m 2 ; n=1823) and nonobese (body mass index <27 kg/m 2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity. © 2017 The Authors. The Journal of Clinical Hypertension Published by Wiley Periodicals, Inc.

Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group trial N0745 (Alliance)

PubMed Central

Hubbard, Joleen M.; Mahoney, Michelle R.; Loui, William S.; Roberts, Lewis R.; Smyrk, Thomas C.; Gatalica, Zoran; Borad, Mitesh; Kumar, Shaji; Alberts, Steven R.

2017-01-01

Background Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis. Objective To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC. Patients and Methods Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1–28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID. Results 17 patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. 7 patients were enrolled onto the phase II component at the MTD: sorafenib 200 mg BID days 1–28 and bevacizumab 2.5 mg/kg every other week. 57% (4/7) had grade 3 AEs at least possibly related to treatment,. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4–16.3) and 13.3 months (95% CI 4.4 – not estimable), respectively. Conclusions The MTD of the combination is sorafenib 200 mg twice daily on days 1–28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.) PMID:27943153

Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema

PubMed Central

Fong, Angie HC; Lai, Timothy YY

2013-01-01

Neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumab treatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed. PMID:23766636

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

PubMed

Bank, J R; Rabelink, T J; de Fijter, J W; Reinders, M E J

2015-01-01

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

Ethinyl estradiol and levonorgestrel in a transdermal contraceptive delivery system.

PubMed

Sriprasert, Intira; Stanczyk, Frank Z; Archer, David F

2015-01-01

The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.

Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice

PubMed Central

Tajerian, Maral; Leu, David; Yang, Phillip; Huang, Ting Ting; Kingery, Wade S; Clark, J David

2015-01-01

Background Complex regional pain syndrome (CRPS) is a painful, disabling and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system (CNS) changes. Ketamine is a centrally-acting agent believed to work through blockade of N-methyl-D-aspartate (NMDA) receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug’s effects and efficacy at different stages of the syndrome remain unclear. Methods We used a mouse model of CRPS (n=8–12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg/kg/day; 7 days) or vehicle infusion during acute (3weeks [3w] post-fracture) and chronic (7w post-fracture) stages. Results Acute phase fracture mice displayed elevated limb temperature, edema and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks post-fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including NMDA receptor 2b (NR2b), Ca2+/calmodulin-dependent protein kinase ii (CaMK2), and brain-derived neurotrophic factor (BNDF). Conclusions Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute stages of CRPS, suggesting that the centrally-acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization. PMID:26492479

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine ({sup 131}I) metuximab injection: Clinical Phase I/II trials

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

Chen Zhinan; Mi Li; Xu Jing

2006-06-01

Purpose: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine ({sup 131}I) metuximab injection (Licartin), a novel {sup 131}I-labeled HAb18G/CD147-specific monoclonal antibody F(ab'){sub 2} fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. Methods and Materials: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. Results: No life-threatening toxicmore » effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p 0.0019). Conclusion: Iodine ({sup 131}I) metuximab injection is safe and active for HCC patients.« less

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.

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

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

PubMed

Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

2014-10-28

Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

PubMed Central

Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

2013-01-01

Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. Trial registration clinicaltrials.gov NCT01237119. PMID:24189085

Investigational Drugs for Visceral Leishmaniasis

PubMed Central

Sundar, Shyam; Chakravarty, Jaya

2014-01-01

Introduction The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed. Areas covered Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL. Expert opinion Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development. PMID:25409760

Phase II drugs currently being investigated for the treatment of hypogonadism.

PubMed

Udedibia, Emeka; Kaminetsky, Jed

2014-12-01

Hypogonadism is the most common endocrine disorder, which affects men of all age groups. Recent shifts in public awareness, increased screening and recognition of symptoms and updated diagnostic criteria have led to an increase in men diagnosed as hypogonadal, including middle-aged and older men who previously would have been considered eugonadal. The increase in testosterone replacement therapy (TRT) has paralleled an increase in advancements of treatment options. Although current therapies are highly efficacious for many men, there remains a need for newer therapies that are more cost-effective, preserve ease of use and administration, mitigate undesirable effects and closely mimic physiological levels of testosterone. In this review, the authors discuss current TRTs and therapies in development for the treatment of hypogonadism. The focus is on therapies under Phase II investigation or those who have recently completed Phase II study. With several new therapies in development, the authors expect advancements in achieving treatment benchmarks that meet the needs of the individual symptomatic hypogonadal male. Increased public awareness of hypogonadism and TRT has led to a welcomed expansion in the choice of TRT options. These include new delivery systems, formulations, routes of administration and non-testosterone modalities.

Phase II trial of the association of a methionine-free diet with cystemustine therapy in melanoma and glioma.

PubMed

Thivat, Emilie; Farges, Marie-Chantal; Bacin, Franck; D'Incan, Michel; Mouret-Reynier, Marie-Ange; Cellarier, Eric; Madelmont, Jean-Claude; Vasson, Marie-Paule; Chollet, Philippe; Durando, Xavier

2009-12-01

In a previous phase I clinical trial of dietary methionine (MET) restriction with cystemustine treatment for melanoma or glioma, we determined the optimal MET-free diet duration to be 1 day. On this basis, a phase II clinical trial was initiated to evaluate safety and efficacy of this combination. Twenty-two patients (20 with metastatic melanoma and 2 with recurrent gloma) received a median of 4 cycles of the association of a 1-day MET-free diet with cystemustine (60 mg/m(2)) every two weeks. This association was well tolerated (toxicity and nutritional status). Toxicity remained mainly hematological and consisted of WHO grade 3-4 thrombocytopenia, leucopenia and neutropenia in 36, 27 and 27% of patients respectively. The median disease-free survival was 1.8 months and the median survival was 4.6 months, with 2 long-duration stabilizations. The plasmatic MET depletion obtained was of 40 + or - 31%.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures.

PubMed

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R; Schreiber, Fred; Anderson, Kyle

2012-01-21

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures

PubMed Central

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E.; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R.; Schreiber, Fred; Anderson, Kyle

2014-01-01

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention. PMID:24533253

Human Data Supporting Glyburide in Ischemic Stroke

PubMed Central

Sheth, Kevin N.; Simard, J. Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W. Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous (IV) formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. Early phase II study of MRI and plasma biomarkers support the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase IIb study and definitive efficacy studies are urgently needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative. PMID:26463916

Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis.

PubMed

Fukihara, Jun; Kondoh, Yasuhiro

2016-12-01

Nintedanib is a new anti-fibrosis agent that is an intracellular tyrosine kinase inhibitor targeting platelet derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor. Although nintedanib is attracting much attention as a new treatment option for patients with idiopathic pulmonary fibrosis (IPF), the clinical evidence is limited mainly to the results from the dose-deciding phase II TOMORROW trial and phase III INPULSIS trials, which evaluated efficacy and safety of nintedanib for patients with IPF, prespecified subgroup analyses, pooled analyses and meta-analyses derived from those trials. Areas covered: In this document, we mainly reviewed reports on working mechanisms of nintedanib, and efficacy and safety of nintedanib for patients with IPF. The literature search was undertaken using Pub Med. Expert commentary: It is unknown whether the efficacy of nintedanib in patients enrolled in the clinical trials will be the same for the entire spectrum of patients, including patients unfit for the clinical trials due to age, severity, timing of IPF diagnosis or diagnosis of interstitial pneumonias other than IPF. Sufficient consideration should be given when selecting candidates for nintedanib in the real world.

The Potential of Cellular- and Viral-Based Immunotherapies for Malignant Glioma-Dendritic Cell Vaccines, Adoptive Cell Transfer, and Oncolytic Viruses.

PubMed

Maxwell, Russell; Luksik, Andrew S; Garzon-Muvdi, Tomas; Lim, Michael

2017-06-01

Malignant gliomas, including glioblastoma and anaplastic astrocytoma, are the most frequent primary brain tumors and present with many treatment challenges. In this review, we discuss the potential of cellular- and viral-based immunotherapies in the treatment of malignant glioma, specifically focusing on dendritic cell vaccines, adoptive cell therapy, and oncolytic viruses. Diverse cellular- and viral-based strategies have been engineered and optimized to generate either a specific or broad antitumor immune response in malignant glioma. Due to their successes in the preclinical arena, many of these therapies have undergone phase I and II clinical testing. These early clinical trials have demonstrated the feasibility, safety, and efficacy of these immunotherapies. Dendritic cell vaccines, adoptive cell transfer, and oncolytic viruses may have a potential role in the treatment of malignant glioma. However, these modalities must be investigated in well-designed phase III trials to prove their efficacy.

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting.

PubMed

De Stefano, Valerio; Rocca, Bianca; Tosetto, Alberto; Soldati, Denise; Petrucci, Giovanna; Beggiato, Eloise; Bertozzi, Irene; Betti, Silvia; Carli, Giuseppe; Carpenedo, Monica; Cattaneo, Daniele; Cavalca, Viviana; Dragani, Alfredo; Elli, Elena; Finazzi, Guido; Iurlo, Alessandra; Lanzarone, Giuseppe; Lissandrini, Laura; Palandri, Francesca; Paoli, Chiara; Rambaldi, Alessandro; Ranalli, Paola; Randi, Maria Luigia; Ricco, Alessandra; Rossi, Elena; Ruggeri, Marco; Specchia, Giorgina; Timillero, Andrea; Turnu, Linda; Vianelli, Nicola; Vannucchi, Alessandro M; Rodeghiero, Francesco; Patrono, Carlo

2018-06-01

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A 2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB 2 , a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB 2 as a reliable end point for dose-finding studies of novel aspirin regimens.

Experimental Lung Cancer Drug Shows Early Promise | Poster

Cancer.gov

By Frank Blanchard, Staff Writer A first-of-its-kind drug is showing early promise in attacking certain lung cancers that are hard to treat because they build up resistance to conventional chemotherapy. The drug, CO-1686, performed well in a preclinical study involving xenograft and transgenic mice, as reported in the journal Cancer Discovery. It is now being evaluated for safety and efficacy in Phase I and II clinical trials.

Secukinumab in the Treatment of Psoriasis and Psoriatic Arthritis: A Review of the Literature.

PubMed

Abrouk, M; Gandy, J; Nakamura, M; Lee, K; Brodsky, M; Singh, R; Zhu, H; Farahnik, B; Bhutani, T; Koo, J

2017-07-01

While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx®) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug.

A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS.

PubMed

Bozik, Michael E; Mitsumoto, Hiroshi; Brooks, Benjamin R; Rudnicki, Stacy A; Moore, Dan H; Zhang, Bing; Ludolph, Albert; Cudkowicz, Merit E; van den Berg, Leonard H; Mather, James; Petzinger, Thomas; Archibald, Donald

2014-09-01

Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

PubMed Central

Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

2011-01-01

Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia.

PubMed

Liu, Yang; Zhang, Yingyuan; Wu, Jufang; Zhu, Demei; Sun, Shenghua; Zhao, Li; Wang, Xuefeng; Liu, Hua; Ren, Zhenyi; Wang, Changzheng; Xiu, Qingyu; Xiao, Zuke; Cao, Zhaolong; Cui, Shehuai; Yang, Heping; Liang, Yongjie; Chen, Ping; Lv, Yuan; Hu, Chengping; Lv, Xiaoju; Liu, Shuang; Kuang, Jiulong; Li, Jianguo; Wang, Dexi; Chang, Liwen

2017-12-01

To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in treating community-acquired pneumonia (CAP) in a Phase II clinical trial. One hundred ninety-two patients with CAP were randomized to receive oral nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at the test of cure (TOC) visit in the full analysis set (FAS). The clinical cure rate of nemonoxacin (500 mg), nemonoxacin (750 mg), and levofloxacin (500 mg) was 93.3%, 87.3%, and 88.5%, respectively, in the FAS (n = 168), and 93.0%, 93.9%, and 88.9%, respectively in the per protocol set (n = 152). At the TOC visit, nemonoxacin at 500 mg and 750 mg was proven to be noninferior to levofloxacin at 500 mg in the FAS in terms of clinical efficacy. The overall bacteriological success rate was 83.3% in both nemonoxacin groups and 80.0% in the levofloxacin 500 mg group in the bacteriological FAS. The comprehensive efficacy rate was comparable among the three groups (87.5% for the nemonoxacin 500 mg group, 93.8% for the nemonoxacin 750 mg group, and 81.3% for the levofloxacin 500 mg group). Most drug-related adverse events were mild and transient, mainly gastrointestinal symptoms such as nausea and vomiting, transient neutropenia, and elevated liver enzymes. No drug-related serious adverse events occurred. Either 500 mg or 750 mg of oral nemonoxacin taken once daily for 7-10 days demonstrated high clinical and bacteriological success rates in Chinese adult patients with CAP. Nemonoxacin at 500 mg once daily for 7-10 days is recommended for future Phase III clinical trials. ClinicalTrials.gov identifier: NCT01537250. Copyright © 2015. Published by Elsevier B.V.

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

Clinical feasibility of the Nintendo Wii™ for balance training post-stroke: a phase II randomized controlled trial in an inpatient setting.

PubMed

Bower, Kelly J; Clark, Ross A; McGinley, Jennifer L; Martin, Clarissa L; Miller, Kimberly J

2014-09-01

To investigate the feasibility and potential efficacy of the Nintendo Wii™ for balance rehabilitation after stroke. Phase II, single-blind, randomized controlled trial. Inpatient rehabilitation facility. Thirty adults (mean age 63.6 (14.7) years) undergoing inpatient rehabilitation who were less than three months post-stroke and able to stand unsupported. Participants were allocated to a Balance Group, using the 'Wii Fit Plus' in standing, or Upper Limb Group, using the 'Wii Sports/Sports Resort' in sitting. Both groups undertook three 45 minute sessions per week over two to four weeks in addition to standard care. The primary focus was feasibility, addressed by recruitment, retention, adherence, acceptability and safety. Efficacy was evaluated by balance, mobility and upper limb outcomes. Twenty-one percent of individuals screened were recruited and 86% (n = 30) of eligible people agreed to participate. Study retention and session adherence was 90% and > 99%, respectively, at two weeks; dropping to 70% and 87% at four weeks due to early discharge. All participants reported enjoying the sessions and most felt they were beneficial. No major adverse events occurred. Wii use by the Balance Group was associated with trends for improved balance, with significantly greater improvement in outcomes including the Step Test and Wii Balance Board-derived centre of pressure scores. The Upper Limb Group had larger, non-significant changes in arm function. A Wii-based approach appears feasible and promising for post-stroke balance rehabilitation. A larger randomized controlled trial is recommended to further investigate efficacy. © The Author(s) 2014.

Determinants of exercise among children. II. A longitudinal analysis.

PubMed

DiLorenzo, T M; Stucky-Ropp, R C; Vander Wal, J S; Gotham, H J

1998-01-01

Research has demonstrated that physical activity serves an important preventive function against the development of cardiovascular disease. The recognition that U.S. children are often sedentary, coupled with the observation that physical activity habits tend to persist into adulthood, has prompted the investigation of exercise determinants consistent with social learning theory. The purposes of the present study were to identify social learning variables relevant to children's exercise and to explore the longitudinal predictive value of the determinants. Data were collected from 111 families (N = 54 girls, N = 57 boys) who were interviewed in both Phase 1 (fifth and sixth grades) and Phase 2 (eight and ninth grades) of this study. Data from mothers (N = 111) were collected during both phases; data from 80 fathers were collected at Phase 2 only. The results of simultaneous stepwise regression analyses indicated that child's enjoyment of physical activity was the only consistent predictor of physical activity during Phase 1. At Phase 2, child's exercise knowledge, mother's physical activity, and child's and mother's friend modeling/support emerged as predictors for girls. For boys, child's self-efficacy for physical activity, exercise knowledge, parental modeling, and interest in sports media were important. Longitudinally, mother's self-efficacy, barriers to exercise, enjoyment of physical activity, and child's self-efficacy for physical activity were important for girls. Only child's exercise knowledge predicted boys' physical activity. The addition of information from fathers nearly doubled the explanatory power of the predictors for both genders. Socialization in the family unit exerts a tremendous influence on health-related behaviors such as exercise. The relative importance of determinants seems to differ for girls and boys and the pattern of these determinants appears to change over time.

Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial.

PubMed

Abe, Masakazu; Hirashima, Yasuyuki; Kasamatsu, Yuka; Kado, Nobuhiro; Komeda, Satomi; Kuji, Shiho; Tanaka, Aki; Takahashi, Nobutaka; Takekuma, Munetaka; Hihara, Hanako; Ichikawa, Yoshikazu; Itonaga, Yui; Hirakawa, Tomoko; Nasu, Kaei; Miyagi, Kanoko; Murakami, Junko; Ito, Kimihiko

2016-02-01

Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.

Sexual risk behaviour of Canadian participants in the first efficacy trial of a preventive HIV-1 vaccine

PubMed Central

Lampinen, Thomas M.; Chan, Keith; Remis, Robert S.; Fikre Merid, Maraki; Rusch, Melanie; Vincelette, Jean; Logue, Ken; Popovic, Vladimir; Alary, Michel; Schechter, Martin T.; Hogg, Robert S.

2005-01-01

Background Phase I and phase II HIV-1 vaccine trials have revealed increases in risky sexual activity among study subjects during the trials, perhaps because the subjects believe that the vaccine being tested is efficacious; subjects may thus suffer harm from their participation. We evaluated the sexual behaviour of Canadian men who have sex with men (MSM) who participated in the phase III Vax004 trial of an HIV-1 vaccine. Methods Using self-reports of sexual behaviours during the 6 months before trial entry as a baseline, we determined changes in reported sexual behaviour after 6, 12 and 18 months of participation in the trial. Results Of 291 HIV-seronegative MSM enrolled from July to October 1999, 260 (89%) completed 18 months of follow-up, 19 (7%) experienced seroconversion, and 12 (4%) did not complete follow-up. Unprotected receptive anal intercourse during the previous 6 months with partners whose HIV-1 serostatus was positive or unknown was reported by 21% of men at enrolment and by 27% at any point during 18 months of follow-up. No increase in this behaviour from baseline was reported by participants, including among men who were motivated to enrol because of expected protection from HIV-1 infection, men who believed they had received the vaccine, men who believed that the vaccine had greater than 50% efficacy, or men who believed that they had received the vaccine and that vaccine efficacy was greater than 50%. Interpretation MSM can be successfully enrolled in HIV-1 vaccine efficacy trials without evident increases in those sexual behaviours most associated with HIV-1 risk. PMID:15710939

Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma.

PubMed

Kong, Lin; Hu, Jiyi; Guan, Xiyin; Gao, Jing; Lu, Rong; Lu, Jiade J

2016-01-01

Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion radiation therapy offers an ideal alternate to conventional X-ray irradiation. The recommended dose of re-irradiation using CIRT for locally recurrent NPC will be determined in the dose-escalating phase (Phase I) of the study. Efficacy in terms of local progression-free survival (LPFS) and overall survival (OS) will be studied in the second phase of the study. Increasing doses of CIRT using raster scanning technology from 55GyE (22×2.5 GyE) to 65 GyE (26× 2.5 GyE) will be delivered in the Phase I part of the study. The primary endpoint of the Phase I part of the study is acute and sub-acute toxicities; the primary endpoint in the Phase II part is local progression-free survival and overall survival. Using the historical 2-year OS rate of 50% in locally recurrent NPC patients treated with photon or proton, we hypothesize that CIRT can improve the 2-year OS rate to 70%. The utilization of conventional radiation techniques including IMXT, brachytherapy, or stereotactic radiation therapy provides moderate efficacy in the treatment of locally recurrent NPC due to the limitations in dose distribution and biological effectiveness. Improved outcome in terms of treatment-induced toxicity, LC, LPFS, and OS are expected using CIRT due to the physical and biological characteristics of carbon ion beam. However, the recommended dose of CIRT used in re-irradiation for the local NPC focus remain to be determined. The recommended dose as well as the efficacy of CIRT in the treatment of locally recurrent NPC will be evaluated in the present trial.

A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy.

PubMed

Nakashima, Kazuhisa; Murakami, Haruyasu; Yokoyama, Kouichi; Omori, Shota; Wakuda, Kazushige; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Nishiyama, Fumie; Kikugawa, Mami; Kaneko, Masayo; Iwamoto, Yumiko; Koizumi, Satomi; Mori, Keita; Isobe, Takeshi; Takahashi, Toshiaki

2017-09-01

The three-drug combination of a 5-hydroxytryptamine type 3 receptor antagonist, a neurokinin 1 receptor antagonist and dexamethasone is recommended for patients receiving highly emetogenic chemotherapy. However, standard antiemetic therapy is not completely effective in all patients. We conducted an open-label, single-center, single-arm Phase II study to evaluate the efficacy of olanzapine in combination with standard antiemetic therapy in preventing chemotherapy-induced nausea and vomiting in patients with thoracic malignancy receiving their first cycle of cisplatin-based chemotherapy. Patients received 5 mg oral olanzapine on Days 1-5 in combination with standard antiemetic therapy. The primary endpoint was complete response (no vomiting and no use of rescue therapy) during the overall Phase (0-120 h post-chemotherapy). Twenty-three men and seven women were enrolled between May and October 2015. The median age was 64 years (range: 36-75 years). The most common chemotherapy regimen was 75 mg/m2 cisplatin and 500 mg/m2 pemetrexed, which was administered to 14 patients. Complete response rates in acute (0-24 h post-chemotherapy), delayed (24-120 h post-chemotherapy) and overall phases were 100%, 83% and 83% (90% confidence interval: 70-92%; 95% confidence interval: 66-93%), respectively. There were no Grade 3 or Grade 4 adverse events. Although four patients (13%) experienced Grade 1 somnolence, no patients discontinued olanzapine. The addition of 5 mg oral olanzapine to standard antiemetic therapy demonstrates promising efficacy in preventing cisplatin-based chemotherapy-induced nausea and vomiting and an acceptable safety profile in patients with thoracic malignancy. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

"I Wanna Be the Very Best!" Agreeableness and Perseverance Predict Sustained Playing to Pokémon Go: A Longitudinal Study.

PubMed

Lalot, Fanny; Zerhouni, Oulmann; Pinelli, Mathieu

2017-10-01

The smartphone game Pokémon Go™ has attracted much scientific attention regarding its potential health-related outcomes. Most studies, however, limited their investigation to short-term outcomes. The aim of the present study is to investigate the role of personality traits in predicting sustained playing to the game on a 6-month period as well as related health outcomes in terms of distance walked per day. Pokémon Go players from 10 countries were recruited through social media and answered an online questionnaire. At Phase I (August 2016), 402 participants provided their game statistics and filled an extensive personality inventory (six main personality traits, impulsivity, need for cognition, need for closure, competitiveness, and self-efficacy). At Phase II (December 2016), 151 participants indicated whether they were still playing or not and provided updated game statistics. No personality traits predicted the distance walked by the players. However, the probability of still being playing the game at Phase II was positively predicted by three personality traits: agreeableness, perseverance, and premeditation. Distance walked per day significantly decreased between Phases I and II but remained substantial. This study identified three personality traits that predicted sustained playing and thus potentially higher game-related physical activity in the long run. In comparison with prior work, this study goes a step forward by (i) investigating personality traits underlying use of the game and related health outcomes, and (ii) providing longitudinal data concerning the use of the game. Findings open new perspectives for the development of other exergames.

Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia.

PubMed

von Stackelberg, Arend; Locatelli, Franco; Zugmaier, Gerhard; Handgretinger, Rupert; Trippett, Tanya M; Rizzari, Carmelo; Bader, Peter; O'Brien, Maureen M; Brethon, Benoît; Bhojwani, Deepa; Schlegel, Paul Gerhardt; Borkhardt, Arndt; Rheingold, Susan R; Cooper, Todd Michael; Zwaan, Christian M; Barnette, Phillip; Messina, Chiara; Michel, Gérard; DuBois, Steven G; Hu, Kuolung; Zhu, Min; Whitlock, James A; Gore, Lia

2016-12-20

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m 2 /d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m 2 /d for the first 7 days, followed by 15 µg/m 2 /d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II study.

PubMed

Martínez, Carmen; Solano, Carlos; Ferrá, Christelle; Sampol, Antonia; Valcárcel, David; Pérez-Simón, José Antonio

2009-05-01

We conducted a phase II trial to investigate the safety and efficacy of alemtuzumab in treating steroid-refractory acute graft-versus-host disease (aGVHD) grade II or higher after stem cell transplantation. Ten adult patients (6 with aGVHD grade III and 4 with aGVHD grade IV) were included in the study. Nine patients had gastrointestinal tract involvement, 7 had skin involvement, and 5 had liver involvement. Five patients responded to treatment, 2 with complete response and 3 with partial response. Eight infectious events (4 of grade 3-4) and 7 cytomegalovirus (CMV) reactivations were observed. Six patients had grade 3-4 cytopenia. All 10 patients died (7 resulting from aGVHD progression, 2 from severe infection, and 1 from to leukemia relapse), at a median of 40 days (range, 4 to 88 days) after alemtuzumab treatment. Overall, our findings suggest that steroid-refractory aGVHD may be improved by treatment with alemtuzumab, but that this treatment does not overcome the dismal prognosis of patients with severe aGVHD, demonstrating the need for alternative therapies to treat this complication.

Prospective phase II study evaluating the efficacy of swallow ability screening tests and pneumonia prevention using a team approach for elderly patients with gastric cancer.

PubMed

Miki, Yuichiro; Makuuchi, Rie; Honda, Shinsaku; Tokunaga, Masanori; Tanizawa, Yutaka; Bando, Etsuro; Kawamura, Taiichi; Yurikusa, Takashi; Tanuma, Akira; Terashima, Masanori

2018-03-01

Aging partly impairs swallowing function, which is considered a risk factor for postoperative pneumonia (PP). We evaluated the efficacy of a new team-based strategy to reduce the incidence of PP in elderly patients with gastric cancer. This single-center, prospective phase II study included elderly patients (≥75 years old) with gastric cancer undergoing gastric surgery. The primary endpoint was the incidence of Clavien-Dindo grade II or higher PP. Patients were initially screened using three swallowing function screening tests: a symptom questionnaire, the modified water swallow test (MSWT), and the repetitive saliva swallowing test (RSST). All patients were provided standard preoperative oral checks and care and simple neck muscle training. For patients who screened positive, a videofluorographic swallowing study was performed; if an abnormality was found, the patient was given intensive swallowing rehabilitation both pre- and postoperatively. Of 86 eligible patients enrolled, PP developed in 3 (3.5%). The 60% confidence interval of 1.8-6.3% had an upper limit below the prespecified threshold of 7.8%. Positive screening results were found for 19 patients (22.1%) on the symptom questionnaire, 3 (3.5%) on the MSWT, and 1 (1.2%) on the RSST. PP was not observed in any patients who screened positive. In conclusion, although the screening tests we adopted here were not sufficient to identify patients at high risk of aspiration pneumonia, perioperative interventions using a team approach might be effective in reducing the incidence of PP in elderly patients with gastric cancer.

Development and validation of a questionnaire assessing the perceived control in health care among older adults with care needs in the Netherlands.

PubMed

Claassens, L; Terwee, C B; Deeg, D J H; Broese van Groenou, M I; Widdershoven, G A M; Huisman, M

2016-04-01

In response to the increased emphasis placed on older people's self-reliance in many welfare societies, we aimed to develop and validate a measurement instrument, assessing perceived control in health care among older adults with care needs. The target group consists of older people who live (semi-)independently and use professional health care, with or without informal care. Phase I (development) of the study consisted of the construction of the instrument based on the input from a variety of stakeholders. Phase II (validation) entailed a quantitative study in a sample of 247 respondents selected from the Longitudinal Aging Study Amsterdam, to assess the instrument's construct validity (structural validity and hypotheses testing) and reliability (internal consistency). The questionnaire consists of 29 items, related to organizing professional care, communication with care professionals, health management in the home situation, planning (more) complex care in the future, and perceived support from the social network. Based on a factor analysis, we identified three subscales: (I.) 'perceived personal control in health care'; (II.) 'anticipated personal control regarding future health care'; and (III.) 'perceived support from the social network,' with internal consistencies varying from Cronbach's α = .71 to .90. Factor I was associated with mastery, self-efficacy, self-esteem (r = .31-.35) and factor III with social loneliness (r = -.42). Factor II correlated less strongly with mastery, self-efficacy, and self-esteem (r < .30). Our questionnaire revealed sufficient construct validity and internal consistency. The instrument provides a basis for further quantitative research regarding control, especially in relation to health care-related outcomes.

A phase I/II trial of oxidized autologous tumor vaccines during the "watch and wait" phase of chronic lymphocytic leukemia.

PubMed

Spaner, David E; Hammond, Caitlin; Mena, Jenny; Foden, Cindy; Deabreu, Andrea

2005-07-01

Based on their activity in patients with advanced stage chronic lymphocytic leukemia (CLL), a phase I/II study was designed to evaluate the feasibility, safety, and efficacy of autologous vaccines made from oxidized tumor cells in patients with earlier stage CLL, and to determine an optimal schedule of injections. Eighteen patients (at risk for disease progression and with white blood cell counts between 15 and 100 x 10(6) cells/ml) were injected intramuscularly with 10 ml of oxidized autologous blood (composed mainly of CLL cells) either 12 times over 6 weeks (group 1), 12 times over 16 days (group 2), or 4 times over 6 weeks (group 3). Fourteen out of eighteen patients had Rai stage 0-II disease, while 4/18 had stage III-IV disease but did not require conventional treatment. Partial clinical responses, associated with enhanced anti-tumor T cell activity in vitro, were observed in 5/18 patients of whom three were in group 2. Stable disease was observed in six patients while disease progression appeared not to be affected in the remaining patients. Toxicity was minimal. Vaccination with oxidized autologous tumor cells appears worthy of further investigation and may be a potential alternative to a "watch and wait" strategy for selected CLL patients.

Bayesian Phase II optimization for time-to-event data based on historical information.

PubMed

Bertsche, Anja; Fleischer, Frank; Beyersmann, Jan; Nehmiz, Gerhard

2017-01-01

After exploratory drug development, companies face the decision whether to initiate confirmatory trials based on limited efficacy information. This proof-of-concept decision is typically performed after a Phase II trial studying a novel treatment versus either placebo or an active comparator. The article aims to optimize the design of such a proof-of-concept trial with respect to decision making. We incorporate historical information and develop pre-specified decision criteria accounting for the uncertainty of the observed treatment effect. We optimize these criteria based on sensitivity and specificity, given the historical information. Specifically, time-to-event data are considered in a randomized 2-arm trial with additional prior information on the control treatment. The proof-of-concept criterion uses treatment effect size, rather than significance. Criteria are defined on the posterior distribution of the hazard ratio given the Phase II data and the historical control information. Event times are exponentially modeled within groups, allowing for group-specific conjugate prior-to-posterior calculation. While a non-informative prior is placed on the investigational treatment, the control prior is constructed via the meta-analytic-predictive approach. The design parameters including sample size and allocation ratio are then optimized, maximizing the probability of taking the right decision. The approach is illustrated with an example in lung cancer.

Proposed Modifications to the Conceptual Model of Coaching Efficacy and Additional Validity Evidence for the Coaching Efficacy Scale II-High School Teams

ERIC Educational Resources Information Center

Myers, Nicholas; Feltz, Deborah; Chase, Melissa

2011-01-01

The purpose of this study was to determine whether theoretically relevant sources of coaching efficacy could predict the measures derived from the Coaching Efficacy Scale II-High School Teams (CES II-HST). Data were collected from head coaches of high school teams in the United States (N = 799). The analytic framework was a multiple-group…

Atezolizumab: A Review in Previously Treated Advanced Non-Small Cell Lung Cancer.

PubMed

Blair, Hannah A

2018-05-21

Atezolizumab (TECENTRIQ™), an immune checkpoint inhibitor, is an immunoglobulin G1 monoclonal antibody that binds to programmed death ligand 1 (PD-L1) and blocks its interactions with programmed death 1 and B7.1 receptors. Atezolizumab is approved as monotherapy in several countries worldwide for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. Approval was based on its clinical benefit in this setting in the phase II POPLAR and phase III OAK trials. In these studies, atezolizumab significantly prolonged overall survival (OS) relative to docetaxel, regardless of PD-L1 status. Increasing PD-L1 expression was associated with OS improvements. Atezolizumab also demonstrated efficacy in the phase II FIR and BIRCH trials, as assessed by objective response rates (ORRs) in patients with tumours expressing PD-L1. Higher ORRs were seen in patients with high PD-L1 expression. Atezolizumab had an acceptable, manageable tolerability profile, with a low incidence of immune-related adverse events. Therefore, atezolizumab is a valuable treatment option for patients with advanced NSCLC that has progressed during or after chemotherapy.

Imaging the Molecular Signatures of Apoptosis and Injury with Radiolabeled Annexin V

PubMed Central

Blankenberg, Francis G.

2009-01-01

Annexin V is a ubiquitous intracellular protein in humans that has a variety of intriguing characteristics, including a nanomolar affinity for the membrane-bound constitutive anionic phospholipid known as phosphatidylserine (PS). PS is selectively expressed on the surface of apoptotic or physiologically stressed cells. As such, radiolabeled forms of annexin V have been used in both animal models and human Phase I and Phase II trials to determine if this tracer can be employed as an early surrogate marker of therapeutic efficacy in NSCLC and non-Hodgkin's lymphoma. Many other pulmonary imaging applications of radiolabeled annexin V are also possible, including the detection and monitoring of active pulmonary inflammation and other pathophysiologic stressors in a variety of diseases. In this article, the salient molecular features of apoptosis (and other forms of cell death) that permits imaging with radiolabeled annexin V will be discussed. The latest results from Phase II imaging trials with NSCLC and non-Hodgkin's lymphoma will be also be detailed. Finally, the potential future application of this tracer for the imaging of other pulmonary pathologies will be outlined. PMID:19687221

A Two-Phase Pilot Study to Evaluate the Safety and Tolerability of an In Situ Polymerizing Collagen.

PubMed

Inglefield, Christopher; Rone-McCrate, Rebecca; Brooks, Robert; Zhu, Jiaxun; Grant, Sheila; DeVore, Dale P

2017-09-01

Demand for collagen-based fillers has declined primarily because of limited long-term clinical benefit and the introduction of hyaluronic acid compositions. In situ polymerizing collagen is a noncrosslinked solution of porcine collagen containing a collagenase shield that undergoes fibrillogenesis on injected into tissues forming a natural matrix. Conduct a prospective, single-center, dual-phase open-label study in 8 subjects to evaluate the safety, tolerability, and efficacy of the porcine collagen composition. In Phase I, potential hypersensitivity of the collagen composition was evaluated after skin testing in the back (men) or forearms of subjects (women). In Phase II, subjects showing no signs of hypersensitivity received collagen injections into the nasolabial area followed by evaluation at 1, 4, 8, and 12 weeks using the Global Aesthetic Improvement Scale. None of the subjects had signs of hypersensitivity and all continued in Phase II. The treating physician(s) reported no post-treatment adverse events. Improvement of the nasolabial fold was observed by the physicians and confirmed by assessment of high-resolution photographs and Global Aesthetic Improvement Scale scores over the 12-week treatment were maintained. In this pilot clinical study in situ polymerizing collagen was shown to be safe and effective throughout the 3-month study period.

Randomized double-blind placebo-controlled multicenter evaluation of efficacy and dose finding of midodrine hydrochloride in women with mild to moderate stress urinary incontinence: a phase II study.

PubMed

Weil, E H; Eerdmans, P H; Dijkman, G A; Tamussino, K; Feyereisl, J; Vierhout, M E; Schmidbauer, C; Egarter, C; Kölle, D; Plasman, J E; Heidler, H; Abbühl, B E; Wein, W

1998-01-01

Midodrine is a potent and selective alpha1-receptor agonist and its potential to increase urethral closure pressure could be useful in the treatment of female stress incontinence. The aim of this randomized double-blind placebo-controlled multicenter study was to evaluate the efficacy and safety of midodrine for the treatment of stress urinary incontinence. The primary criterion of efficacy was the maximum urethral closure pressure at rest. Voiding diaries, symptom and incontinence questionnaires and patient/investigator global assessment were also used to evaluate its efficacy. After 4 weeks of treatment no significant changes in MUCP were found. The global assessment by the patient and investigator did indicate that patients on active treatment had a more positive assessment than the placebo group. In conclusion, midodrine did not cause significant improvements in urodynamic parameters, but there were subjective improvements in some of the patients in the treated groups. Furthermore midodrine was well tolerated.

Obeticholic Acid

PubMed Central

Smith, Susan M.; Pegram, Angela H.

2017-01-01

Objective: To review the pharmacology, efficacy, and safety of obeticholic acid (OCA) and determine its clinical role relative to other agents in the treatment of patients with primary biliary cholangitis (PBC). Data Sources: A PubMed search (1946 to November 2016) was conducted using the terms INT-747, obeticholic acid, OCA, farnesoid X receptor agonists, FXR agonists, primary biliary cirrhosis, and primary biliary cholangitis. Study Selection and Data Extraction: Phase II and III studies evaluating the use of OCA in PBC patients were included in this review. Data Synthesis: OCA, a farnesoid X receptor (FXR) agonist, is indicated for adult patients with PBC in combination with ursodeoxycholic acid (UDCA) or as monotherapy if unable to tolerate UDCA. Two clinical trials were identified evaluating OCA for the treatment of PBC. Study end points utilized biochemical markers (alkaline phosphatase [ALP] and bilirubin). A phase II study (n = 165) to determine efficacy and safety of OCA at 3 different doses (10 mg, 25 mg, 50 mg) demonstrated statistically significant reductions in ALP (P < .0001 for all OCA groups versus placebo) after 12 weeks. A phase III trial (n = 217) assessed lower OCA doses (5 mg and 10 mg) with a longer study duration (12 months). Statistically significant differences (P < .001) between the 5 to 10 mg group (46%) and the 10 mg group (47%) compared to the placebo group (10%) were found. The primary adverse effect reported in both trials was pruritus. Conclusions: OCA is the first FXR agonist approved for the treatment of PBC. Ongoing research to evaluate clinical outcomes with OCA is currently underway.

Daunorubicin and Cytarabine Liposome in Newly Diagnosed Therapy-Related Acute Myeloid Leukemia (AML) or AML With Myelodysplasia-Related Changes.

PubMed

Kim, Miryoung; Williams, Sherry

2018-03-01

To evaluate the efficacy and safety of daunorubicin and cytarabine liposome in older adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). A literature search of PubMed and MEDLINE (January 2017 to January 2018) was performed using the terms CPX-351, Vyxeos, daunorubicin and cytarabine liposome, and acute myeloid leukemia. Phase I, II, and III clinical trials evaluating the efficacy and safety of daunorubicin and cytarabine liposome were reviewed with a specific focus on its use in older patients with newly diagnosed AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. The phase II trial demonstrated that daunorubicin and cytarabine liposome improved response rates (RR), but there was no difference in event-free survival and overall survival in the overall patient population. However, clinical benefit was most pronounced in secondary AML with an increased RR and survival. The phase III trial illustrated that daunorubicin and cytarabine liposome improved survival and RR with tolerable toxicity compared with standard 7 plus 3 (daunorubicin and cytarabine) in patients 60 to 75 years of age with t-AML or AML-MRC. More patients proceeded to a stem cell transplant, and 30-day and 60-day mortality was lower with daunorubicin and cytarabine liposome. Grade 3 to 5 toxicities were similar between the 2 groups, except daunorubicin and cytarabine liposome had prolonged cytopenia and a higher risk of hemorrhage. Daunorubicin and cytarabine liposome improves RR and survival, with tolerable toxicity in older patients with t-AML or AML-MRC.

A randomized, double-blind, cross-over, phase IV trial of oros-methylphenidate (CONCERTA(®)) and generic novo-methylphenidate ER-C (NOVO-generic).

PubMed

Fallu, Angelo; Dabouz, Farida; Furtado, Melissa; Anand, Leena; Katzman, Martin A

2016-08-01

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with onset during childhood. Multiple aspects of a child's development are hindered, in both home and school settings, with negative impacts on social, emotional, and cognitive functioning. If left untreated, ADHD is commonly associated with poor academic achievement and low occupational status, as well as increased risk of substance abuse and delinquency. The objective of this study was to evaluate adult ADHD subject reported outcomes when switched from a stable dose of CONCERTA(®) to the same dose of generic Novo-methylphenidate ER-C(®). Randomized, double-blind, cross-over, phase IV trial consisted of two phases in which participants with a primary diagnosis of ADHD were randomized in a 1:1 ratio to 3 weeks of treatment with CONCERTA or generic Novo-Methylphenidate ER-C. Following 3 weeks of treatment, participants were crossed-over to receive the other treatment for an additional 3 weeks. Primary efficacy was assessed through the use of the Treatment Satisfaction Questionnaire for Medication, Version II (TSQM-II). Participants with ADHD treated with CONCERTA were more satisfied in terms of efficacy and side effects compared to those receiving an equivalent dose of generic Novo-Methylphenidate ER-C. All participants chose to continue with CONCERTA treatment at the conclusion of the study. Although CONCERTA and generic Novo-Methylphenidate ER-C have been deemed bioequivalent, however the present findings demonstrate clinically and statistically significant differences between generic and branded CONCERTA. Further investigation of these differences is warranted.

Boron neutron capture therapy (BNCT) for glioblastoma multiforme: a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA).

PubMed

Henriksson, Roger; Capala, Jacek; Michanek, Annika; Lindahl, Sten-Ake; Salford, Leif G; Franzén, Lars; Blomquist, Erik; Westlin, Jan-Erik; Bergenheim, A Tommy

2008-08-01

To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.

A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes.

PubMed

Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Yamamoto, Daigo; Yoshidome, Katsuhide; Ogura, Hiroyuki; Terasawa, Risa; Matsunami, Nobuki; Takahashi, Yuko; Nitta, Toshikatsu; Morimoto, Takashi; Fujioka, Hiroya; Kawaguchi, Kanako; Uchiyama, Kazuhisa

2018-05-01

Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC. We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL). A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1-53.2%). The CBR was 54.3% (95% CI 37.8-70.8%). The median PFS was 6.2 months (95% CI 2.7-9.4 months) and median OS was 21.4 months (95% CI 11.5-32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients. Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.

Controlling motion sickness and spatial disorientation and enhancing vestibular rehabilitation with a user-worn see-through display.

PubMed

Krueger, Wesley W O

2011-01-01

An eyewear mounted visual display ("User-worn see-through display") projecting an artificial horizon aligned with the user's head and body position in space can prevent or lessen motion sickness in susceptible individuals when in a motion provocative environment as well as aid patients undergoing vestibular rehabilitation. In this project, a wearable display device, including software technology and hardware, was developed and a phase I feasibility study and phase II clinical trial for safety and efficacy were performed. Both phase I and phase II were prospective studies funded by the NIH. The phase II study used repeated measures for motion intolerant subjects and a randomized control group (display device/no display device) pre-posttest design for patients in vestibular rehabilitation. Following technology and display device development, 75 patients were evaluated by test and rating scales in the phase II study; 25 subjects with motion intolerance used the technology in the display device in provocative environments and completed subjective rating scales, whereas 50 patients were evaluated before and after vestibular rehabilitation (25 using the display device and 25 in a control group) using established test measures. All patients with motion intolerance rated the technology as helpful for nine symptoms assessed, and 96% rated the display device as simple and easy to use. Duration of symptoms significantly decreased with use of the technology displayed. In patients undergoing vestibular rehabilitation, there were no significant differences in amount of change from pre- to posttherapy on objective balance tests between display device users and controls. However, those using the technology required significantly fewer rehabilitation sessions to achieve those outcomes than the control group. A user-worn see-through display, utilizing a visual fixation target coupled with a stable artificial horizon and aligned with user movement, has demonstrated substantial benefit for individuals susceptible to motion intolerance and spatial disorientation and those undergoing vestibular rehabilitation. The technology developed has applications in any environment where motion sensitivity affects human performance.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

PubMed

Naseri, Mohammad Hassan; Madani, Hoda; Ahmadi Tafti, Seyed Hossein; Moshkani Farahani, Maryam; Kazemi Saleh, Davood; Hosseinnejad, Hossein; Hosseini, Saeid; Hekmat, Sepideh; Hossein Ahmadi, Zargham; Dehghani, Majid; Saadat, Alireza; Mardpour, Soura; Hosseini, Seyedeh Esmat; Esmaeilzadeh, Maryam; Sadeghian, Hakimeh; Bahoush, Gholamreza; Bassi, Ali; Amin, Ahmad; Fazeli, Roghayeh; Sharafi, Yaser; Arab, Leila; Movahhed, Mansour; Davaran, Saeid; Ramezanzadeh, Narges; Kouhkan, Azam; Hezavehei, Ali; Namiri, Mehrnaz; Kashfi, Fahimeh; Akhlaghi, Ali; Sotoodehnejadnematalahi, Fattah; Vosough Dizaji, Ahmad; Gourabi, Hamid; Syedi, Naeema; Shahverdi, Abdol Hosein; Baharvand, Hossein; Aghdami, Nasser

2018-07-01

The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751). Copyright© by Royan Institute. All rights reserved.

Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants

PubMed Central

Gargano, Nicola; Madrid, Lola; Valentini, Giovanni; D'Alessandro, Umberto; Halidou, Tinto; Sirima, Sodiomon; Tshefu, Antoinette; Mtoro, Ali; Gesase, Samwel

2017-01-01

ABSTRACT Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.) PMID:29061746

Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants.

PubMed

Gargano, Nicola; Madrid, Lola; Valentini, Giovanni; D'Alessandro, Umberto; Halidou, Tinto; Sirima, Sodiomon; Tshefu, Antoinette; Mtoro, Ali; Gesase, Samwel; Bassat, Quique

2018-01-01

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences ( P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.). Copyright © 2017 Gargano et al.

Efficacy and safety of sequential use of everolimus in Japanese patients with advanced renal cell carcinoma after failure of first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor: a multicenter phase II clinical trial.

PubMed

Oyama, Masafumi; Sugiyama, Takayuki; Nozawa, Masahiro; Fujimoto, Kiyohide; Kishida, Takeshi; Kimura, Go; Tokuda, Noriaki; Hinotsu, Shiro; Shimozuma, Kojiro; Akaza, Hideyuki; Ozono, Seiichiro

2017-06-01

Many studies have shown the efficacy of everolimus after pretreatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated the efficacy and safety of everolimus as a second-line treatment after the failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy in Japanese patients with advanced renal cell carcinoma. This was an open-label, multicenter, phase II trial conducted in Japan through the central registration system. A total of 57  patients were enrolled. Patients were administered 10 mg of everolimus q.d. orally. The primary efficacy endpoint was progression-free survival achieved by administration of everolimus. The median progression-free survival of patients administered everolimus was 5.03 months (95% confidence interval: 3.70-6.20). The median overall survival was not reached. The objective response rate was 9.4% (95% confidence interval: 3.1-20.7). The progression-free survival in the group of <100% relative dose intensity was 6.70 months (95% confidence interval: 4.13-11.60), and that in the group of 100% relative dose intensity was 3.77 months (hazard ratio: 2.79, 95% confidence interval: 2.77-5.63). The commonly observed adverse events and laboratory abnormalities were stomatitis (49.1%), hypertriglyceridemia (26.4%), interstitial lung disease (26.4%), anemia (22.6%) and hypercholesterolemia (22.6%). The median progression-free survival was almost similar to that recorded in the RECORD-1 study, whereas prolongation of overall survival was observed in the present study compared with the RECORD-1 study. The treatment outcomes of first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy and second-line everolimus treatment in Japanese patients were successfully established in the present study. © The Author 2017. Published by Oxford University Press.

Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure.

PubMed

Fox, Susan H; Lang, Anthony E; Brotchie, Jonathan M

2006-10-01

Studies in MPTP-lesioned nonhuman primates have demonstrated the potential of nondopaminergic drugs in reducing the problems of levodopa-induced dyskinesia (LID). Here we review the process of translating findings from the monkey to man. Agents targeting glutamate, adensosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed for antidyskinetic potential in human studies. Eleven nondopaminergic drugs with antidyskinetic efficacy in the MPTP primate have been advanced to proof-of-concept phase IIa trials in PD patients (amantadine, istradefylline, idazoxan, fipamezole, sarizotan, quetiapine, clozapine, nabilone, rimonabant, naloxone, and naltrexone). For all six nondopaminergic transmitter systems reviewed, the MPTP-lesioned primate correctly predicted phase II efficacy of at least one drug. Of the 11 specific molecules tested in both monkeys and humans, 8 showed clear antidyskinetic properties in both human and monkey. In the instances where the primate studies did not, or did not consistently, predict the outcome of the human studies, the discrepancy may reflect limitations in the validity of the model or limitations in the design of either the clinical or the preclinical studies. We find that the major determinant of success in predicting efficacy is to ensure that primate studies are conducted in a statistically rigorous way and incorporate designs and outcome measures with clinical applicability. On the other hand, phase IIa trials should strive to replicate the preclinical study, especially in terms of protocol, drug dose equivalence, and outcome measure, so as to test the same hypothesis. Failure to meet these criteria carries the risk of false negative conclusions in phase IIa trials.

Drug development: from concept to marketing!

PubMed

Tamimi, Nihad A M; Ellis, Peter

2009-01-01

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

Model‐Informed Development and Registration of a Once‐Daily Regimen of Extended‐Release Tofacitinib

PubMed Central

Lamba, M; Hutmacher, MM; Furst, DE; Dikranian, A; Dowty, ME; Conrado, D; Stock, T; Nduaka, C; Cook, J

2017-01-01

Extended‐release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model‐informed, exposure–response (E‐R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E‐R analyses were conducted using validated clinical endpoints from phase II dose–response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration. PMID:27859030

Guselkumab for the treatment of moderate-to-severe plaque psoriasis.

PubMed

Yang, Eric J; Sanchez, Isabelle M; Beck, Kristen; Sekhon, Sahil; Wu, Jashin J; Bhutani, Tina

2018-04-01

Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study.

PubMed

Klinge, L; Straub, V; Neudorf, U; Voit, T

2005-02-01

Infantile Pompe disease (IPD) is a fatal, autosomal recessive muscle-wasting disorder. Due to a deficiency of the lysosomal enzyme acid alpha-glucosidase patients develop a generalized myopathy, diaphragmatic weakness, and cardiomyopathy leading to death usually within the first year of life. So far there is no therapy available. We report on the safety and efficacy of transgenically derived recombinant human precursor acid alpha-glucosidase (rhGAA) in a 10-month follow-up study in two children with IPD who previously completed a 48-week course of enzyme replacement therapy (ERT) with the same medication at the same dose in a phase II clinical trial. Under this therapy cardiac status and muscle strength had improved, leading to survival beyond the age of one year. These results, together with data from two other phase II clinical trials encouraged further evaluation of the long-term safety and efficacy of enzyme replacement therapy in patients with infantile-onset Pompe disease. During the 10-month follow-up period, ERT was well-tolerated and neither patient experienced a single infusion-associated reaction. The initial improvements in cardiac size and function, as measured by left ventricular mass index and the fractional shortening, were maintained in both patients, and a continued improvement of motor function, as measured by the Alberta infant motor scale, was observed.

Adoptive Cell Therapies for Glioblastoma

PubMed Central

Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

2013-01-01

Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly “self,” it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts. PMID:24273748

Adoptive cell therapies for glioblastoma.

PubMed

Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

2013-01-01

Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly "self," it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts.

Web-Based Tailored Intervention for Preparation of Parents and Children for Outpatient Surgery (WebTIPS): Formative Evaluation and Randomized Controlled Trial

PubMed Central

Fortier, Michelle A.; Bunzli, Elizabeth; Walthall, Jessica; Olshansky, Ellen; Saadat, Haleh; Santistevan, Ricci; Mayes, Linda; Kain, Zeev N.

2015-01-01

Background The purpose of this two-phase project was to conduct formative evaluation and test the preliminary efficacy of a newly developed web-based, tailored behavioral preparation program (WebTIPS) for children undergoing outpatient surgery and their parents Methods Phase I enrolled 13 children aged 2–7 years undergoing outpatient elective surgery and their parents for formative evaluation of WebTIPS. Parent participation focus groups which are common in qualitative research and are a method of asking research participants about their perceptions and attitudes regarding a product or concept. In phase II, children age 2–7 years in two medical centers were randomly assigned to receive the WebTIPS program (n = 38) compared to children receiving standard of care (n = 44). The primary outcome of phase II was child and parent preoperative anxiety. Results In phase I, parents reported WebTIPS to be both helpful (p < 0.001) and easy to use (p < 0.001). In phase II, children in the WebTIPS group (36.2 ± 14.1) were less anxious than children in the standard of care group (46.0 ± 19.0) at entrance to the operating room (p = 0.02; Cohen’s d = 0.59) and introduction of the anesthesia mask (43.5 ± 21.7 vs. 57.0 ± 21.2, respectively, p = 0.01; Cohen’s d = 0.63). Parents in the WebTIPS group (32.1 ± 7.4) also experienced less anxiety compared to parents in the control group (36.8 ± 7.1) in the preoperative holding area (p = 0.004; Cohen’s d = 0.65). Conclusions WebTIPS was well received by parents and children and led to reductions in preoperative anxiety. PMID:25790213

Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512

PubMed Central

Bhatia, Shailender; Moon, James; Margolin, Kim A.; Weber, Jeffrey S.; Lao, Christopher D.; Othus, Megan; Aparicio, Ana M.; Ribas, Antoni; Sondak, Vernon K.

2012-01-01

Background Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma. Methods Twenty-five patients with stage IV uveal melanoma who had received 0–1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m2) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Results No confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0–14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1–6 months] and the 6-month PFS was 29% [95% CI: 13%–48%]. The median OS was 11 months [95% CI: 7–14 months]. Conclusion In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients. Trial Registration ClinicalTrials.gov NCT00329641 PMID:23226204

EffenDys-Fentanyl Buccal Tablet for the Relief of Episodic Breathlessness in Patients With Advanced Cancer: A Multicenter, Open-Label, Randomized, Morphine-Controlled, Crossover, Phase II Trial.

PubMed

Simon, Steffen T; Kloke, Marianne; Alt-Epping, Bernd; Gärtner, Jan; Hellmich, Martin; Hein, Rebecca; Piel, Maren; Cornely, Oliver A; Nauck, Friedemann; Voltz, Raymond

2016-11-01

Episodic breathlessness is a frequent and burdensome symptom in cancer patients but pharmacological treatment is limited. To determine time to onset, efficacy, feasibility, and safety of transmucosal fentanyl in comparison to immediate-release morphine for the relief of episodic breathlessness. Phase II, investigator-initiated, multicenter, open-label, randomized, morphine-controlled, crossover trial with open-label titration of fentanyl buccal tablet (FBT) in inpatients with incurable cancer. The primary outcome was time to onset of meaningful breathlessness relief. Secondary outcomes were efficacy (breathlessness intensity difference at 10 and 30 minutes; sum of breathlessness intensity difference at 15 and 60 minutes), feasibility, and safety. Study was approved by local ethics committees. Twenty-five of 1341 patients were eligible, 10 patients agreed to participate (four female, mean age 58 ± 11, mean Karnofsky score 67 ± 11). Two patients died before final visits and two patients dropped-out because of disease progression leaving six patients for analysis with 61 episodes of breathlessness. Mean time to onset was for FBT 12.7 ± 10.0 and for immediate-release morphine 23.6 ± 15.1 minutes with a mean difference of -10.9 minutes (95% CI = -24.5 to 2.7, P = 0.094). Efficacy measures were predominately in favor for FBT. Both interventions were safe. Feasibility failed because of too much study demands for a very ill patient group. The description of a faster and greater relief of episodic breathlessness by transmucosal fentanyl versus morphine justifies further evaluation by a full-powered trial. Copyright © 2016. Published by Elsevier Inc.

Efficacy and safety of bilastine in Japanese patients with chronic spontaneous urticaria: A multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II/III study.

PubMed

Hide, Michihiro; Yagami, Akiko; Togawa, Michinori; Saito, Akihiro; Furue, Masutaka

2017-04-01

Bilastine, a novel non-sedating second-generation H 1 -antihistamine, has been widely used in the treatment of allergic rhinoconjunctivitis and urticaria with a recommended dose of 20 mg once daily in most European countries since 2010. We evaluated its efficacy and safety in Japanese patients with chronic spontaneous urticaria (CSU). We conducted a multicenter, randomized, double-blind, placebo-controlled phase II/III study (trial registration No. JapicCTI-142574). Patients (age, 18-74 years) were randomly assigned to receive bilastine 20 mg, 10 mg or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline (Day -3 to 0) in total symptom score (TSS) at 2 weeks (Day 8-14), consisting of the itch and rash scores. A total of 304 patients were randomly allocated to bilastine 20 mg (101 patients), bilastine 10 mg (100 patients), and placebo (103 patients). The changes in TSS at 2 weeks were significantly decreased by bilastine 20 mg than did placebo (p < 0.001), demonstrating the superiority of bilastine 20 mg. Bilastine 10 mg also showed a significant difference from placebo (p < 0.001). The TSS changes for the bilastine showed significant improvement from Day 1, and were maintained during the treatment period. The Dermatology Life Quality Index scores were also improved in bilastine than in placebo. The bilastine treatments were safe and well tolerated. Two-week treatment with bilastine (20 or 10 mg) once daily was effective and tolerable in Japanese patients with CSU, demonstrating an early onset of action. Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

A phase II trial of tideglusib in Alzheimer's disease.

PubMed

Lovestone, Simon; Boada, Mercè; Dubois, Bruno; Hüll, Michael; Rinne, Juha O; Huppertz, Hans-Jürgen; Calero, Miguel; Andrés, María V; Gómez-Carrillo, Belén; León, Teresa; del Ser, Teodoro

2015-01-01

The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer's disease (AD). To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD. Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints. 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9-16% in active, 3.5% placebo) were the most frequent adverse events. Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients.

A Prospective, Nonrandomized, no Placebo-Controlled, Phase I/II Clinical Trial Assessing the Safety and Efficacy of Intramuscular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in Patients With Severe Buerger’s Disease

PubMed Central

Ra, Jeong Chan; Jeong, Euicheol C.; Kang, Sung Keun; Lee, Seog Ju; Choi, Kyoung Ho

2017-01-01

Buerger’s disease is a rare and severe disease affecting the blood vessels of the limbs. Adipose tissue-derived mesenchymal stem cells (ADSCs) have the potential to cure Buerger’s disease when developed as a stem cell drug. In the present study, we conducted a prospective, nonrandomized, no placebo-controlled, phase I/II clinical trial with a 2-year follow-up questionnaire survey. A total of 17 patients were intramuscularly administered autologous ADSCs at a dose of 5 million cells/kg. The incidence of adverse events (AEs), adverse drug reaction (ADR), and serious adverse events (SAEs) was monitored. No ADRs and SAEs related to stem cell treatment occurred during the 6-month follow-up. In terms of efficacy, the primary endpoint was increase in total walking distance (TWD). The secondary endpoint was improvement in rest pain, increase in pain-free walking distance (PFWD), toe–brachial pressure index (TBPI), transcutaneous oxygen pressure (TcPO2), and arterial brachial pressure index (ABPI). ADSCs demonstrated significant functional improvement results including increased TWD, PFWD, and rest pain reduction. No amputations were reported during the 6-month clinical trial period and in the follow-up questionnaire survey more than 2 years after the ADSC injection. In conclusion, intramuscular injection of ADSCs is very safe and is shown to prompt functional improvement in patients with severe Buerger’s disease at a dosage of 300 million cells per 60 kg of body weight. However, the confirmatory therapeutic efficacy and angiogenesis need further study. PMID:28713639

A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma.

PubMed

Smaletz, Oren; Diz, Maria D P E; do Carmo, Claudio C; Sabbaga, Jorge; Cunha-Junior, Geraldo F; Azevedo, Sergio J; Maluf, Fernando C; Barrios, Carlos H; Costa, Ronaldo L; Fontana, Ana G; Madrigal, Vivian; Wainstein, Alberto J; Yeda, Fernanda P; Alves, Venâncio A; Moro, Ana M; Blasbalg, Roberto; Scott, Andrew M; Hoffman, Eric W

2015-08-01

The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested. Copyright © 2015 Elsevier Inc. All rights reserved.

Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

PubMed Central

2011-01-01

Background Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate. Methods Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks. Results Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred. Conclusion The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate. Trial Registration (ClinicalTrials.gov identifier: NCT00784628) PMID:21736751

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study.

PubMed

Yamazaki, Naoya; Kiyohara, Yoshio; Uhara, Hisashi; Uehara, Jiro; Fujimoto, Manabu; Takenouchi, Tatsuya; Otsuka, Masaki; Uchi, Hiroshi; Ihn, Hironobu; Minami, Hironobu

2017-06-01

Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI-142533.). © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

PubMed

Reardon, David A; Norden, Andrew D; Desjardins, Annick; Vredenburgh, James J; Herndon, James E; Coan, April; Sampson, John H; Gururangan, Sridharan; Peters, Katherine B; McLendon, Roger E; Norfleet, Julie A; Lipp, Eric S; Drappatz, Jan; Wen, Patrick Y; Friedman, Henry S

2012-01-01

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma

PubMed Central

Norden, Andrew D.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Sampson, John H.; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger E.; Norfleet, Julie A.; Lipp, Eric S.; Drappatz, Jan; Wen, Patrick Y.; Friedman, Henry S.

2011-01-01

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication. PMID:21938530

An update on vaccines for tuberculosis - there is more to it than just waning of BCG efficacy with time.

PubMed

Romano, Marta; Huygen, Kris

2012-12-01

Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide. After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials. It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.

The Novel Antipsychotic Cariprazine (RGH-188): State-of-the-Art in the Treatment of Psychiatric Disorders.

PubMed

De Berardis, Domenico; Orsolini, Laura; Iasevoli, Felice; Prinzivalli, Emiliano; de Bartolomeis, Andrea; Serroni, Nicola; Mazza, Monica; Valchera, Alessandro; Fornaro, Michele; Vecchiotti, Roberta; Carano, Alessandro; Sepede, Gianna; Vellante, Federica; Matarazzo, Ilaria; Pompili, Maurizio; Perna, Giampaolo; Conti, Chiara; Segura-García, Cristina; Martinotti, Giovanni; Di Giannantonio, Massimo

2016-01-01

Cariprazine (RGH-188) is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development (phase III clinical trials) in patients with schizophrenia (S) and in patients with bipolar disorder (BD), as well as an adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. Cariprazine has completed phase III trials for the acute treatment of schizophrenia and bipolar mania, phase II trials for the bipolar depression and MDD whilst it is undergoing phase III trials as an adjunct to antidepressants. The present review aims at proving a comprehensive summary of the current evidence on the safety, tolerability and efficacy of cariprazine in the treatment of schizophrenia, BD (manic/mixed/ depressive episode) and MDD. A systematic search was conducted on PubMed/Medline/ Scopus and the database on Clinical Trials from inception until April 2015 by typing a set of specified keywords. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. Further studies should be carried out to better investigate its pharmacodynamic and clinical potential, particularly as alternative to current antipsychotic drugs.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

PubMed

Ogura, Michinori; Tobinai, Kensei; Hatake, Kiyohiko; Uchida, Toshiki; Suzuki, Tatsuya; Kobayashi, Yukio; Mori, Masakazu; Terui, Yasuhito; Yokoyama, Masahiro; Hotta, Tomomitsu

2013-01-01

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. © 2012 Japanese Cancer Association.

Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS.

PubMed

Arnold, Douglas L; Fisher, Elizabeth; Brinar, Vesna V; Cohen, Jeffrey A; Coles, Alasdair J; Giovannoni, Gavin; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W; Stojanovic, Miroslav; Weiner, Howard L; Lake, Stephen L; Margolin, David H; Thomas, David R; Panzara, Michael A; Compston, D Alastair S

2016-10-04

To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a. Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS. NCT00530348 and NCT00548405. The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints. © 2016 American Academy of Neurology.

Alectinib for treatment of ALK-positive non-small-cell lung cancer.

PubMed

Avrillon, Virginie; Pérol, Maurice

2017-02-01

Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival. From the results and those expected of Phase III ALEX study, alectinib might become the frontline treatment of ALK-positive NSCLC. This article summarizes the therapeutic options in ALK-positive advanced NSCLC, and the chemical, pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy of alectinib.

Enzastaurin: A lesson in drug development.

PubMed

Bourhill, T; Narendran, A; Johnston, R N

2017-04-01

Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic. Copyright © 2017 Elsevier B.V. All rights reserved.

Phase II Evaluation of IPI-926, an Oral Hedgehog Inhibitor, in Patients with Myelofibrosis

PubMed Central

Sasaki, Koji; Gotlib, Jason R.; Mesa, Ruben A.; Newberry, Kate J.; Ravandi, Farhad; Cortes, Jorge E.; Kelly, Patrick; Kutok, Jeffery L.; Kantarjian, Hagop M.; Verstovsek, Srdan

2016-01-01

The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160-mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis, or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis. PMID:25641433

Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial

PubMed Central

Martín-Martorell, P; Roselló, S; Rodríguez-Braun, E; Chirivella, I; Bosch, A; Cervantes, A

2008-01-01

This is a phase II institutional exploratory trial of biweekly irinotecan and cetuximab administration regimen in metastatic colorectal cancer patients progressing to at least one previous chemotherapy line. A total of 40 patients were treated between November 2005 and November 2007 with irinotecan 180 mg m−2 and cetuximab 500 mg m−2 q2w (every 2 weeks), in every 21-day cycles, until unacceptable toxicity or progressive disease. An overall response rate of 22.5% was obtained (two complete and seven partial responses). The disease control rate was 60%. The time to progression was 3.4 months and the overall survival was 8 months. The toxicity compared very favourably to weekly cetuximab combination schedules. Grade 3/4 adverse effects were observed in 12 patients. Overall, our results turn up very similar both in terms of toxicity and efficacy to those obtained by weekly and biweekly administration regimens. PMID:18665167

Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia.

PubMed

Hankins, Jane S; Wynn, Lynn W; Brugnara, Carlo; Hillery, Cheryl A; Li, Chin-Shang; Wang, Winfred C

2008-01-01

In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.

Assessment of the efficacy and safety of eslicarbazepine acetate in acute mania and prevention of recurrence: experience from multicentre, double-blind, randomised phase II clinical studies in patients with bipolar disorder I.

PubMed

Grunze, Heinz; Kotlik, Eduardo; Costa, Raquel; Nunes, Teresa; Falcão, Amílcar; Almeida, Luis; Soares-da-Silva, Patrício

2015-03-15

Eslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures. To evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I. Two 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600-1800mg or 800-2400mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions - Bipolar Version (CGI-BP) over Part II in study BIA-2093-205. In study BIA-2093-203 (n=160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800-2400mg showed a greater reduction in YMRS score (p=0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800-2400mg group (from preceding and worst phase) and for ESL 600-1800mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 (n=38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 (n=85, ITT), at least 50% of patients showed no worsening in all treatment groups (p=0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL. ESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode. Copyright © 2014 Elsevier B.V. All rights reserved.

Population Pharmacokinetics and Exposure-Response (Efficacy and Safety/Tolerability) of Empagliflozin in Patients with Type 2 Diabetes.

PubMed

Baron, Kyle T; Macha, Sreeraj; Broedl, Uli C; Nock, Valerie; Retlich, Silke; Riggs, Matthew

2016-09-01

The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure-response (E-R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration. Population pharmacokinetic and E-R models were developed based on two Phase I, four Phase II, and four Phase III studies. Variability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m(2). All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion. Based on the results from the PK and E-R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved. Boehringer Ingelheim.

Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis.

PubMed

Gensicke, Henrik; Leppert, David; Yaldizli, Özgür; Lindberg, Raija L P; Mehling, Matthias; Kappos, Ludwig; Kuhle, Jens

2012-01-01

Multiple sclerosis (MS) is an inflammatory and degenerative disease leading to demyelination and axonal damage in the CNS. Autoimmunity plays a central role in MS pathogenesis. Per definition, monoclonal antibodies are recombinant biological compounds with a well defined target, thus carrying the promise of targeting pathogenic cells or molecules with high specificity, avoiding undesired off-target effects. Natalizumab was the first monoclonal antibody to be approved for the treatment of MS. Several other monoclonal antibodies are in development and have demonstrated promising efficacy in phase II studies. They can be categorized according to their mode of action into compounds targeting (i) leukocyte migration into the CNS (natalizumab); (ii) cytolytic antibodies (rituximab, ocrelizumab, ofatumumab, alemtuzumab); or (iii) antibodies and recombinant proteins targeting cytokines and chemokines and their receptors (daclizumab, ustekinumab, atacicept, tabalumab [Ly-2127399], secukinumab [AIN457]). In this review, we discuss the specific molecular targets, clinical efficacy and safety of these compounds and discuss criteria to anticipate the position of monoclonal antibodies in the diversifying armamentarium of MS therapy in the coming years.

Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease-A Phase II Study.

PubMed

Kuzmina, Larisa A; Petinati, Natalia A; Parovichnikova, Elena N; Lubimova, Lidia S; Gribanova, Elena O; Gaponova, Tatjana V; Shipounova, Irina N; Zhironkina, Oxana A; Bigildeev, Alexey E; Svinareva, Daria A; Drize, Nina J; Savchenko, Valery G

2012-01-01

The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9-1.3 × 10(6)/kg when the blood counts indicated recovery. aGVHD of stage II-IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study.

Alp Rose stem cells, olive oil squalene and a natural alkyl polyglucoside emulsifier: Are they appropriate ingredients of skin moisturizers - in vivo efficacy on normal and sodium lauryl sulfate - irritated skin?.

PubMed

Filipović, Mila; Gledović, Ana; Lukić, Milica; Tasić-Kostov, Marija; Isailović, Tanja; Pantelić, Ivana; Vuleta, Gordana; Savić, Snežana

2016-11-01

Since skin moisturization may be achieved by both actives and chosen carrier, plant stem cells, squalene and natural alkyl polyglucoside emulsifier may be potential components of contemporary cosmetic products. The aim of the study was in vivo evaluation of the skin irritation potential and the efficacy of Alpine Rose stem cells incorporated into li-posomes and olive oil squalene as ingredients of moisturizing creams, with respect to the novel emulsifier used for creams’ stabilization. With the employment of noninvasive skin biophysical measurements, skin hydration (EC), transepi-dermal water loss (TEWL), erythema index (EI) and viscoelas-ticity were measured on 76 healthy volunteers. In the first phase, skin irritation after a 24-hour occlusion and the long-term efficacy of creams (a 21-day study) on healthy skin were evaluated. Phase II of the study focused on the cream efficacy assessment after a 6-day treatment of sodium lauryl sulfate-irritated skin. After a 24-hour occlusion, there were no significant changes in the EI for any tested sample. In the second phase of the study, the EI was not significantly altered for the cream containing squalene, while the application of all active samples resulted in a significant reduction of TEWL. In both phases of the study an EC increase was recorded, espe-cially for the squalene-containing cream. Due to the lack of skin irritation and skin barrier impairment along with the marked hydration effect, it could be said that the in-vestigated actives incorporated into alkyl polyglucoside emulsi-fier-stabilized creams may be safely applied as ingredients for "tailor-made" cosmetic moisturizers intended for normal and dry skin care, whereas olive oil squalene could be used for the treatment of irritated or sensitive skin as well. [Projekat Ministarstva nauke Republike Srbije, br. TR34031

SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE COMBINATION OF SORAFENIB AND TANESPIMYCIN

PubMed Central

Vaishampayan, Ulka N.; Burger, Angelika M.; Sausville, Edward A.; Heilbrun, Lance K.; Li, Jing; Horiba, Naomi; Egorin, Merrill J.; Ivy, Percy; Pacey, Simon; Lorusso, Patricia M.

2010-01-01

PURPOSE Heat shock protein 90 inhibition affects the Raf-kinase signaling pathway and could enhance anti-tumor effects of sorafenib, a Raf-kinase inhibitor. The combination of sorafenib and tanespimycin (17-AAG/17-allyl-amino-geldanamycin; NSC # 330507/KOS-953) was evaluated in a phase I trial with the primary objective of defining a phase II dose PATIENTS AND METHODS The dose cohorts consisted of fixed continuous oral dosing of sorafenib 400 mg twice daily, starting 14 days prior to tanespimycin which was administered intravenously, at escalating doses, (starting at 300 mg/m,2 with 50 mg/m2 increments), on days 1, 8 and 15, in a 28-day cycle. Toxicity was assessed weekly; response was evaluated every 2 cycles. RESULTS Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were: renal cancer (12), melanoma (6) and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in 1 patient each were observed at 450 mg/m2 of tanespimycin. 114 cycles were administered with a median of four cycles (range 1–17 cycles). Plasma concentrations of sorafenib and metabolites reached steady-state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS Recommended phase II doses of this combination are sorafenib 400 mg twice daily and tanespimycin 400 mg/m2 on days 1, 8 and 15 every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma. PMID:20525756

The Value of Botox-A in Acute Radiation Proctitis: Results From a Phase I/II Study Using a Three-Dimensional Scoring System

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

Vuong, Te, E-mail: tvuong@jgh.mcgill.ca; Waschke, Kevin; Niazi, Tamim

Purpose: Acute radiation proctitis (ARP) is a common side effect of pelvic radiotherapy, and its management is challenging in daily practice. The present phase I/II study evaluates the safety and efficacy of the botulinum toxin A (BTX-A) in ARP treatment for rectal cancer patients undergoing neoadjuvant high-dose-rate endorectal brachytherapy (HDREBT). Methods and Materials: Fifteen patients, treated with neoadjuvant HDREBT, 26-Gy in 4 fractions, received the study treatment that consisted of a single injection of BTX-A into the rectal wall. The injection was performed post-HDREBT and prior to the development of ARP. The control group, 20 such patients, did not receivemore » the BTX-A injection. Both groups had access to standard treatment with hydrocortisone rectal aerosol foam (Cortifoam) and anti-inflammatory and narcotic medication. The ARP was clinically evaluated by self-administered daily questionnaires using visual analog scores to document frequency and urgency of bowel movements, rectal burning/tenesmus, and pain symptoms before and after HDREBT. Results: At the time of this analysis, there was no observed systemic toxicity. Patient compliance with the self-administered questionnaire was 100% from week 1 to 4, 70% during week 5, and 40% during week 6. The maximum tolerated dose was established at the 100-U dose level, and noticeable mean differences were observed in bowel frequency (p = 0.016), urgency (p = 0.007), and pain (p = 0.078). Conclusions: This study confirms the feasibility and efficacy of BTX-A intervention at 100-U dose level for study patients compared to control patients. A phase III study with this dose level is planned to validate these results.« less

Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial.

PubMed

Bolli, Roberto; Hare, Joshua M; Henry, Timothy D; Lenneman, Carrie G; March, Keith L; Miller, Kathy; Pepine, Carl J; Perin, Emerson C; Traverse, Jay H; Willerson, James T; Yang, Phillip C; Gee, Adrian P; Lima, João A; Moyé, Lem; Vojvodic, Rachel W; Sayre, Shelly L; Bettencourt, Judy; Cohen, Michelle; Ebert, Ray F; Simari, Robert D

2018-07-01

SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC). AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium. The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP). This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome. Copyright © 2018. Published by Elsevier Inc.

An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results.

PubMed

Packiam, Vignesh T; Lamm, Donald L; Barocas, Daniel A; Trainer, Andrew; Fand, Benjamin; Davis, Ronald L; Clark, William; Kroeger, Michael; Dumbadze, Igor; Chamie, Karim; Kader, A Karim; Curran, Dominic; Gutheil, John; Kuan, Arthur; Yeung, Alex W; Steinberg, Gary D

2017-07-26

CG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising activity in patients with high-grade non-muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy. At interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies. Of 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%-62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%-78%), CIS ± Ta/T1 50% (33%-67%), and pure Ta/T1 33% (8%-70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment-related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment-related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment-related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment-related AEs. This phase II study demonstrates that intravesical CG0070 yielded an overall 47% CR rate at 6 months for all patients and 50% for patients with CIS, with an acceptable level of toxicity for patients with high-risk BCG-unresponsive NMIBC. There is a particularly strong response and limited progression in patients with pure CIS. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

PubMed Central

Keiser, Jennifer; Sayed, Hanan; El-Ghanam, Maged; Sabry, Hoda; Anani, Saad; El-Wakeel, Aly; Hatz, Christoph; Utzinger, Jürg; el-Din, Sayed Seif; El-Maadawy, Walaa; Botros, Sanaa

2011-01-01

Background Fascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance. Triclabendazole is the only available drug for treatment. Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether). Methodology We carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6×80 mg over 3 consecutive days, and (ii) 3×200 mg within 24 h in 36 Fasciola-infected individuals in Egypt. Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration. Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral triclabendazole. In case of treatment failure, triclabendazole was re-administered at 20 mg/kg in two divided doses. Principal Findings CRs achieved with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. The corresponding ERRs were 63% and nil, respectively. Artemether was well tolerated. A high efficacy was observed with triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%). Conclusions/Significance Artemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to triclabendazole. The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated. PMID:21909440

The Efficacy and Safety of Shen Guo Lao Nian Granule for Common Cold of Qi-Deficiency Syndrome: Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase II Clinical Trial

PubMed Central

Fu, Juanjuan; Ding, Hong; Yang, Haimiao; Huang, Yuhong

2017-01-01

Background Common cold is one of the most frequently occurring illnesses in primary healthcare services and represents considerable disease burden. Common cold of Qi-deficiency syndrome (CCQDS) is an important but less addressed traditional Chinese medicine (TCM) pattern. We designed a protocol to explore the efficacy, safety, and optimal dose of Shen Guo Lao Nian Granule (SGLNG) for treating CCQDS. Methods/Design This is a multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. A total of 240 eligible patients will be recruited from five centers. Patients are randomly assigned to high-dose group, middle-dose group, low-dose group, or control group in a 1 : 1 : 1 : 1 ratio. All drugs are required to be taken 3 times daily for 5 days with a 5-day follow-up period. Primary outcomes are duration of all symptoms, total score reduction on Jackson's scale, and TCM symptoms scale. Secondary outcomes include every single TCM symptom duration and score reduction, TCM main symptoms disappearance rate, curative effects, and comparison between Jackson's scale and TCM symptom scale. Ethics and Trial Registration This study protocol was approved by the Ethics Committee of Clinical Trials and Biomedicine of West China Hospital of Sichuan University (number IRB-2014-12) and registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006349). PMID:29430253

Phase II Study to Assess the Efficacy of Hypofractionated Stereotactic Radiotherapy in Patients With Large Cavernous Sinus Hemangiomas

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

Wang Xin; Liu Xiaoxia; Mei Guanghai

Purpose: Cavernous sinus hemangioma is a rare vascular tumor. The direct microsurgical approach usually results in massive hemorrhage. Although radiosurgery plays an important role in managing cavernous sinus hemangiomas as a treatment alternative to microsurgery, the potential for increased toxicity with single-session treatment of large tumors is a concern. The purpose of this study was to assess the efficacy of hypofractionated stereotactic radiotherapy in patients with large cavernous sinus hemangiomas. Methods: Fourteen patients with large (volume >20 cm{sup 3}) cavernous sinus hemangiomas were enrolled in a prospective Phase II study between December 2007 and December 2010. The hypofractionated stereotactic radiotherapymore » dose was 21 Gy delivered in 3 fractions. Results: After a mean follow-up of 15 months (range, 6-36 months), the magnetic resonance images showed a mean of 77% tumor volume reduction (range, 44-99%). Among the 6 patients with cranial nerve impairments before hypofractionated stereotactic radiotherapy, 1 achieved symptomatic complete resolution and 5 had improvement. No radiotherapy-related complications were observed during follow-up. Conclusion: Our current experience, though preliminary, substantiates the role of hypofractionated stereotactic radiotherapy for large cavernous sinus hemangiomas. Although a longer and more extensive follow-up is needed, hypofractionated stereotactic radiotherapy of 21 Gy delivered in 3 fractions is effective in reducing the tumor volume without causing any new deficits and can be considered as a treatment modality for large cavernous sinus hemangiomas.« less

Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study.

PubMed

Hummel, Sandra; Beyerlein, Andreas; Pfirrmann, Markus; Hofelich, Anna; Much, Daniela; Hivner, Susanne; Bunk, Melanie; Herbst, Melanie; Peplow, Claudia; Walter, Markus; Kohn, Denise; Hummel, Nadine; Kratzsch, Jürgen; Hummel, Michael; Füchtenbusch, Martin; Hasford, Joerg; Ziegler, Anette-G

2018-03-01

Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Understanding long-term protection of human papillomavirus vaccination against cervical carcinoma: Cancer registry-based follow-up.

PubMed

Rana, Muhammad Mohsin; Huhtala, Heini; Apter, Dan; Eriksson, Tiina; Luostarinen, Tapio; Natunen, Kari; Paavonen, Jorma; Pukkala, Eero; Lehtinen, Matti

2013-06-15

Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) Grade 2/3. Long-term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population-based recruitment between September 2002 and March 2003, 1,749 16- to 17-year old Finns participated in a multi-national randomized Phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow-up started at the country-wide, population-based Finnish Cancer Registry (FCR) six months after the active follow-up and voluntary cross-vaccination in April 2007. A cluster randomized, population-based reference cohort of 15,744 unvaccinated, originally 18-19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007-2011 (HPV vaccine and placebo cohorts) and 2006-2010 and 2008-2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The four years passive follow-up resulted in 3,464, 3,444 and 62,876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow-up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100,000 (95% confidence interval 0.0-106.5), 87.1/100,000 (95% CI 17.9-254.5) and 93.8/100,000 (95% CI 71.4-121), respectively. Long-term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end-points by passive cancer registry-based follow-up is feasible. Copyright © 2012 UICC.

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

PubMed

Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

2017-05-01

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use.

PubMed

Hanaizi, Zahra; Unkrig, Christoph; Enzmann, Harald; Camarero, Jorge; Sancho-Lopez, Arantxa; Salmonson, Tomas; Gisselbrecht, Christian; Laane, Edward; Pignatti, Francesco

2014-04-01

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph⁺) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph⁺ leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.

Single-dose palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy containing steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL).

PubMed

Di Renzo, Nicola; Montanini, Antonella; Mannina, Donato; Dondi, Alessandra; Muci, Stefania; Mancuso, Salvatrice; De Paolis, M Rosaria; Plati, Caterina; Stelitano, Caterina; Patti, Catia; Olivieri, Attilio; Liardo, Eliana; Buda, Gabriele; Cantaffa, Renato; Federico, Massimo

2011-10-01

The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids. Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0-120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint. Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0-24 h) and delayed (24-120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%. This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin's lymphoma receiving MEC regimen containing steroids.

Controlling Motion Sickness and Spatial Disorientation and Enhancing Vestibular Rehabilitation with a User-Worn See-Through Display

PubMed Central

Krueger, Wesley W.O.

2010-01-01

Objectives/Hypotheses An eyewear mounted visual display (“User-worn see-through display”) projecting an artificial horizon aligned with the user's head and body position in space can prevent or lessen motion sickness in susceptible individuals when in a motion provocative environment as well as aid patients undergoing vestibular rehabilitation. In this project, a wearable display device, including software technology and hardware, was developed and a phase I feasibility study and phase II clinical trial for safety and efficacy were performed. Study Design Both phase I and phase II were prospective studies funded by the NIH. The phase II study used repeated measures for motion intolerant subjects and a randomized control group (display device/no display device) pre-post test design for patients in vestibular rehabilitation. Methods Following technology and display device development, 75 patients were evaluated by test and rating scales in the phase II study; 25 subjects with motion intolerance used the technology in the display device in provocative environments and completed subjective rating scales while 50 patients were evaluated before and after vestibular rehabilitation (25 using the display device and 25 in a control group) using established test measures. Results All patients with motion intolerance rated the technology as helpful for nine symptoms assessed, and 96% rated the display device as simple and easy to use. Duration of symptoms significantly decreased with use of the technology displayed. In patients undergoing vestibular rehabilitation, there were no significant differences in amount of change from pre- to post-therapy on objective balance tests between display device users and controls. However, those using the technology required significantly fewer rehabilitation sessions to achieve those outcomes than the control group. Conclusions A user-worn see-through display, utilizing a visual fixation target coupled with a stable artificial horizon and aligned with user movement, has demonstrated substantial benefit for individuals susceptible to motion intolerance and spatial disorientation and those undergoing vestibular rehabilitation. The technology developed has applications in any environment where motion sensitivity affects human performance. PMID:21181963

[Osimertinib (Tagrisso®): Activity, indication and modality of use in non-small cell lung cancer].

PubMed

Giroux Leprieur, Etienne; Cortot, Alexis B; Cadranel, Jacques; Wislez, Marie

2016-10-01

The acquisition of a resistance EGFR mutation in exon 20 (T790M) occurs in half of the cases of secondary resistance to EGFR tyrosine kinase inhibitors (TKI), given in first-line treatment in advanced EGFR-mutated non-small cell lung cancers (NSCLC). Osimertinib (AZD9291, Tagrisso ® ) is a third-generation, irreversible EGFR TKI, active in case of T790M mutation. A large phase I trial showed the efficacy of osimertinib after failure of first-generation EGFR TKI (erlotinib, gefitinib), with response rate at 51% and up to 61% in case of T790M mutation. Progression-free survival was 9.6 months in case of T790M. Toxicity profile was acceptable, with mainly digestive (diarrhea) and skin (rash) side effects. Preliminary data from a phase II trial confirmed these efficacy and safety data. Screening of T790M mutation at the time of progression with TKI can be performed in circulating tumor DNA in plasma, with good diagnostic performances. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

[Gene Therapy for Inherited RETINAL AND OPTIC NERVE Disorders: Current Knowledge].

PubMed

Ďuďáková, Ľ; Kousal, B; Kolářová, H; Hlavatá, L; Lišková, P

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

PubMed

Uronis, Hope E; Cushman, Stephanie M; Bendell, Johanna C; Blobe, Gerard C; Morse, Michael A; Nixon, Andrew B; Dellinger, Andrew; Starr, Mark D; Li, Haiyan; Meadows, Kellen; Gockerman, Jon; Pang, Herbert; Hurwitz, Herbert I

2013-06-01

Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT-510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT-510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Thirty-four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment-related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D-dimer, von Willebrand factor, placental growth factor, and stromal-derived factor 1 in response to treatment with the combination of bevacizumab and ABT-510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful.

A phase II trial for the efficacy of physiotherapy intervention for early-onset hip osteoarthritis: study protocol for a randomised controlled trial.

PubMed

Kemp, Joanne L; Moore, Kate; Fransen, Marlene; Russell, Trevor G; Crossley, Kay M

2015-01-27

Early-onset hip osteoarthritis is commonly seen in people undergoing hip arthroscopy and is associated with increased pain, reduced ability to participate in physical activity, reduced quality of life and reduced range of motion and muscle strength. Despite this, the efficacy of non-surgical interventions such as exercise therapies remains unknown. The primary aim is to establish the feasibility of a phase III randomised controlled trial investigating a targeted physiotherapy intervention for people with early-onset hip osteoarthritis. The secondary aims are to determine the size of treatment effects of a physiotherapy intervention, targeted to improve hip joint range and hip-related symptoms in early-onset hip osteoarthritis following hip arthroscopy, compared to a health-education control. This protocol describes a randomised, assessor- and participant-blind, controlled clinical trial. We will include 20 participants who are (i) aged between 18 and 50 years; (ii) have undergone hip arthroscopy during the past six to 12 months; (iii) have early-onset hip osteoarthritis (defined as chondrolabral pathology) at the time of hip arthroscopy; and (iv) experience hip-related pain during activities. Primary outcome will be the feasibility of a phase III clinical trial. Secondary outcomes will be (i) perceived global change score; (ii) hip-related symptoms (measured using the Hip disability and Osteoarthritis Outcome Score (HOOS) pain subscale, activity subscale, and sport and recreation subscale); (iii) hip quality of life (measured using the HOOS quality of life subscale and International Hip Outcome tool; (iv) hip muscle strength and (v) hip range of motion. The physiotherapy intervention is semi-standardised, including joint and soft tissue mobilisation and stretching, hip and trunk muscle retraining and functional and activity-specific retraining and education. The control intervention encompasses individualised health education, with the same frequency and duration as the intervention. The trial primary end-point is the conclusion of the 12-week intervention, and follow-up measures will be collected at the 12-week post-baseline assessment. The findings of this study will provide guidance regarding the feasibility of a full-scale phase III randomised controlled trial, prior to its undertaking. The trial protocol was registered with the Australian Clinical Trials Registry (number: 12614000426684 ) on 17 April 2014.

The MUK five protocol: a phase II randomised, controlled, parallel group, multi-centre trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs. cyclophosphamide, bortezomib (Velcade) and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma.

PubMed

Brown, Sarah; Hinsley, Samantha; Ballesteros, Mónica; Bourne, Sue; McGarry, Paul; Sherratt, Debbie; Flanagan, Louise; Gregory, Walter; Cavenagh, Jamie; Owen, Roger; Williams, Cathy; Kaiser, Martin; Low, Eric; Yong, Kwee

2016-01-01

Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ≥ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. The trial is registered under ISRCTN17354232, December 2012.

A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial.

PubMed

Bachet, Jean-Baptiste; Chibaudel, Benoist; Bonnetain, Franck; Validire, Pierre; Hammel, Pascal; André, Thierry; Louvet, Christophe

2015-10-06

Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC. AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed. The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC. AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

Pooled Systemic Efficacy and Safety Data from the Pivotal Phase II Studies (NP28673 and NP28761) of Alectinib in ALK-positive Non-Small Cell Lung Cancer.

PubMed

Yang, James Chih-Hsin; Ou, Sai-Hong Ignatius; De Petris, Luigi; Gadgeel, Shirish; Gandhi, Leena; Kim, Dong-Wan; Barlesi, Fabrice; Govindan, Ramaswamy; Dingemans, Anne-Marie C; Crino, Lucio; Lena, Herve; Popat, Sanjay; Ahn, Jin Seok; Dansin, Eric; Golding, Sophie; Bordogna, Walter; Balas, Bogdana; Morcos, Peter N; Zeaiter, Ali; Shaw, Alice T

2017-10-01

Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report the pooled efficacy and safety data after 15 and 18 months more follow-up than in the respective primary analyses. Enrolled patients had ALK receptor tyrosine kinase gene (ALK)-positive NSCLC and had progressed while taking, or could not tolerate, crizotinib. Patients received oral alectinib, 600 mg twice daily. The primary end point in both studies was objective response rate assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included disease control rate, duration of response, progression-free survival, overall survival, and safety. The pooled data set included 225 patients (n = 138 in NP28673 and n = 87 in NP28761). The response-evaluable population included 189 patients (84% [n = 122 in NP28673 and n = 67 in NP28761]). In the response-evaluable population, objective response rate as assessed by the IRC was 51.3% (95% confidence interval [CI]: 44.0-58.6 [all PRs]), the disease control rate was 78.8% (95% CI: 72.3-84.4), and the median duration of response was 14.9 months (95% CI: 11.1-20.4) after 58% of events. Median progression-free survival as assessed by the IRC was 8.3 months (95% CI: 7.0-11.3) and median overall survival was 26.0 months (95% CI: 21.4-not estimable). Grade 3 or higher adverse events (AEs) occurred in 40% of patients, 6% of patients had treatment withdrawn on account of AEs, and 33% had AEs leading to dose interruptions/modification. This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

PubMed

Filippi, Luca; Cavallaro, Giacomo; Berti, Elettra; Padrini, Letizia; Araimo, Gabriella; Regiroli, Giulia; Bozzetti, Valentina; De Angelis, Chiara; Tagliabue, Paolo; Tomasini, Barbara; Buonocore, Giuseppe; Agosti, Massimo; Bossi, Angela; Chirico, Gaetano; Aversa, Salvatore; Pasqualetti, Roberta; Fortunato, Pina; Osnaghi, Silvia; Cavallotti, Barbara; Vanni, Maurizio; Borsari, Giulia; Donati, Simone; Nascimbeni, Giuseppe; la Marca, Giancarlo; Forni, Giulia; Milani, Silvano; Cortinovis, Ivan; Bagnoli, Paola; Dal Monte, Massimo; Calvani, Anna Maria; Pugi, Alessandra; Villamor, Eduardo; Donzelli, Gianpaolo; Mosca, Fabio

2017-07-14

Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus).

PubMed

Weiss, Glen J; Waypa, Jordan; Blaydorn, Lisa; Coats, Jessica; McGahey, Kayla; Sangal, Ashish; Niu, Jiaxin; Lynch, Cynthia A; Farley, John H; Khemka, Vivek

2017-06-27

Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.

Vaccine profile of herpes zoster (HZ/su) subunit vaccine.

PubMed

Cunningham, Anthony L; Heineman, Thomas

2017-07-01

Herpes zoster (HZ) causes an often severe and painful rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN) and by dissemination in immune-compromised patients. HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age-related or other causes of decreased T cell immunity. A live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 8 years. Areas covered: A new HZ subunit (HZ/su) vaccine combines a key surface VZV glycoprotein (E) with a T cell-boosting adjuvant system (AS01 B ) and is administered by two intramuscular injections two months apart. Expert commentary: HZ/su showed excellent efficacy of ~90% in immunocompetent adults ≥50 and ≥70 years of age, respectively, in the ZOE-50 and ZOE-70 phase III controlled trials. Efficacy was unaffected by advancing age and persisted for >3 years. Approximately 9.5% of subjects had severe, but transient (1-2 days) injection site pain, swelling or redness. Compliance with both vaccine doses was high (95%). The vaccine will have a major impact on HZ management. Phase I-II trials showed safety and immunogenicity in severely immunocompromised patients. Phase III trial results are expected soon.

[Development of Peptide Vaccines for Triple-Negative Breast Cancer Treatment].

PubMed

Toh, Uhi; Saku, Shuko; Okabe, Mina; Iwakuma, Nobutaka; Kimitsuki, Yuko; Akashi, Momoko; Ogo, Etsuyo; Yamada, Akira; Shichijo, Shigeki; Itoh, Kyogo; Akagi, Yoshito

2016-10-01

Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.

Adjuvant sunitinib following chemoradiotherapy and surgery for locally advanced esophageal cancer: a phase II trial.

PubMed

Horgan, A M; Darling, G; Wong, R; Guindi, M; Liu, G; Jonker, D J; Lister, J; Xu, W; MacKay, H M; Dinniwell, R; Kim, J; Pierre, A; Shargall, Y; Asmis, T R; Agboola, O; Seely, A J; Ringash, J; Wells, J; Marginean, E C; Haider, M; Knox, J J

2016-11-01

The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m 2 ) + Cisplatin (30 mg/m 2 ) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4-8. Sunitinib was commenced 4-13 weeks after surgery and continued for one year. Sixty-one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12-month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3-year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2-year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2-year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer. © 2015 International Society for Diseases of the Esophagus.

A novel two-chain IGF-II-derived peptide from purified β-cell granules.

PubMed

Buchanan, Christina M; Phillips, Anthony R J; Cooper, Garth J S

2010-10-01

Insulin-like growth factor II (IGF-II) is a potent mitogen that regulates prenatal growth and development in both humans and rodents. Its role in post-natal life is less clear although immunohistochemical studies have observed IGF-II-like immunoreactivity (IGF-II-LI) associated with insulin-producing pancreatic β-cells. Here we isolated secretory granules from a β-cell line, βTC6-F7, and characterized the nature of the IGF-II-LI located therein. Secretory granules were isolated from cultured mouse βTC6-F7 cells by ultracentrifugation. Granule protein content was separated by reversed-phase HPLC, and assayed for IGF-II (radioimmunoassay) prior to identification by gas-phase NH(2)-terminal sequencing and MALDI-TOF MS. Effects of glucose incorporation into muscle glycogen were determined by incubating with isolated rat soleus muscle strips. βTC6-F7 cells contained 60 ± 8 pmol of IGF-II-LI per 10⁶ cells compared to 340 ± 44 pmol insulin-LI per 10⁶ cells. IGF-II immunoreactive fractions were found to contain an IGF-II-like molecule with a molecular mass of 6847.6 Da. The protein was found to be a two-chain insulin-like product of Igf2 that corresponds to mouse des(37-40)IGF-II, which we termed 'vesiculin'. This molecule was also detectable in βTC6-F7 cells by intact-cell mass spectrometry. Mouse vesiculin evoked concentration-dependent stimulation of muscle glycogen synthesis ex vivo with an EC(50) value of 131 nM ± 1.35. Vesiculin, des(37-40)IGF-II, is a novel two-chain insulin-like hormone and the major "IGF-II-like" peptide found in purified mouse βTC6-F7 secretory granules. It stimulated ex vivo muscle glycogen synthesis with an efficacy greater than or equal to the intrinsic potency of IGF-II when compared to insulin derived from the same species. Copyright © 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.

Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension.

PubMed

Aptel, Florent; Choudhry, Reena; Stalmans, Ingeborg

2016-08-01

This study compared the efficacy, safety, and pharmacokinetics of a preservative-free latanoprost formulation to an established, benzalkonium chloride (BAK) containing formulation for the treatment of open-angle glaucoma or ocular hypertension. This was a phase II, randomized, cross-over, investigator-masked, multi-center, pilot study (NCT01494753). A total of 30 untreated adult patients (aged ≥18 years) with primary open angle glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, or ocular hypertension received either preservative-free or preserved latanoprost once daily in both eyes for 6 weeks, before crossing over to receive the other treatment. Efficacy (intraocular pressure [IOP] at 8 am, midday, 4 pm and 8 pm, and global efficacy assessment by investigator), safety (adverse events, ocular symptoms and global tolerance, slit lamp examination, funduscopy, visual field examination, visual acuity, and heart rate), and pharmacokinetics were assessed at Days 0, 42, and 84. Both treatments resulted in a reduction in IOP that was similar for the preservative-free and the preserved formulation at all time points. Similarly, the overall diurnal reduction was similar in both groups (6.3 mmHg [27.9% reduction] and 6.4 mmHg [28.1% reduction] for preserved and preservative-free latanoprost, respectively). There were no differences in global efficacy assessment or in the safety and tolerance of each treatment. Systemic concentrations of latanoprost were very low; AUC0-30 and Cmax were lower and tmax was longer for preservative-free latanoprost. Preservative-free latanoprost showed similar efficacy at all time points compared to BAK preservative containing formulation, with no difference in tolerance, allowing progression to phase III clinical development.

Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials.

PubMed

Talley, N J; Tack, J; Ptak, T; Gupta, R; Giguère, M

2008-06-01

Functional dyspepsia (FD) is a common disorder but there is currently little efficacious drug therapy. Itopride, a prokinetic approved in several countries, showed promising efficacy in FD in a phase IIb trial. The aim of this study was to test the efficacy and safety of this drug in FD. Two similar placebo-controlled clinical trials were conducted (International and North America). Males and females, 18-65 years old, with a diagnosis of FD (Rome II) and the absence (by upper endoscopy) of any relevant structural disease were recruited. All were negative for Helicobacter pylori and, if present, heartburn could not exceed one episode per week. Following screening, patients were randomised to itopride 100 mg three times daily or identical placebo. The co-primary end points were: (1) global patient assessment (GPA) of efficacy; and (2) Leeds Dyspepsia Questionnaire (LDQ). Symptoms were evaluated at weeks 2, 4 and 8. Secondary measures of efficacy included Nepean Dyspepsia Index (NDI) quality of life. The GPA responder rates at week 8 on itopride versus placebo were similar in both trials (45.2% vs 45.6% and 37.8 vs 35.4%, respectively; p = NS). A significant benefit of itopride over placebo was observed for the LDQ responders in the International (62% vs 52.7%, p = 0.04) but not the North American trial (46.9% vs 44.8%). The safety and tolerability profile were comparable with placebo, with the exception of prolactin elevations, which occurred more frequently on itopride (18/579) than placebo (1/591). In this population with FD, itopride did not show a difference in symptom response from placebo.

[Efficacy of nebulizer therapy with acetylcystein in outpatients with chronic obstructive lung disease].

PubMed

Stepanishcheva, L A; Ignatova, G L; Blinova, E V

2005-01-01

Chronic obstructive lung disease (COLD) is a widespread illness with constantly growing mortality. Mucolytic therapy plays a significant role in treatment of patients with COLD. The paper contains the results of nebulization with acetyl-cystein as part of rehabilitation program in outpatients with stable clinical course of I-II stage of COLD. The results demonstrated significant clinical improvement, as well as positive changes in external respiration parameters (1 sforced expiratory volume), increase of physical activity tolerance, and disappearance of acute inflammation phase reactants in saliva.

Treatment of nonneovascular idiopathic macular telangiectasia type 2 with intravitreal ranibizumab: results of a phase II clinical trial.

PubMed

Toy, Brian C; Koo, Euna; Cukras, Catherine; Meyerle, Catherine B; Chew, Emily Y; Wong, Wai T

2012-05-01

To evaluate the safety and preliminary efficacy of intravitreal ranibizumab for nonneovascular idiopathic macular telangiectasia Type 2. Single-center, open-label Phase II clinical trial enrolling five participants with bilateral nonneovascular idiopathic macular telangiectasia Type 2. Intravitreal ranibizumab (0.5 mg) was administered every 4 weeks in the study eye for 12 months with the contralateral eye observed. Outcome measures included changes in best-corrected visual acuity, area of late-phase leakage on fluorescein angiography, and retinal thickness on optical coherence tomography. The study treatment was well tolerated and associated with few adverse events. Change in best-corrected visual acuity at 12 months was not significantly different between treated study eyes (0.0 ± 7.5 letters) and control fellow eyes (+2.2 ± 1.9 letters). However, decreases in the area of late-phase fluorescein angiography leakage (-33 ± 20% for study eyes, +1 ± 8% for fellow eyes) and in optical coherence tomography central subfield retinal thickness (-11.7 ± 7.0% for study eyes and -2.9 ± 3.5% for fellow eyes) were greater in study eyes compared with fellow eyes. Despite significant anatomical responses to treatment, functional improvement in visual acuity was not detected. Intravitreal ranibizumab administered monthly over a time course of 12 months is unlikely to provide a general and significant benefit to patients with nonneovascular idiopathic macular telangiectasia Type 2.

Development of Levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis

PubMed Central

Stockmann, Chris; Sherwin, Catherine M.T.; Ampofo, Krow; Spigarelli, Michael G.

2017-01-01

Inhaled therapies allow for the targeted delivery of antimicrobials directly into the lungs and have been widely used in the treatment of cystic fibrosis (CF) acute pulmonary exacerbations. Nebulized levofloxacin solution (MP-376) is a novel therapy that is currently being evaluated in phase I, II, and III clinical trials among patients with stable CF and recent isolation of Pseudomonas aeruginosa from sputum. Phase I studies have investigated the single and multiple-dose pharmacokinetics of MP-376 and shown that it is rapidly absorbed from the lungs and results in low systemic concentrations. A subsequent phase IB study found that MP-376 pharmacokinetics were comparable among adults and children 6–16 years of age. Further phase II studies reported that sputum P. aeruginosa density decreased in a dose-dependent manner among patients who were randomized to MP-376 when compared with patients who received placebo. Improvements in pulmonary function and a decrease in the need for other antipseudomonal antibiotics were also reported for patients who received inhaled levofloxacin. The most common adverse event was dysgeusia (abnormal taste sensation), which was reported by nearly half of the participants who received MP-376. No serious drug-related adverse events were reported. These findings are encouraging; however, data from the two ongoing phase III trials are needed to determine whether MP-376 demonstrates substantial evidence of safety and efficacy as a chronic CF maintenance therapy and therefore may be useful in routine clinical practice. PMID:24334337

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

PubMed

Mega, J L; Braunwald, E; Mohanavelu, S; Burton, P; Poulter, R; Misselwitz, F; Hricak, V; Barnathan, E S; Bordes, P; Witkowski, A; Markov, V; Oppenheimer, L; Gibson, C M

2009-07-04

Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Results of the phase II study of photodynamic therapy in Japan

NASA Astrophysics Data System (ADS)

Konaka, Chimori; Kato, Harubumi; Okunaka, Tetsuya; Hayata, Yoshihiro

1994-07-01

Photodynamic therapy (PDT) utilizing Photofrin has proven to be an effective modality used in the treatment of solid tumors. In particular, it can be applied via endoscopy to lesions developing in luminal organs. A phase II study was conducted for submission to the Japanese Ministry of Health and Welfare. In this protocol an excimer dye laser was used to deliver 630 nm light via a quartz fiber passed through an endoscopic working channel two days subsequent to i.v. injection of photosensitizer. In this study, 98 patients with superficial cancer of various organs were treated. Of these, 88 patients could be evaluated, including 33 with roentgenographically occult lung cancer, 10 with esophageal cancer, 24 with gastric cancer, 18 with cervical cancer and three with bladder cancer. Complete remission as evaluated endoscopically, pathologically, and cytologically was obtained in 83 out of 98 (84.7). There was no serious complication except mild skin photosensitivity, which was seen in four patients. It was concluded that PDT can be efficacious in the treatment of superficial cancers and that complete remission can be achieved when suitable photoradiation conditions are met.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

PubMed

Vogl, Dan T; Martin, Thomas G; Vij, Ravi; Hari, Parameswaran; Mikhael, Joseph R; Siegel, David; Wu, Ka Lung; Delforge, Michel; Gasparetto, Cristina

2017-08-01

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m 2 . Dose-limiting toxicities (DLTs) at 2.4 mg/m 2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Phase II trial of CH5424802 (alectinib hydrochloride) for recurrent or refractory ALK-positive anaplastic large cell lymphoma: study protocol for a non-randomized non-controlled trial.

PubMed

Nagai, Hirokazu; Fukano, Reiji; Sekimizu, Masahiro; Kada, Akiko; M Saito, Akiko; Asada, Ryuta; Mori, Tetsuya

2017-08-01

Currently, a standard therapy has not been established for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. While there are many treatment options, such as hematopoietic stem cell transplantation, patients with resistant disease to conventional chemotherapies have particularly poor prognosis. There is urgent need to develop new drugs because of the lack of a standard therapy and poor prognoses. This phase II trial is designed for evaluating the efficacy and safety of alectinib hydrochloride for patients with recurrent or refractory anaplastic lymphoma kinase -positive anaplastic large cell lymphoma. The primary endpoint is the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints are pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events. The results of this trial will be the pivotal data for the drug approval of alectinib hydrochloride for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study.

PubMed

Brandes, Alba A; Ermani, Mario; Basso, Umberto; Paris, Myriam K; Lumachi, Franco; Berti, Franco; Amistà, Pietro; Gardiman, Marina; Iuzzolino, Paolo; Turazzi, Sergio; Monfardini, Silvio

2002-01-01

To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m(2)/daily for 5 days every 4 weeks. The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14-42%) and 8% (CI = 2-27%), respectively, with a median TTP of 11.7 weeks (CI = 9-22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7-31%). TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM. Copyright 2002 S. Karger AG, Basel

A Case Report of Gastrointestinal Hemorrhage and Perforation During Apatinib Treatment of Gastric Cancer.

PubMed

Li, Xiao-Fen; Tan, Yi-Nuo; Cao, Ying; Xu, Jing-Hong; Zheng, Shu; Yuan, Ying

2015-09-01

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which shows good efficacy and safety in clinical trials for chemotherapy-refractory gastric cancer patients. Till now, there is no case report after apatinib came in the market. We presented a 55-year-old Chinese woman with advanced gastric cancer, who received apatinib after failure of second-line chemotherapy. On the 19th day of apatinib administration, she suffered from gastrointestinal hemorrhage. Then, her condition rapidly deteriorated to gastrointestinal perforation. Although the patient received timely medical and surgical treatment, she finally died of septic shock. Although apatinib shows exciting efficacy and good tolerance in phase II and III clinical trials, this novel targeted drug should be prescribed carefully and close clinical monitoring is needed when using it.

A Case Report of Gastrointestinal Hemorrhage and Perforation During Apatinib Treatment of Gastric Cancer

PubMed Central

Li, Xiao-Fen; Tan, Yi-Nuo; Cao, Ying; Xu, Jing-Hong; Zheng, Shu; Yuan, Ying

2015-01-01

Abstract Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which shows good efficacy and safety in clinical trials for chemotherapy-refractory gastric cancer patients. Till now, there is no case report after apatinib came in the market. We presented a 55-year-old Chinese woman with advanced gastric cancer, who received apatinib after failure of second-line chemotherapy. On the 19th day of apatinib administration, she suffered from gastrointestinal hemorrhage. Then, her condition rapidly deteriorated to gastrointestinal perforation. Although the patient received timely medical and surgical treatment, she finally died of septic shock. Although apatinib shows exciting efficacy and good tolerance in phase II and III clinical trials, this novel targeted drug should be prescribed carefully and close clinical monitoring is needed when using it. PMID:26426663

Naltrexone/bupropion for the treatment of obesity and obesity with Type 2 diabetes.

PubMed

Apovian, Caroline M

2016-03-01

Contrave(®) is a combination of naltrexone hydrochloride extended release and bupropion hydrochloride extended release for the treatment of obesity, and is used with lifestyle modification. Its safety and efficacy were assessed in four randomized, double-blind, placebo-controlled, 56-week Phase III clinical trials in 4536 adult subjects: COR-1, COR-II, COR-BMOD and COR-DM. All four studies demonstrated statistically significant and clinically meaningful weight loss following up to 52 weeks of treatment with naltrexone/bupropion compared with placebo. The average weight loss from baseline across the four studies was approximately 11-22 lbs (5-9 kg). Results show the efficacy of Contrave for weight loss, as well as significant improvements in cardiometabolic markers. This review focuses on the four studies, their outcomes and the mechanism of action of Contrave.

Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study.

PubMed

Eron, Joseph J; Clotet, Bonaventura; Durant, Jacques; Katlama, Christine; Kumar, Princy; Lazzarin, Adriano; Poizot-Martin, Isabelle; Richmond, Gary; Soriano, Vincent; Ait-Khaled, Mounir; Fujiwara, Tamio; Huang, Jenny; Min, Sherene; Vavro, Cindy; Yeo, Jane

2013-03-01

Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.

[Alemtuzumab for relapsing-remitting multiple sclerosis. Results of two randomized controlled phase III studies].

PubMed

Klotz, L; Meuth, S G; Kieseier, B; Wiendl, H

2013-08-01

In November 2012 the results of 2 clinical phase III trials were published which addressed the effects of alemtuzumab in patients with relapsing-remitting multiple sclerosis (MS). In the CARE-MS-I study patients with early untreated MS (EDSS ≤ 3.0, disease duration < 5 years) were included, whereas CARE-MS-II investigated the effects of alemtuzumab in patients with persisting disease activity under standard disease-modifying treatment (EDSS ≤ 5.0, disease duration < 10 years). These groups were compared to patients under treatment with frequently applied interferon β 1a (3 times  44 µg subcutaneous). Both studies clearly demonstrated a superiority of alemtuzumab compared to interferon in terms of reduction of relapse rate as well as the number of new or enlarging T2 lesions and gadolinium-enhancing lesions. Moreover, the CARE-MS-II study showed a significant delay in disease progression by alemtuzumab. The portfolio and the frequency of relevant side effects, such as infusion-related reactions, development of secondary autoimmunity or infections were within the expected range. Taken together these studies confirm the high anti-inflammatory efficacy of alemtuzumab and hence provide the first evidence of superiority of a monotherapy in direct comparison to standard disease-modifying treatment in two phase III trials in relapsing-remitting MS. These data in the context of the mode of action of alemtuzumab provide evidence for the relevance of immune cells, especially T cells, in the pathophysiology of MS. Experience with long-term effects of alemtuzumab, e.g. from the phase II extension trial as well as the side effect profile argue in favor of a sustained reprogramming of the immune system as a consequence of immune cell depletion by alemtuzumab.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

PubMed

Goss, G; Tsai, C-M; Shepherd, F A; Ahn, M-J; Bazhenova, L; Crinò, L; de Marinis, F; Felip, E; Morabito, A; Hodge, R; Cantarini, M; Johnson, M; Mitsudomi, T; Jänne, P A; Yang, J C-H

2018-03-01

Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. NCT01802632; NCT02094261.

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

PubMed

van der Heijde, Désirée; Deodhar, Atul; Wei, James C; Drescher, Edit; Fleishaker, Dona; Hendrikx, Thijs; Li, David; Menon, Sujatha; Kanik, Keith S

2017-08-01

To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. NCT01786668. 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/.

The efficacy and safety of docetaxel-based chemotherapy combined with dexamethasone 1 mg daily oral administration: JMTO Pca 10-01 phase II trial.

PubMed

Tanaka, Nobumichi; Nishimura, Kazuo; Okajima, Eijiro; Ina, Kenji; Ogawa, Osamu; Nagata, Hirohiko; Akakura, Koichiro; Fujimoto, Kiyohide; Gotoh, Momokazu; Teramukai, Satoshi; Hirao, Yoshihiko

2017-03-01

Previously, one randomized control trial (TAX327) revealed the efficacy of docetaxel-based chemotherapy combined with prednisone. On the other hand, several studies showed a high prostate specific antigen (PSA) response with low-dose dexamethasone in castration-resistant prostate cancer (CRPC) patients. The objective of this study was to evaluate the efficacy and safety of docetaxel-based chemotherapy combined with dexamethasone in CRPC patients. This study was a single-arm multi-institutional phase II trial. Patients received 75 mg/m2 of docetaxel, and 0.5 mg of dexamethasone orally twice a day continuing throughout the treatment period. Treatment was planned for 10 cycles, and continued for at least four cycles depending on the observation of PSA flare. The primary endpoint was PSA response defined as a reduction from baseline of at least 50% that continued for at least 3 weeks. Secondary endpoints were safety, PSA flare, time to PSA failure and adherence rate to protocol treatment (10 cycles). Between January 2011 and February 2014, a total of 76 chemotherapy-naïve CRPC patients were enrolled. Seventy-five patients received docetaxel-based chemotherapy combined with dexamethasone. The median age and PSA level at enrollment were 71 years (53-85) and 23.2 ng/mL (2.9-852), respectively. PSA response rate was 76.8% (90% confidence interval (CI): 66.9-84.9). Of all patients, 30 patients completed 10 cycles of chemotherapy (40%). The incidence rate of PSA flare was 10.7% (eight patients). The median time to PSA failure was 369 days (95% CI: 245-369). The most frequently observed adverse event was hematotoxicity (neutropenia of G2 or greater: 100%). The present study showed a significantly high PSA response compared with previous reports. Most patients tolerated the protocol treatment well, whereas hematotoxicity was often observed. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

PubMed

Niho, Seiji; Ohe, Yuichiro; Ohmatsu, Hironobu; Umemura, Shigeki; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2017-06-01

We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m 2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. Copyright © 2017. Published by Elsevier B.V.

Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase II Randomized Clinical Trial.

PubMed

Wysham, Carol H; MacConell, Leigh; Hardy, Elise

2016-10-01

This study investigated the efficacy and safety of multiple exenatide once-monthly suspension (QMS) doses of exenatide-containing microspheres in Miglyol referenced against the clinical dose of exenatide once-weekly (QW) microspheres in aqueous solution. In this phase II, randomized, controlled, single-blind study, 121 adults (∼30/arm) with type 2 diabetes and HbA1c 7.1-11.0% (54-97 mmol/mol) were randomized 1:1:1:1 to subcutaneous exenatide QW 2 mg (self-administered) or exenatide QMS 5, 8, or 11 mg (caregiver-administered) for 20 weeks. The primary end point was change in HbA1c. At baseline, mean age was 50 years, HbA1c was 8.5% (69 mmol/mol), fasting plasma glucose (FPG) was 184 mg/dL, and body weight was 98 kg. At week 20, mean ± SD HbA1c reductions were -1.54% ± 1.26% with exenatide QW and -1.29% ± 1.07%, -1.31% ± 1.66%, and -1.45% ± 0.93% with exenatide QMS 5, 8, and 11 mg, respectively (evaluable population: n = 110). There were no significant differences in HbA1c reductions among the exenatide QMS doses. FPG reductions were -34 ± 48 mg/dL with exenatide QW and -25 ± 43, -30 ± 52, and -49 ± 49 mg/dL with exenatide QMS 5, 8, and 11 mg, respectively. Weight decreased with all treatments. For exenatide QMS, nausea (16.7-23.3%) and headache (16.7-26.7%) were the most common adverse events. No major or minor hypoglycemia occurred. All doses of exenatide QMS resulted in efficacy and tolerability profiles consistent with exenatide QW. These results combined with pharmacokinetic and pharmacodynamic modeling could inform dose selection for further development. © 2016 by the American Diabetes Association.

Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction).

PubMed

Sanz-Ruiz, Ricardo; Casado Plasencia, Ana; Borlado, Luis R; Fernández-Santos, María Eugenia; Al-Daccak, Reem; Claus, Piet; Palacios, Itziar; Sádaba, Rafael; Charron, Dominique; Bogaert, Jan; Mulet, Miguel; Yotti, Raquel; Gilaberte, Immaculada; Bernad, Antonio; Bermejo, Javier; Janssens, Stefan; Fernández-Avilés, Franciso

2017-06-23

Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging-based efficacy end points. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439398. © 2017 American Heart Association, Inc.

Success and failure of vaccines against renin-angiotensin system components.

PubMed

Brown, Morris J

2009-10-01

Therapeutic vaccination pre-dated modern drugs as a possible strategy for treating hypertension. This approach is now being rediscovered, through use of modified angiotensins as immunogens together with carriers and adjuvants. Effective blockade of the renin-angiotensin system (RAS) with treatment twice a year might suit patients who dislike taking drugs on a daily basis and would also be an attractive option for those who have blood pressures in the prehypertensive range, if it can prevent hypertension itself from developing. Proof of concept with a vaccine whose efficacy is easy to measure will encourage development of further vaccines directed against targets such as aldosterone or other pathways where alternative treatments are scarce or absent. Two angiotensin-based vaccines are currently in development: PMD3117 comprises modified angiotensin I coupled to keyhole limpet hemocyanin, and Cyt006-AngQb is a conjugate of angiotensin II linked to virus particles. Early phase II studies in patients with hypertension demonstrated some efficacy, but the vaccines are not as effective as existing inhibitors of the RAS. Large studies now in progress will establish whether further modification of the immunogen or adjuvant is required to boost antibody titers.

Safinamide: FCE 26743, NW 1015, PNU 151774, PNU 151774E.

PubMed

2004-01-01

Safinamide [NW 1015, PNU 151774E; FCE 26743] is a potent anticonvulsant and antiparkinsonian compound that is being developed by Newron Pharmaceuticals in Europe. It has been shown to antagonise the calcium and sodium channels, as well as inhibit monoamine oxidase type-B (MAO-B). Phase III trials for the treatment of Parkinson's disease are underway in Germany and Europe, while phase II trials in patients with epilepsy are ongoing in Italy. Newron Pharmaceuticals was founded at the end of 1998 after Pharmacia & Upjohn announced its worldwide restructuring programme. Newron obtained the rights to safinamide, which Pharmacia Corporation (now Pfizer) had been developing as PNU 151774E. Safinamide was originated by Farmitalia-CarloErba in Italy. Newron now owns all intellectual property associated with the drug.A multinational phase II trial for Parkinson's disease in Europe has shown positive results in slowing the progression of the disease; however, due to the placebo-effect seen in this study, a longer (6-month) phase IIb study is planned for the second quarter of 2003. In July 2003, Newron received an IND from the US FDA authorising a phase I trial to confirm that no dietary restrictions are needed in patients while being treated with safinamide. This study is be conducted in 12 healthy volunteers at the University of Vienna, Austria, and will be followed by efficacy studies in Parkinson's disease in the US. Five phase I trials were completed in April 2001 in Switzerland. Safinamide combines sodium and calcium channel modulatory activity with monoamine oxidase B inhibition.

Delafloxacin for the treatment of respiratory and skin infections.

PubMed

Bassetti, Matteo; Della Siega, Paola; Pecori, Davide; Scarparo, Claudio; Righi, Elda

2015-03-01

There has been a striking increase in the emergence of multidrug-resistant pathogens in recent times. Delafloxacin is a novel, broad-spectrum fluoroquinolone with antimicrobial activity against resistant Gram-positive, Gram-negative and anaerobic organisms. It has the potential to treat a variety of infections including complicated skin and skin structure infections and respiratory tract infections. In this review, the authors report the microbiological spectrum of activity of delafloxacin as well as its pharmacokinetic characteristics. They also report the results of recent studies investigating its safety and efficacy. The profile of delafloxacin offers several advantages. Delafloxacin presents a broad spectrum of activity against pathogens involved in respiratory infections and complicated skin and skin structure infections (SSSIs), including methicillin-resistant Staphylococcus aureus. It has also shown activity against Gram-negative pathogens, such as quinolone-susceptible and -resistant strains of Escherichia coli and Klebsiella pneumoniae and quinolone-susceptible Pseudomonas aeruginosa. The availability of an oral formulation supports its use in sequential therapy. The efficacy and tolerability of delafloxacin have been demonstrated in Phase II clinical trials in comparison with moxifloxacin for respiratory infections and linezolid and vancomycin in SSSIs. Compared with other quinolones such as moxifloxacin, delafloxacin showed comparable efficacy and a lower rate of adverse effects. The results of new Phase III studies are awaited to confirm delafloxacin's future applications in the treatment of SSSIs.

Improving practice in community-based settings: a randomized trial of supervision - study protocol.

PubMed

Dorsey, Shannon; Pullmann, Michael D; Deblinger, Esther; Berliner, Lucy; Kerns, Suzanne E; Thompson, Kelly; Unützer, Jürgen; Weisz, John R; Garland, Ann F

2013-08-10

Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes 'gold standard' supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. ClinicalTrials.gov NCT01800266.

Improving practice in community-based settings: a randomized trial of supervision – study protocol

PubMed Central

2013-01-01

Background Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes ‘gold standard’ supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. Methods/Design The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. Discussion This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. Trial registration ClinicalTrials.gov NCT01800266 PMID:23937766

Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

PubMed

Schuster, Cornelia; Eikesdal, Hans P; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E; Akslen, Lars A; Straume, Oddbjørn

2012-01-01

VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. ClinicalTrials.gov NCT00139360.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.

PubMed

Dutton, P; Love, S B; Billingham, L; Hassan, A B

2018-05-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

Antimalarial compounds in Phase II clinical development.

PubMed

Held, Jana; Jeyaraj, Sankarganesh; Kreidenweiss, Andrea

2015-03-01

Malaria is a major health problem in endemic countries and chemotherapy remains the most important tool in combating it. Treatment options are limited and essentially rely on a single drug class - the artemisinins. Efforts are ongoing to restrict the evolving threat of artemisinin resistance but declining sensitivity has been reported. Fueled by the ambitious aim of malaria eradication, novel antimalarial compounds, with improved properties, are now in the progressive phase of drug development. Herein, the authors describe antimalarial compounds currently in Phase II clinical development and present the results of these investigations. Thanks to recent efforts, a number of promising antimalarial compounds are now in the pipeline. First safety data have been generated for all of these candidates, although their efficacy as antimalarials is still unclear for most of them. Of particular note are KAE609, KAF156 and DSM265, which are of chemical scaffolds new to malaria chemotherapy and would truly diversify antimalarial options. Apart from SAR97276, which also has a novel chemical scaffold that has had its development stopped, all other compounds in the pipeline belong to already known substance classes, which have been chemically modified. At this moment in time, there is not one standout compound that will revolutionize malaria treatment but several compounds that will add to its control in the future.

Small Business Innovation Research GRC Phase I, Phase II, and Post-Phase II Opportunity Assessment for 2015

NASA Technical Reports Server (NTRS)

Nguyen, Hung D.; Steele, Gynelle C.

2016-01-01

This report outlines the 2015 Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) Phase I, Phase II, and Post-Phase II opportunity contract award results associated with NASA's Aeronautics Research Mission Directorate (ARMD), Human Exploration and Operations Mission Directorate (HEOMD), Science Mission Directorate (SMD), and Space Technology Mission Directorate (STMD) for NASA Glenn Research Center. The report also highlights the number of Phase I, Phase II, and Post-Phase II contracts awarded by mission directorate. The 2015 Phase I contract awards to companies in Ohio and their corresponding technologies are also discussed.

Discovery and clinical introduction of first-in-class imipridone ONC201.

PubMed

Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S

2016-11-08

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Discovery and clinical introduction of first-in-class imipridone ONC201

PubMed Central

Allen, Joshua E.; Kline, C. Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala K.; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S.

2016-01-01

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. PMID:27602582

A multicenter phase II study of salvage photodynamic therapy using talaporfin sodium (ME2906) and a diode laser (PNL6405EPG) for local failure after chemoradiotherapy or radiotherapy for esophageal cancer

PubMed Central

Yano, Tomonori; Kasai, Hiroi; Horimatsu, Takahiro; Yoshimura, Kenichi; Teramukai, Satoshi; Morita, Satoshi; Tada, Harue; Yamamoto, Yoshinobu; Kataoka, Hiromi; Kakushima, Naomi; Ishihara, Ryu; Isomoto, Hajime; Muto, Manabu

2017-01-01

Photodynamic therapy (PDT) showed promising efficacy for local failure after chemoradiotherapy (CRT) for esophageal cancer. However, PDT required long sun shade period. This study aimed to evaluate the safety and efficacy of PDT using second generation photosensitizer, talaporfin sodium for local failure after CRT. This was the multi-institutional non-randomized phase II study. Patients with histologically proven local failure limited within the muscularis propria after 50Gy or more radiotherapy (RT) for esophageal cancer were eligible. We set the primary endpoint as local complete response (L-CR) per patients. And, secondary endpoints were confirmed L-CR, local progression free survival (L-PFS), progression free survival (PFS), overall survival (OS), L-CR per lesions (Lesion L-CR), and confirmed Lesion L-CR. The PDT procedure commenced with intravenous administration of a 40 mg/m2 dose of talaporfin sodium followed by diode laser irradiation at a 664 nm wavelength. 26 eligible patients were enrolled and all were treated with PDT. Twenty three patients with 25 lesions were assessed L-CR after PDT; the L-CR rate per patients was 88.5% (95% CI: 69.8%-97.6%). No skin phototoxicity was observed, and no grade 3 or worse non-hematological toxicities related to PDT were observed. PDT using talaporfin sodium and a diode laser is a safe and curative salvage treatment for local failure after CRT or RT for patients with esophageal cancer. PMID:28212527

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.

PubMed

Rafii, Michael S; Skotko, Brian G; McDonough, Mary Ellen; Pulsifer, Margaret; Evans, Casey; Doran, Eric; Muranevici, Gabriela; Kesslak, Patrick; Abushakra, Susan; Lott, Ira T

2017-01-01

ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer.

PubMed

Digumarti, Raghunadharao; Bapsy, P P; Suresh, Attili V; Bhattacharyya, G S; Dasappa, Lokanatha; Shan, Joseph S; Gerber, David E

2014-11-01

Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating and tumor-specific vascular targeting properties. Preclinical studies have shown activity against numerous solid tumors and at least an additive effect in combination with chemotherapy. This study evaluated bavituximab in combination with paclitaxel and carboplatin in patients with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC). This phase II, open-label study (NCT00687817) was conducted in 49 patients with stage IIIB/IV NSCLC utilizing a Simon two-stage design. Patients were treated with up to six cycles of carboplatin area under the concentration-time curve (AUC) 5 plus paclitaxel 175 mg/m2 every 21 days with weekly bavituximab 3 mg/kg followed by bavituximab monotherapy until progression or unacceptable toxicity. The primary efficacy endpoint of overall response rate (ORR) was 40.8% (complete response [CR] 2.0%, partial response [PR] was 38.8%). Median progression-free survival (PFS) and overall survival (OS) were 6.0 and 12.4 months, respectively. Treatment-related adverse events (AEs) occurred in 40.8% of patients. The most common treatment-related AEs were anemia (10.2%), asthenia, vomiting, paresthesia, anorexia, and fatigue (6.1% each). One patient with a central, cavitating squamous tumor developed fatal hemoptysis and aspiration. Bavituximab in combination with paclitaxel-carboplatin as first-line therapy demonstrated a tolerable safety profile and potential efficacy in this single-arm phase II trial in patients with advanced local or metastatic NSCLC. Randomized trials with this regimen are in progress. NCT00687817. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Efficacy evaluation of an anti-caries varnish: protocol for a phase II randomised controlled trial

PubMed Central

Tut, Ohnmar; Rothen, Marilynn; Mancl, Lloyd; Gallen, Marcelle; Tanzer, Jason M

2017-01-01

Introduction Dental caries (tooth decay) is a common disease in which the products of sugar metabolism by certain bacteria that populate the tooth surface induce the development and progression of lesions (cavities). This is a phase II single-centre randomised, double-blind, active-controlled, parallel-group trial to assess the efficacy of a combination povidone iodine and sodium fluoride dental varnish to determine if it is superior to a varnish containing only sodium fluoride in the prevention of new caries lesions. The objective of this report is to describe the rationale and protocol for the trial. Methods and analysis The study site is Pohnpei State, Federated States of Micronesia. The study population is 284 children 48–84 months old. The primary outcome will be the surface-level primary molar caries increment (d2-3mfs/DMFS) at 2 years post baseline. The incremental dental caries at 1 year will also be compared between the two interventions. The secondary outcome is the Facial Image Scale after the initial treatment and after the fifth treatment at 1 year that gauges the child’s response to the treatment. Ethics and dissemination The Western Institutional Review Board (designated IRB) and the Institutional Review Board of the College of Micronesia-FSM approved all study procedures. The US Food and Drug Administration (FDA) has issued IND 128835 covering this study. The study results will be published and submitted to the FDA in support of a new drug application. Trialregistration number NCT03082196. PMID:28667230

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II, multicenter noncomparative study.

PubMed

Benhamou, Ygal; Paintaud, Gilles; Azoulay, Elie; Poullin, Pascale; Galicier, Lionel; Desvignes, Céline; Baudel, Jean-Luc; Peltier, Julie; Mira, Jean-Paul; Pène, Frédéric; Presne, Claire; Saheb, Samir; Deligny, Christophe; Rousseau, Alexandra; Féger, Frédéric; Veyradier, Agnès; Coppo, Paul

2016-12-01

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange-based regimen received two infusions of rituximab 375 mg m -2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell-driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti-ADAMTS13 depletion in a similar manner to the standard four-rituximab infusions schedule. The 1-year relapse-free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four-rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246-1251, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence

PubMed Central

Liu, Chun-Jen; Chang, Juliana; Lee, Po-Huang; Lin, Deng-Yn; Wu, Cheng-Chung; Jeng, Long-Bin; Lin, Yih-Jyh; Mok, King-Tong; Lee, Wei-Chen; Yeh, Hong-Zen; Ho, Ming-Chih; Yang, Sheng-Shun; Yang, Mei-Due; Yu, Ming-Chin; Hu, Rey-Heng; Peng, Cheng-Yuan; Lai, Kuan-Lang; Chang, Stanley Shi-Chung; Chen, Pei-Jer

2014-01-01

AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection. METHODS: A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival. RESULTS: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence. CONCLUSION: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC. PMID:25170226

Results of NCCTG N0275 (Alliance) - a phase II trial evaluating resection followed by adjuvant radiation therapy for patients with desmoplastic melanoma.

PubMed

Rule, William G; Allred, Jacob B; Pockaj, Barbara A; Markovic, Svetomir N; DiCaudo, David J; Erickson, Lori A; Deming, Richard L; Schild, Steven E

2016-08-01

To examine, in a prospective fashion, the utilization and efficacy of adjuvant radiation therapy (RT) in patients with resected desmoplastic melanoma (DM). Adult patients with resected, margin-negative, and nonmetastatic DM were eligible for this single-arm prospective phase II study. Patients were to receive postoperative RT, 30 Gy in five fractions, to the operative bed with 2- to 3-cm margins (depending on the tumor location). Nodal basin RT was not allowed. The primary study endpoint was the 2-year local recurrence rate (LRR). Secondary endpoints included the incidence of regional and distant metastatic disease, progression-free survival, overall survival (OS), and treatment-related toxicity. Twenty patients with a single de novo DM lesion meeting trial eligibility criteria were enrolled and treated. The 2-year LRR was 10%, with two patients demonstrating a LR within 2 years of completion of protocol therapy. No regional or distant failures occurred. OS at 2 and 5 years was 95 and 77%, respectively. There were no grade 3 or higher acute or late adverse events that were related to the protocol therapy. Adjuvant RT after wide local excision (WLE) for DM is efficacious and well tolerated. It should be considered for DM patients after margin-negative WLE. Additional study is needed to further refine low-risk patient populations that can potentially have adjuvant RT omitted as part of the treatment plan. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

PubMed

Yoneyama, Koichiro; Schmitt, Christophe; Kotani, Naoki; Levy, Gallia G; Kasai, Ryu; Iida, Satofumi; Shima, Midori; Kawanishi, Takehiko

2017-12-06

Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

[What's new in dermatological treatments?].

PubMed

Martin, L

2010-12-01

Although the isolated clinical cases published are sometimes helpful in individual situations in which the therapeutic options have been exhausted, this type of publication cannot be generalized. For this reason, the selection presented covering the period from November 2009 to October 2010 is to a very large extent based on controlled trials, either because they contribute important information or because they raise great hope for a significant number of patients. For the first time in cutaneous oncology, a treatment (ipilimumab) has significantly increased overall survival in patients with metastatic melanoma (phase III), although this gain remains modest (4-6 months) and adverse immunological effects are frequent (30-40%). A phase I trial with treatment specifically targeting the mutant BRAF protein has shown an objective response in 81% of the patients treated in the metastatic phase of melanoma, thus allowing its development to be pursued. Grouping two studies in a rare tumor such as dermatofibrosarcoma also gives hope with imatinib as a neoadjuvant treatment when the initial tumor is inoperable, with, however, an inconsistent response of approximately 50% and only if the tumor presents reorganization of chromosomes 17 and 22. Cutaneous inflammatory diseases are still dominated by dual therapies in psoriasis, with, notably, an effectiveness trial on etanercept at different doses not showing a difference in efficacy depending on dose for the joint component of psoriasis, but also by the publication of a direct comparison of two dual therapies, ustekinumab versus etanercept. In atopic dermatitis, a controversial article invites one to reflect upon the progress made in the management of children by clinical nurses, as in the Netherlands and in Great Britain, in an attempt to contend with the shortage of dermatologists. Since the use of biotherapies is not the prerogative of psoriasis, infliximab was assessed in a phase II trial in Verneuil disease without demonstrating significant efficacy on the main criterion, but it did show a tendency to reduce the score used. This trial suffered from a weakness both in methodology and statistical power, thus precluding any conclusion. The rarity of therapeutic trials on drug eruptions warrants their mention. A French phase II study gives a glimpse of a trend toward efficacy in terms of survival in the treatment of toxic epidermal necrolysis with cyclosporine. As for infectious dermatosis and sexually transmitted infections, a French multicenter study has shown significantly higher efficacy with ivermectin than with malathion in treating pediculosis without increasing the side effects. Today, however, this systemic treatment cannot be a first-line treatment outside of certain specific situations. A large cohort study (somewhat unsatisfactory in its methodology) has not demonstrated the teratogenicity of antiherpes treatments in 830,000 infants. In prevention of HIV transmission, no microbicidal gel had shown efficacy to date. This has now been accomplished in South Africa with a 1% tenofovir gel. The results of a preliminary trial on therapeutic vaccination against HPV16 proposed to women who are carriers of cervical intraepithelial neoplasia opens the way for wide vaccine therapy of cutaneous virus-induced neoplasia. In conclusion, several articles analyzing the dermatology literature provide an opportunity to reflect on the quality of such articles, Boutron's being absolutely in-dis-pen-sa-ble! Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Deferasirox for managing iron overload in people with thalassaemia.

PubMed

Meerpohl, Joerg J; Antes, Gerd; Rücker, Gerta; Fleeman, Nigel; Motschall, Edith; Niemeyer, Charlotte M; Bassler, Dirk

2012-02-15

Thalassemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusion. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone have been found to be efficacious. However, a systematic review of the effectiveness and safety of the new oral chelator deferasirox in people with thalassaemia is needed. To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and secondary iron overload. We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, EBMR, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE and three trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/. Date of the most recent searches of these databases: 24 June 2010.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 03 November 2011. Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment. Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. Four studies met the inclusion criteria.Two studies compared deferasirox to placebo or standard therapy of deferoxamine (n = 47). The placebo-controlled studies, a pharmacokinetic and a dose escalation study, showed that deferasirox leads to net iron excretion in transfusion-dependent thalassaemia patients. In these studies, safety was acceptable and further investigation in phase II and phase III trials was warranted.Two studies, one phase II study (n = 71) and one phase III study (n = 586) compared deferasirox to standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared; in the phase III trial, similar or superior efficacy for surrogate parameters of ferritin and liver iron concentration could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg/d and 51.6 mg/d respectively. Data on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs. Deferasirox offers an important alternative line of treatment for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy in the long run and will translate to similar benefits as has been shown for deferoxamine, needs to be confirmed. Data on safety, particularly on rare toxicities and long-term safety, are still limited.Therefore, we think that deferasirox should be offered as an alternative to all patients with thalassaemia who either show intolerance to deferoxamine or poor compliance with deferoxamine. In our opinion, data are still too limited to support the general recommendation of deferasirox as first-line treatment instead of deferoxamine. If a strong preference for deferasirox is expressed, it could be offered as first-line option to individual patients after a detailed discussion of the potential benefits and risks.

Apatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors.

PubMed

Scott, A J; Messersmith, W A; Jimeno, A

2015-04-01

Aberrant proangiogenic pathways have long been implicated in tumorigenesis and metastasis. Antiangiogenic therapies have shown efficacy in the treatment of a variety of solid tumors including lung, breast, colon, glioblastomas, and other solid tumor types. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), is an orally bioavailable agent currently being studied in multiple tumor types. Apatinib has shown a survival benefit in gastric cancer in a phase III trial and non-small cell lung cancer in a phase II trial. With a favorable side effect profile and improved outcomes, apatinib has demonstrated a substantial potential to augment therapeutic options in a variety of tumor types. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Identifying a maximum tolerated contour in two-dimensional dose-finding

PubMed Central

Wages, Nolan A.

2016-01-01

The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided. PMID:26910586

The Role of Xenobiotic-Metabolizing Enzymes in Anthelmintic Deactivation and Resistance in Helminths.

PubMed

Matoušková, Petra; Vokřál, Ivan; Lamka, Jiří; Skálová, Lenka

2016-06-01

Xenobiotic-metabolizing enzymes (XMEs) modulate the biological activity and behavior of many drugs, including anthelmintics. The effects of anthelmintics can often be abolished by XMEs when the drugs are metabolized to an inefficient compound. XMEs therefore play a significant role in anthelmintic efficacy. Moreover, differences in XMEs between helminths are reflected by differences in anthelmintic metabolism between target species. Taking advantage of the newly sequenced genomes of many helminth species, progress in this field has been remarkable. The present review collects up to date information regarding the most important XMEs (phase I and phase II biotransformation enzymes; efflux transporters) in helminths. The participation of these XMEs in anthelmintic metabolism and their possible roles in drug resistance are evaluated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design of a phase III multicenter trial to evaluate the efficacy of the RTS,S/AS01 malaria vaccine in children across diverse transmission settings in Africa

PubMed Central

2011-01-01

Background GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making. Methods The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub-Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV-infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories. Conclusions This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions. Trial registration Clinicaltrials.gov NCT00866619 PMID:21816029

A psychological approach to providing self-management education for people with type 2 diabetes: the Diabetes Manual

PubMed Central

Sturt, Jackie; Taylor, Hafrun; Docherty, Andrea; Dale, Jeremy; Louise, Taylor

2006-01-01

Background The objectives of this study were twofold (i) to develop the Diabetes Manual, a self-management educational intervention aimed at improving biomedical and psychosocial outcomes (ii) to produce early phase evidence relating to validity and clinical feasibility to inform future research and systematic reviews. Methods Using the UK Medical Research Council's complex intervention framework, the Diabetes Manual and associated self management interventions were developed through pre-clinical, and phase I evaluation phases guided by adult-learning and self-efficacy theories, clinical feasibility and health policy protocols. A qualitative needs assessment and an RCT contributed data to the pre-clinical phase. Phase I incorporated intervention development informed by the pre-clinical phase and a feasibility survey. Results The pre-clinical and phase I studies resulted in the production in the Diabetes Manual programme for trial evaluation as delivered within routine primary care consultations. Conclusion This complex intervention shows early feasibility and face validity for both diabetes health professionals and people with diabetes. Randomised trial will determine effectiveness against clinical and psychological outcomes. Further study of some component parts, delivered in alternative combinations, is recommended. PMID:17129376

Molecular Basis of Allele-Specific Efficacy of a Blood-Stage Malaria Vaccine: Vaccine Development Implications

PubMed Central

Ouattara, Amed; Takala-Harrison, Shannon; Thera, Mahamadou A.; Coulibaly, Drissa; Niangaly, Amadou; Saye, Renion; Tolo, Youssouf; Dutta, Sheetij; Heppner, D. Gray; Soisson, Lorraine; Diggs, Carter L.; Vekemans, Johan; Cohen, Joe; Blackwelder, William C.; Dube, Tina; Laurens, Matthew B.; Doumbo, Ogobara K.; Plowe, Christopher V.

2013-01-01

The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02A, a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02A had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen. PMID:23204168

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.

PubMed

Pinter, M M; Pogarell, O; Oertel, W H

1999-04-01

Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

Safety and efficacy of quetiapine in bipolar depression.

PubMed

Bogart, Gregory T; Chavez, Benjamin

2009-11-01

To review the clinical data investigating the efficacy and safety of quetiapine in bipolar depression. Searches of MEDLINE and PubMed (1977-July 2009) were conducted using the key words quetiapine and bipolar depression. The references of literature found were cross-referenced. The pharmaceutical company that produces quetiapine was contacted to obtain the posters for the EMBOLDEN I and EMBOLDEN II trials. Only double-blind, placebo-controlled trials were included for review, as well as any subanalyses of the literature that matched this criterion. There was a total of 5 double-blind, placebo-controlled trials and 5 subanalyses reviewed. The results of these data demonstrated quetiapine's efficacy in the treatment of depressive phases of bipolar disorder, including statistically significant improvement in the Montgomery-Asberg Depression Rating Scale (MADRS). In the trials reviewed in this article, the change in MADRS scores ranged from -15.4 to -16.94 within the quetiapine groups, and from -10.26 to -11.93 in the placebo groups. There were also statistically significant improvements in the Hamilton Anxiety Rating Scale, the Short Form of the Quality of Life Enjoyment and Satisfaction Questionnaire, the Pittsburgh Sleep Quality Index, and the Sheehan Disability Scale. All of these trials had a duration of 8 weeks and therefore cannot be applied to the long-term use of quetiapine in bipolar depression. The most common adverse events were sedation, somnolence, and dry mouth. The overall dropout rates for the trials reviewed ranged from 24% to 47%. Based on the literature reviewed here, quetiapine appears to be a safe and efficacious short-term treatment option for bipolar depression. Patients with bipolar type I showed greater improvement on the MADRS than those with bipolar type II. Patients with a rapid-cycling disease course showed an improvement in depressive symptoms, regardless of bipolar type.

Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success?

PubMed

Chan, John K; Ueda, Stefanie M; Sugiyama, Valerie E; Stave, Christopher D; Shin, Jacob Y; Monk, Bradley J; Sikic, Branimir I; Osann, Kathryn; Kapp, Daniel S

2008-03-20

To identify the characteristics of phase II studies that predict for subsequent "positive" phase III trials (those that reached the proposed primary end points of study or those wherein the study drug was superior to the standard regimen investigating targeted agents in advanced tumors. We identified all phase III clinical trials of targeted therapies against advanced cancers published from 1985 to 2005. Characteristics of the preceding phase II studies were reviewed to identify predictive factors for success of the subsequent phase III trial. Data were analyzed using the chi(2) test and logistic regression models. Of 351 phase II studies, 167 (47.6%) subsequent phase III trials were positive and 184 (52.4%) negative. Phase II studies from multiple rather than single institutions were more likely to precede a successful trial (60.4% v 39.4%; P < .001). Positive phase II results were more likely to lead to a successful phase III trial (50.8% v 22.5%; P = .003). The percentage of successful trials from pharmaceutical companies was significantly higher compared with academic, cooperative groups, and research institutes (89.5% v 44.2%, 45.2%, and 46.3%, respectively; P = .002). On multivariate analysis, these factors and shorter time interval between publication of phase II results and III study publication were independent predictive factors for a positive phase III trial. In phase II studies of targeted agents, multiple- versus single-institution participation, positive phase II trial, pharmaceutical company-based trials, and shorter time period between publication of phase II to phase III trial were independent predictive factors of success in a phase III trial. Investigators should be cognizant of these factors in phase II studies before designing phase III trials.

Self-management toolkit and delivery strategy for end-of-life pain: the mixed-methods feasibility study.

PubMed

Bennett, Michael I; Mulvey, Matthew R; Campling, Natasha; Latter, Sue; Richardson, Alison; Bekker, Hilary; Blenkinsopp, Alison; Carder, Paul; Closs, Jose; Farrin, Amanda; Flemming, Kate; Gallagher, Jean; Meads, David; Morley, Stephen; O'Dwyer, John; Wright-Hughes, Alexandra; Hartley, Suzanne

2017-12-01

Pain affects most people approaching the end of life and can be severe for some. Opioid analgesia is effective, but evidence is needed about how best to support patients in managing these medicines. To develop a self-management support toolkit (SMST) and delivery strategy and to test the feasibility of evaluating this intervention in a future definitive trial. Phase I - evidence synthesis and qualitative interviews with patients and carers. Phase II - qualitative semistructured focus groups and interviews with patients, carers and specialist palliative care health professionals. Phase III - multicentre mixed-methods single-arm pre-post observational feasibility study. Phase I - six patients and carers. Phase II - 15 patients, four carers and 19 professionals. Phase III - 19 patients recruited to intervention that experienced pain, living at home and were treated with strong opioid analgesia. Process evaluation interviews with 13 patients, seven carers and 11 study nurses. Self-Management of Analgesia and Related Treatments at the end of life (SMART) intervention comprising a SMST and a four-step educational delivery approach by clinical nurse specialists in palliative care over 6 weeks. Recruitment rate, treatment fidelity, treatment acceptability, patient-reported outcomes (such as scores on the Brief Pain Inventory, Self-Efficacy for Managing Chronic Disease Scale, Edmonton Symptom Assessment Scale, EuroQol-5 Dimensions, Satisfaction with Information about Medicines Scale, and feasibility of collecting data on health-care resource use for economic evaluation). Phase I - key themes on supported self-management were identified from evidence synthesis and qualitative interviews. Phase II - the SMST was developed and refined. The delivery approach was nested within a nurse-patient consultation. Phase III - intervention was delivered to 17 (89%) patients, follow-up data at 6 weeks were available on 15 patients. Overall, the intervention was viewed as acceptable and valued. Descriptive analysis of patient-reported outcomes suggested that interference from pain and self-efficacy were likely to be candidates for primary outcomes in a future trial. No adverse events related to the intervention were reported. The health economic analysis suggested that SMART could be cost-effective. We identified key limitations and considerations for a future trial: improve recruitment through widening eligibility criteria, refine the SMST resources content, enhance fidelity of intervention delivery, secure research nurse support at recruiting sites, refine trial procedures (including withdrawal process and data collection frequency), and consider a cluster randomised design with nurse as cluster unit. (1) The recruitment rate was lower than anticipated. (2) The content of the intervention was focused on strong opioids only. (3) The fidelity of intervention delivery was limited by the need for ongoing training and support. (4) Recruitment sites where clinical research nurse support was not secured had lower recruitment rates. (5) The process for recording withdrawal was not sufficiently detailed. (6) The number of follow-up visits was considered burdensome for some participants. (7) The feasibility trial did not have a control arm or assess randomisation processes. A future randomised controlled trial is feasible and acceptable. This study is registered as PROSPERO CRD42014013572; Current Controlled Trials ISRCTN35327119; and National Institute for Health Research (NIHR) Portfolio registration 162114. The NIHR Health Technology Assessment programme.

Applying neurobiology to the treatment of adults with anorexia nervosa.

PubMed

Hill, Laura; Peck, Stephanie Knatz; Wierenga, Christina E; Kaye, Walter H

2016-01-01

Anorexia nervosa is a severe, biologically based brain disorder with significant medical complications. It is critical that new, effective treatments are developed to interrupt the persistent course of the illness due to the medical and psychological sequelae. Several psychosocial, behavioral and pharmacologic interventions have been investigated in adult anorexia nervosa; however, evidence shows that their impact is weak and treatment effects are generally small. This paper describes a new neurobiological anorexia nervosa model that shifts focus from solely external influences, such as social and family, to include internal influences that integrate genetic and neurobiological contributions, across the age span. The model serves as a theoretical structure for a new, five-day treatment, outlined in this paper, targeting anorexia nervosa temperament, which integrates neurobiological dimensions into evidence-based treatment interventions. The treatment is in two phases. Phase I is a five day, 40 hour treatment for anorexia nervosa adults. Phase II is the follow-up and is currently being developed. Preliminary qualitative acceptability data on 37 adults with anorexia nervosa and 60 supports (e.g., spouses, parents, aunts, friends, partners, children of anorexia nervosa adults) are promising from Phase I. Clients with anorexia nervosa and their supports report that learning neurobiological facts improved their understanding of the illness and helped equip them with better tools to manage anorexia nervosa traits and symptoms. In addition, nutritional knowledge changed significantly. This is the first neurobiologically based, five-day treatment for adults with anorexia nervosa and their supports. It is a new model that outlines underlying genetic and neurobiological contributions to anorexia nervosa that serves as a foundation to treat both traits and symptoms. Preliminary qualitative findings are promising, with both clients and supports reporting that the neurobiological treatment approach helped them better understand the illness, while better conceptualizing how to respond to their traits and manage their symptoms. Data in Phase I shows promise as a neurobiologically based intervention for anorexia nervosa, and it serves as a foundation for the development of Phase II. Evidence of ongoing program efficacy will be described as data are reported on Phase II. NCT NCT02852538 Registered 1 August 2016.

Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia.

PubMed

Konopleva, Marina; Pollyea, Daniel A; Potluri, Jalaja; Chyla, Brenda; Hogdal, Leah; Busman, Todd; McKeegan, Evelyn; Salem, Ahmed Hamed; Zhu, Ming; Ricker, Justin L; Blum, William; DiNardo, Courtney D; Kadia, Tapan; Dunbar, Martin; Kirby, Rachel; Falotico, Nancy; Leverson, Joel; Humerickhouse, Rod; Mabry, Mack; Stone, Richard; Kantarjian, Hagop; Letai, Anthony

2016-10-01

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106-17. ©2016 AACRSee related commentary by Pullarkat and Newman, p. 1082This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

A Multicenter Phase II Study of Local Radiation Therapy for Stage IEA Mucosa-Associated Lymphoid Tissue Lymphomas: A Preliminary Report From the Japan Radiation Oncology Group (JAROG)

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

Isobe, Koichi; Kagami, Yoshikazu; Higuchi, Keiko

2007-11-15

Purpose: The aim of this study was to evaluate the efficacy and toxicity of moderate dose radiation therapy (RT) for mucosa-associated lymphoid tissue (MALT) lymphoma in a prospective multicenter phase II trial. Methods and Materials: The subjects in this study were 37 patients with MALT lymphoma between April 2002 and November 2004. There were 16 male and 21 female patients, ranging in age from 24 to 82 years, with a median of 56 years. The primary tumor originated in the orbit in 24 patients, in the thyroid and salivary gland in 4 patients each, and 5 in the others. Themore » median tumor dose was 30.6 Gy (range, 30.6-39.6 Gy), depending on the primary site and maximal tumor diameter. The median follow-up was 37.3 months. Results: Complete remission (CR) or CR/unconfirmed was achieved in 34 patients (92%). The 3-year overall survival, progression-free survival, and local control probability were 100%, 91.9%, and 97.3%, respectively. Thirteen patients experienced Grade 1 acute toxicities including dermatitis, mucositis, and conjunctivitis. One patient developed Grade 2 taste loss. Regarding late toxicities, Grade 2 reactions including hypothyroidism, and radiation pneumonitis were observed in three patients, and Grade 3 cataract was seen in three patients. Conclusions: This prospective phase II study demonstrated that moderate dose RT was highly effective in achieving local control with acceptable morbidity in 37 patients with MALT lymphoma.« less

Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

PubMed

Christoph, Annette; Eerdekens, Marie-Henriette; Kok, Maurits; Volkers, Gisela; Freynhagen, Rainer

2017-09-01

Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 μg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy.

PubMed

Rapoport, Bernardo; Schwartzberg, Lee; Chasen, Martin; Powers, Dan; Arora, Sujata; Navari, Rudolph; Schnadig, Ian

2016-04-01

Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC. Patients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6-8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2-6. Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021). Over cycles 1-6, time-to-first emesis was significantly longer with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2-6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Histone deacetylase inhibitors: current status and overview of recent clinical trials.

PubMed

Ma, Xujun; Ezzeldin, Hany H; Diasio, Robert B

2009-10-01

Histone deacetylase (HDAC) inhibitors are a new group of anticancer agents that have a potential role in the regulation of gene expression, induction of cell death, apoptosis and cell cycle arrest of cancer cells by altering the acetylation status of chromatin and other non-histone proteins. In clinical trials, HDAC inhibitors have demonstrated promising antitumour activity as monotherapy in cutaneous T-cell lymphoma and other haematological malignancies. In solid tumours, several HDAC inhibitors have been shown to be efficacious as single agents; however, results of most clinical trials were in favour of using HDAC inhibitors either prior to the initiation of chemotherapy or in combination with other treatments. Currently, the molecular basis of response to HDAC inhibitors in patients is not fully understood. In this review, we summarize the current status of HDAC inhibitors, as single agents or in combination with other agents in different phases of clinical trials. In most of the clinical trials, HDAC inhibitors were tolerable and exerted biological or antitumor activity. HDAC inhibitors have been studied in phase I, II and III clinical trials with variable efficacy. The combination of HDAC inhibitors with other anticancer agents including epigenetic or chemotherapeutic agents demonstrated favourable clinical outcome.

Checkpoint inhibitors and radiation treatment in Hodgkin's lymphoma : New study concepts of the German Hodgkin Study Group.

PubMed

Baues, C; Semrau, R; Gaipl, U S; Bröckelmann, P J; Rosenbrock, J; Engert, A; Marnitz, S

2017-02-01

Patients with classical Hodgkin's lymphoma (cHL) have a good prognosis even in advanced stages. However, combined chemo- and radiotherapy, as the standard of care, is also associated with treatment-related toxicities such as organ damage, secondary neoplasias, infertility, or fatigue and long-term fatigue. Many patients suffer from this burden although their cHL was cured. Therefore, the efficacy of immune checkpoint inhibitors like anti-PD1/PD-L1 antibodies in the treatment of solid cancers and also in HL offers new options. A remarkable and durable response rate with a favorable toxicity profile was observed in heavily pretreated cHL patients. Planning to perform prospective randomized clinical trials in the content of radio-immune treatment in patients with Hodgkin's lymphoma (HL), we transferred the results of preliminary clinical studies and basic research in clinical relevant study concepts. Based on these promising early phase trial data, the German Hodgkin Study Group (GHSG) will investigate innovative treatment regimens in upcoming phase II trials. The therapeutic efficacy and potential synergies of anti-PD1 antibodies in combination with chemo- or radiotherapy will be investigated in various settings of HL.

State of the art and perspectives in the treatment of glioblastoma.

PubMed

Grimm, Sean A; Chamberlain, Marc C

2012-09-01

Glioblastoma is the most common malignant primary brain tumor. Cures are rare and median survival varies from several to 22 months. Standard treatment for good performance patients consists of maximal safe surgical resection followed by radiotherapy with concurrent temozolomide (TMZ) chemotherapy and six cycles of postradiotherapy TMZ. At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. Most patients with good performance status are treated with cytotoxic chemotherapy or targeted biologic therapy following or in lieu of repeat surgery. Cytotoxic chemotherapy options include nitrosoureas, rechallenge with TMZ, platins, phophoramides and topoisomerase inhibitors, although efficacy is limited. Despite the intense effort of developing biologic agents that target angiogenesis and growth and proliferative pathways, bevacizumab is the only agent that has shown efficacy in clinical trials. It was awarded accelerated approval in the USA after demonstrating an impressive radiographic response in two open-label, prospective Phase II studies. Two randomized, Phase III trials of upfront bevacizumab have completed and may demonstrate survival benefit; however, results are pending at this time. Given the limited treatment options at tumor recurrence, consideration for enrollment on a clinical trial is encouraged.

Investigational opioid antagonists for treating opioid-induced bowel dysfunction.

PubMed

Mozaffari, Shilan; Nikfar, Shekoufeh; Abdollahi, Mohammad

2018-03-01

Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC. Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued. Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients' quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.

Efficacy, pharmacokinetic and pharmacodynamic profile of ceftolozane + tazobactam in the treatment of complicated urinary tract infections.

PubMed

Wagenlehner, Florian M; Alidjanov, Jakhongir F

2016-08-01

Urinary tract infections (UTIs) are the second most common nosocomially acquired infections, responsible for approximately 21% of healthcare-associated pyelonephritis and 10.5% of urosepsis. Worldwide trends of increasing resistance resulted in the urgent need for novel antimicrobials that would be active against bacterial resistance mechanisms as an alternative to carbapenems, which are considered last resort antibiotics. The current review is based on a Medline search of published English language literature and contains summary information regarding the evaluation of pharmacologic properties, efficacy, safety and activity of ceftolozane+tazobactam against common bacterial resistance mechanisms. In vivo and vitro studies demonstrated high activity of ceftolozane+tazobactam in the combination of 2:1 against a variety of uropathogens, including ESBL-producers. Phase II and Phase III studies performed in patients with complicated UTIs showed good tolerability and safety of ceftolozane+tazobactam when prescribed intravenously 1.5 g every 8 h for 7 days and at least non-inferiority to a high dose (750 mg) of levofloxacin. The pharmacokinetics of ceftolozane+tazobactam makes it a worthy alternative to carbapenems in cases of complicated UTIs, also caused by multidrug resistant uropathogens.

Initial Efficacy Results of RTOG 0319: Three-Dimensional Conformal Radiation Therapy (3D-CRT) Confined to the Region of the Lumpectomy Cavity for Stage I/ II Breast Carcinoma

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

Vicini, Frank, E-mail: fvicini@beaumont.ed; Winter, Kathryn; Wong, John

2010-07-15

Purpose: This prospective study (Radiation Therapy Oncology Group 0319) examines the use of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Initial data on efficacy and toxicity are presented. Methods and Materials: Patients with Stage I or II breast cancer with lesions {<=}3 cm, negative margins and with {<=}3 positive nodes were eligible. The 3D-CRT was 38.5 Gy in 3.85 Gy/fraction delivered 2x/day. Ipsilateral breast, ipsilateral nodal, contralateral breast, and distant failure (IBF, INF, CBF, DF) were estimated using the cumulative incidence method. Mastectomy-free, disease-free, and overall survival (MFS, DFS, OS) were recorded. The Nationalmore » Cancer Institute Common Terminology Criteria for Adverse Events, version 3, was used to grade acute and late toxicity. Results: Fifty-eight patients were entered and 52 patients are eligible and evaluable for efficacy. The median age of patients was 61 years with the following characteristics: 46% tumor size <1 cm; 87% invasive ductal histology; 94% American Joint Committee on Cancer Stage I; 65% postmenopausal; 83% no chemotherapy; and 71% with no hormone therapy. Median follow-up is 4.5 years (1.7-4.8). Four-year estimates (95% CI) of efficacy are: IBF 6% (0-12%) [4% within field (0-9%)]; INF 2% (0-6%); CBF 0%; DF 8% (0-15%); MFS 90% (78-96%); DFS 84% (71-92%); and OS 96% (85-99%). Only two (4%) Grade 3 toxicities were observed. Conclusions: Initial efficacy and toxicity using 3D-CRT to deliver APBI appears comparable to other experiences with similar follow-up. However, additional patients, further follow-up, and mature Phase III data are needed to evaluate the extent of application, limitations, and value of this particular form of APBI.« less

A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer.

PubMed

Yamazaki, Kentaro; Kuwano, Hiroyuki; Ojima, Hitoshi; Otsuji, Toshio; Kato, Takeshi; Shimada, Ken; Hyodo, Ichinosuke; Nishina, Tomohiro; Shirao, Kuniaki; Esaki, Taito; Ohishi, Takashi; Denda, Tadamichi; Takeuchi, Masahiro; Boku, Narikazu

2015-03-01

Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6. Patients with mCRC and no prior chemotherapy were randomly assigned to receive either SOL or mFOLFOX6. SOL consisted of S-1 (40-60 mg bid) plus oral LV (25 mg bid) for 1 week and oxaliplatin (85 mg/m(2)) on day 1, repeated every 2 weeks. Among 107 patients enrolled from July 2008 through July 2009, 105 (56 in the SOL group and 49 in the mFOLFOX6 group) were eligible and evaluated. The median progression-free survival was 9.6 months in the SOL group and 6.9 months in the mFOLFOX6 group [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.49-1.40]. The median overall survival was 29.9 and 25.9 months, respectively (HR 0.91, 95 % CI 0.55-1.49). The response rate was 55 % in both groups. Grade 3 or 4 adverse drug reactions were neutropenia (20 % with SOL vs 41 % with mFOLFOX6), sensory neuropathy (20 vs 2.0 %), anorexia (13 vs 7.8 %), fatigue (11 vs 5.9 %), and diarrhea (11 vs 3.9 %). SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.

A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17.

PubMed

Yeh, Chun-Nan; Chen, Ming-Huang; Chen, Yen-Yang; Yang, Ching-Yao; Yen, Chueh-Chuan; Tzen, Chin-Yuan; Chen, Li-Tzong; Chen, Jen-Shi

2017-07-04

Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients with Non-Small-Cell Lung Cancer.

PubMed

Spigel, David R; Chaft, Jamie E; Gettinger, Scott; Chao, Bo H; Dirix, Luc; Schmid, Peter; Chow, Laura Q M; Hicks, Rodney J; Leon, Larry; Fredrickson, Jill; Kowanetz, Marcin; Sandler, Alan; Funke, Roel; Rizvi, Naiyer A

2018-05-15

The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced non-small-cell lung cancer (NSCLC) selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into Cohort 1 (chemotherapy-naïve/>6 months between adjuvant chemotherapy and recurrence), Cohort 2 (≥ second-line without brain metastases), or Cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab, Day 1 (21-day cycles). Primary endpoint: investigator-assessed modified Response Evaluation Criteria in Solid Tumors (mRECIST), objective response rate (ORR; RECIST v1.1). Secondary endpoints: overall survival, progression-free survival, duration of response, safety. Patients (n=138) were enrolled (137 evaluable for response: Cohort 1, n=31; Cohort 2, n=93; Cohort 3, n=13). Investigator-assessed ORR was 32%, 21%, and 23% for Cohorts 1, 2, and 3, respectively. Treatment-related adverse events (TRAEs) were reported in 81%, 67%, and 69% of patients, respectively, including grade 3-4 TRAEs in 16%, 19%, and 15%. Moreover, 88.6% (n=86/97) paired baseline tumor samples had <5% change in TC/IC PD-L1 expression over time. Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line; front-line trials are ongoing, confirming these favorable results. Copyright © 2018. Published by Elsevier Inc.

Efficacy of Progesterone for Acute Traumatic Brain Injury: a Meta-analysis of Randomized Controlled Trials.

PubMed

Wang, Zhen; Shi, LiGen; Ding, Wu; Shao, FangJie; Yu, Jun; Zhang, Jianmin

2016-12-01

Progesterone, a steroid hormone, has been shown to have multifactorial neuroprotective effects in a variety of animal models of acute traumatic brain injury (TBI). Translation to humans showed positive effects in previous phase II trials, but unfortunately, negative results were observed in two recent phase III trials. The present study focuses on the efficacy of progesterone on acute TBI based on the published data of randomized controlled trials (RCTs). MEDLINE, EMBASE, and Cochrane Library were used to search from January 1980 to August 2015 for English language studies. The primary outcome was a favorable outcome in the Glasgow outcome scale (GOS). The secondary outcomes included mortality and adverse events. A total of 2396 patients from 5 RCTs were included in the present study. There were no significant differences in favorable outcome (relative risk (RR) 1.07, 95 % confidence interval (CI) 0.91 to 1.27, P = 0.41) and mortality rate (RR 0.85, 95 % CI 0.65 to 1.13, P = 0.27) between progesterone and placebo groups. In a subgroup analysis, favorable outcome (RR 1.45, 95 % CI 1.11 to 1.89, P = 0.007) and decreased mortality rate (RR 0.58, 95 % CI 0.41 to 0.84, P = 0.004) are only observed in the phase II RCTs. The included factors were the severity of TBI, method of drug administration, and duration of observation and had no influence on the observed outcomes. Sensitivity analysis showed that all the outcomes were stable after excluding Shakeri (Clin Neurol Neurosurg 115: 2019-2022, 2013) or Wright (N Engl J Med 371: 2457-2466, 2014) trials. The quality of the evidence was varied from high to low. In conclusion, progesterone has no significant improvement in the functional recovery and mortality rate after acute TBI.

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

PubMed

Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

2016-08-01

Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins

PubMed Central

Lakraj, Amanda-Amrita D.; Moghimi, Narges; Jabbari, Bahman

2013-01-01

Clinical features, anatomy and physiology of hyperhidrosis are presented with a review of the world literature on treatment. Level of drug efficacy is defined according to the guidelines of the American Academy of Neurology. Topical agents (glycopyrrolate and methylsulfate) are evidence level B (probably effective). Oral agents (oxybutynin and methantheline bromide) are also level B. In a total of 831 patients, 1 class I and 2 class II blinded studies showed level B efficacy of OnabotulinumtoxinA (A/Ona), while 1 class I and 1 class II study also demonstrated level B efficacy of AbobotulinumtoxinA (A/Abo) in axillary hyperhidrosis (AH), collectively depicting Level A evidence (established) for botulinumtoxinA (BoNT-A). In a comparator study, A/Ona and A/Inco toxins demonstrated comparable efficacy in AH. For IncobotulinumtoxinA (A/Inco) no placebo controlled studies exist; thus, efficacy is Level C (possibly effective) based solely on the aforementioned class II comparator study. For RimabotulinumtoxinB (B/Rima), one class III study has suggested Level U efficacy (insufficient data). In palmar hyperhidrosis (PH), there are 3 class II studies for A/Ona and 2 for A/Abo (individually and collectively level B for BoNT-A) and no blinded study for A/Inco (level U). For B/Rima the level of evidence is C (possibly effective) based on 1 class II study. Botulinum toxins (BoNT) provide a long lasting effect of 3–9 months after one injection session. Studies on BoNT-A iontophoresis are emerging (2 class II studies; level B); however, data on duration and frequency of application is inconsistent. PMID:23612753

Chemomodulatory effect of Moringa oleifera, Lam, on hepatic carcinogen metabolising enzymes, antioxidant parameters and skin papillomagenesis in mice.

PubMed

Bharali, Rupjyoti; Tabassum, Jawahira; Azad, Mohammed Rekibul Haque

2003-01-01

The modulatory effects of a hydro-alcoholic extract of drumsticks of Moringa oliefera Lam at doses of 125 mg/kg bodyweight and 250 mg/ kg body weight for 7 and 14 days, respectively, were investigated with reference to drug metabolising Phase I (Cytochrome b(5) and Cytochrome p(450) ) and Phase II (Glutathione-S- transferase) enzymes, anti-oxidant enzymes, glutathione content and lipid peroxidation in the liver of 6-8 week old female Swiss albino mice. Further, the chemopreventive efficacy of the extract was evaluated in a two stage model of 7,12 - dimethylbenz(a)anthracene induced skin papillomagenesis. Significant increase (p<0.05 to p<0.01) in the activities of hepatic cytochrome b(5), cytochrome p(450), catalase, glutathione peroxidase ( GPx ), glutathione reductase (GR), acid soluble sulfhydryl content (-SH ) and a significant decrease ( p<0.01 ) in the hepatic MDA level were observed at both dose levels of treatment when compared with the control values. Glutathione-S- transferase ( GST )activity was found to be significantly increased (p<0.01 ) only at the higher dose level. Butylated hydroxyanisol (BHA ) fed at a dose of 0.75% in the diet for 7 and 14 days (positive control ) caused a significant increase (p<0.05 to p<0.01) in the levels of hepatic phase I and phase II enzymes, anti- oxidant enzymes, glutathione content and a decrease in lipid peroxidation. The skin papillomagenesis studies demonstrated a significant decrease (p<0.05 ) in the percentage of mice with papillomas, average number of papillomas per mouse and papillomas per papilloma bearing mouse when the animals received a topical application of the extract at a dose of 5mg/ kg body weight in the peri-initiation phase 7 days before and 7 days after DMBA application, Group II ), promotional phase (from the day of croton oil application and continued till the end of the experiment, Group III ) and both peri and post initiation stages (from 7 days prior to DMBA application and continued till the end of the experiment, Group IV) compared to the control group (Group I ). The percentage inhibition of tumor multiplicity has been recorded to be 27, 72, and 81 in Groups II, III, and IV, respectively. These findings are suggestive of a possible chemopreventive potential of Moringa oliefera drumstick extract against chemical carcinogenesis.

Therapy for Clostridium difficile infection - any news beyond Metronidazole and Vancomycin?

PubMed

Manthey, C F; Eckmann, L; Fuhrmann, V

2017-11-01

Infections with Clostridium difficile (CDI) represent a major burden for the health care system. Treatment is generally by antibiotic therapy with metronidazole and vancomycin, but efficacy remains suboptimal. Areas covered: This review discusses established and emerging treatment options for CDI, and current therapeutic guidelines, taking into account disease severity and risk of relapse. Expert commentary: New therapeutic approaches, including antibodies and new classes of antibiotics, and new measures for preventing infection with vaccines are under development in phase II/III clinical trials. We performed a systematic literature review using the search terms 'Clostridium difficile' and 'treatment'.

Preparation of thermo-responsive membranes. II.

PubMed

Nozawa, I; Suzuki, Y; Sato, S; Sugibayashi, K; Morimoto, Y

1991-05-01

Two types of liquid crystal (LC)-immobilized membranes were prepared by a soaking method and sandwich method to control the permeation of indomethacin, as a model drug, in response to local and systemic fever. Monooxyethylene trimethylolpropane tristearate (MTTS) was used as a model LC because it has a gel-liquid crystal phase transition temperature near the body temperature, 39-40 degrees C in phosphate buffered saline (pH 7.4). Two porous polypropylene (PP) membranes were soaked into 20% MTTS chloroform solution in the soaking method, and two PP membranes were poured with the melted MTTS and pressed in the sandwich method. Thermo-response efficacy of the soaked membrane was dependent upon the content of MTTS in MTTS membrane, and the MTTS content above the void volume of PP membrane (38%) was needed for high efficacy. On the other hand, the sandwich membrane exhibited higher thermo-response efficacy than the soaked membrane, because more LC was embedded in the pores of sandwich membrane than that of the soaked membrane. The sandwich membrane permeation of indomethacin was sharply controlled by temperature changes between 32 and 38 degrees C.

A phase II study with antioxidants, both in the diet and supplemented, pharmaconutritional support, progestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/cachexia and oxidative stress.

PubMed

Mantovani, Giovanni; Macciò, Antonio; Madeddu, Clelia; Gramignano, Giulia; Lusso, Maria Rita; Serpe, Roberto; Massa, Elena; Astara, Giorgio; Deiana, Laura

2006-05-01

To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants, and drugs, all given orally, in a population of advanced cancer patients with cancer-related anorexia/cachexia and oxidative stress. An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d alpha-lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with 2 cans per day (n-3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: (a) clinical (Eastern Cooperative Oncology Group performance status); (b) nutritional [lean body mass (LBM), appetite, and resting energy expenditure]; (c) laboratory [proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes]; (d) quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF). From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D(VAS), and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were "responders" or "high responders." The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe. The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study is warranted.

Treatment of Non-neovascular Idiopathic Macular Telangiectasia Type 2 with Intravitreal Ranibizumab: Results of a Phase II Clinical Trial

PubMed Central

Toy, Brian C.; Koo, Euna; Cukras, Catherine; Meyerle, Catherine B.; Chew, Emily Y.; Wong, Wai T.

2015-01-01

Purpose To evaluate the safety and preliminary efficacy of intravitreal ranibizumab for non-neovascular idiopathic macular telangiectasia, type 2 (IMT2). Methods Single-center, open-label phase II clinical trial enrolling 5 participants with bilateral non-neovascular IMT2. Intravitreal ranibizumab (0.5mg) was administered every 4 weeks in the study eye for 12 months with the contralateral eye observed. Outcome measures included changes in: best corrected visual acuity (BCVA), area of late-phase leakage on fluorescein angiography (FA), and retinal thickness on optical coherence tomography (OCT). Results The study treatment was well-tolerated and associated with few adverse events. Change in BCVA at 12 months was not significantly different between treated study eyes (0.0±7.5 letters) and control fellow eyes (+2.2±1.9 letters). However, decreases in the area of late-phase FA leakage (−33±20% for study eyes, +1±8% for fellow eyes) and in OCT central subfield retinal thickness (−11.7±7.0% for study eyes and −2.9±3.5% for fellow eyes) were greater in study eyes compared to fellow eyes. Conclusions Despite significant anatomical responses to treatment, functional improvement in visual acuity was not detected. Intravitreal ranibizumab administered monthly over a time course of 12 months is unlikely to provide a general and significant benefit to patients with non-neovascular IMT2. PMID:22266930

Dose escalation methods in phase I cancer clinical trials.

PubMed

Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

2009-05-20

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study.

PubMed

Klintmalm, G B; Feng, S; Lake, J R; Vargas, H E; Wekerle, T; Agnes, S; Brown, K A; Nashan, B; Rostaing, L; Meadows-Shropshire, S; Agarwal, M; Harler, M B; Garcia-Valdecasas, J-C

2014-08-01

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

PubMed Central

Eron, Joseph J.; Clotet, Bonaventura; Durant, Jacques; Katlama, Christine; Kumar, Princy; Lazzarin, Adriano; Poizot-Martin, Isabelle; Richmond, Gary; Soriano, Vincent; Ait-Khaled, Mounir; Fujiwara, Tamio; Huang, Jenny; Min, Sherene; Vavro, Cindy; Yeo, Jane; Walmsley, Sharon L.; Cox, Joseph; Reynes, Jacques; Morlat, Philippe; Vittecoq, Daniel; Livrozet, Jean-Michel; Fernández, Pompeyo Viciana; Gatell, Jose M.; DeJesus, Edwin; DeVente, Jerome; Lalezari, Jacob P.; McCurdy, Lewis H.; Sloan, Louis A.; Young, Benjamin; LaMarca, Anthony; Hawkins, Trevor

2013-01-01

Background. Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1–infected subjects with genotypic evidence of RAL resistance. Methods. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log10 copies/mL from baseline or was <400 copies/mL. Results. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Conclusion. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL. PMID:23225901

Libertas: rationale and study design of a multicentre, Phase II, double-blind, randomised, placebo-controlled investigation to evaluate the efficacy, safety and tolerability of locally applied NRL001 in patients with faecal incontinence.

PubMed

Siproudhis, L; Jones, D; Shing, R Ng Kwet; Walker, D; Scholefield, J H

2014-03-01

Faecal incontinence affects up to 8% of adults. Associated social isolation and subsequent depression can have devastating effects on quality of life (QoL). Faecal incontinence is an underreported health problem as the social isolation and stigma that patients experience makes it difficult for sufferers to discuss their condition with a physician. There have been few well-designed, placebo-controlled clinical trials of treatment for faecal incontinence and little clinical evidence is available to inform the most appropriate management strategies. Libertas, a robustly designed study will investigate the efficacy and safety of NRL001 (1R,2S-methoxamine), an α1 -adrenoceptor agonist, in the treatment of faecal incontinence. Libertas is a multicentre, Phase II, double-blind, randomised, placebo-controlled, parallel group study. Patient recruitment took place across 55 study centres in Europe. Patients suffering with faecal incontinence were randomised into four groups (approximately 110 each) to receive once daily self-administered doses of NRL001 (5, 7.5 or 10 mg or placebo in a suppository formulation) for 8 weeks. The primary objective of Libertas is to assess the impact of once daily administration of NRL001 on the severity and frequency of incontinence episodes as assessed by the Wexner score at 4 weeks, compared with placebo. Secondary outcomes include measures of efficacy of NRL001 compared with placebo following 8 weeks treatment; safety and tolerability; evaluation of plasma pharmacokinetics; establishment of any pharmacokinetic/pharmacodynamic relationship to adverse events; dose-response relationship; the efficacy of NRL001 therapy at 4 and 8 weeks assessed by the Vaizey score; and QoL using the Faecal Incontinence Quality of Life and the EQ-5D-5L Healthcare Questionnaires following 4 and 8 weeks NRL001 therapy. Overall patient satisfaction with the treatment will also be evaluated. This is the first randomised controlled study to investigate the efficacy and safety of a selective α1 -adrenoceptor agonist for the treatment of faecal incontinence. Furthermore, this is the first time the impact of NRL001 on assessments of QoL, health outcomes and patient satisfaction will be assessed. Innovative strategies were developed to meet the challenge of recruiting patients for this study, for example, media advertising, posters and mailshots as allowed by each study centre. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.

PubMed

Tedesco-Silva, Helio; Pescovitz, Mark D; Cibrik, Diane; Rees, Michael A; Mulgaonkar, Shamkant; Kahan, Barry D; Gugliuzza, Kristene K; Rajagopalan, P R; Esmeraldo, Ronaldo de M; Lord, Hélène; Salvadori, Maurizio; Slade, Jennifer M

2006-12-27

Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.

A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease

PubMed Central

Sperling, R.; Keren, R.; Porsteinsson, A.P.; van Dyck, C.H.; Tariot, P.N.; Gilman, S.; Arnold, D.; Abushakra, S.; Hernandez, C.; Crans, G.; Liang, E.; Quinn, G.; Bairu, M.; Pastrak, A.; Cedarbaum, J.M.

2011-01-01

Objective: This randomized, double-blind, placebo-controlled, dose-ranging phase 2 study explored safety, efficacy, and biomarker effects of ELND005 (an oral amyloid anti-aggregation agent) in mild to moderate Alzheimer disease (AD). Methods: A total of 353 patients were randomized to ELND005 (250, 1,000, or 2,000 mg) or placebo twice daily for 78 weeks. Coprimary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale. The primary analysis compared 250 mg (n =84) to placebo (n =82) after an imbalance of infections and deaths led to early discontinuation of the 2 higher dose groups. Results: The 250 mg dose demonstrated acceptable safety. The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL. Brain ventricular volume showed a small but significant increase in the overall 250 mg group (p =0.049). At the 250 mg dose, scyllo-inositol concentrations increased in CSF and brain and CSF Aβx-42 was decreased significantly compared to placebo (p =0.009). Conclusions: Primary clinical efficacy outcomes were not significant. The safety and CSF biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD. Classification of evidence: Due to the small sample sizes, this Class II trial provides insufficient evidence to support or refute a benefit of ELND005. PMID:21917766

The 2007 Feinberg lecture: a new road map for neuroprotection.

PubMed

Donnan, Geoffrey A

2008-01-01

There have now been numerous phase III trials of neuroprotection that have failed to live up to the expectations created by preclinical testing in animal models, the most recent of which was the second pivotal trial of the spin trap agent NXY-059. We have reached a stage at which research in this area should stop altogether or radical new approaches adopted. The purpose of this article is to review how we reached this stage and make recommendations for a new approach to neuroprotection research. The background to neuroprotection research is reviewed and its problems are highlighted based on the research of others and of our own research group. From this, a series of questions are posed that require answers if the field is to progress. A road map for future research is then proposed. The road map involves the following steps for putative neuroprotectants: (1) better proof of efficacy in animal models; (2) in vivo evidence of efficacy in human tissue using cell cultures or brain slices; (3) in vivo studies of their distribution in the normal and ischemic human brain, particularly focusing on the ischemic penumbra; (4) demonstration of efficacy in novel human models of cerebral ischemia; and (5) phase II and III clinical trails with penumbral selection using imaging techniques. The accumulated evidence suggests that neuroprotection failure in clinical trial is due to identifiable preclinical and clinical factors. Neuroprotection research should be pursued but with a very different and more rigorous approach.

A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).

PubMed

Radwan, Noura; Phillips, Ryan; Ross, Ashley; Rowe, Steven P; Gorin, Michael A; Antonarakis, Emmanuel S; Deville, Curtiland; Greco, Stephen; Denmeade, Samuel; Paller, Channing; Song, Daniel Y; Diehn, Maximilian; Wang, Hao; Carducci, Michael; Pienta, Kenneth J; Pomper, Martin G; DeWeese, Theodore L; Dicker, Adam; Eisenberger, Mario; Tran, Phuoc T

2017-06-29

We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18 F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease. Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory. The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state. ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

PubMed Central

Schuster, Cornelia; Eikesdal, Hans P.; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E.; Akslen, Lars A.; Straume, Oddbjørn

2012-01-01

Background VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. Trial Registration ClinicalTrials.gov NCT00139360. PMID:22719881

EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial.

PubMed

Rice, Andrew S C; Dworkin, Robert H; McCarthy, Tom D; Anand, Praveen; Bountra, Chas; McCloud, Philip I; Hill, Julie; Cutter, Gary; Kitson, Geoff; Desem, Nuket; Raff, Milton

2014-05-10

Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. Spinifex Pharmaceuticals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Apatinib for the treatment of gastric cancer.

PubMed

Geng, Ruixuan; Li, Jin

2015-01-01

Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients. The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo. Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.

A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma.

PubMed

Wang, T-F; Fiala, M A; Cashen, A F; Uy, G L; Abboud, C N; Fletcher, T; Wu, N; Westervelt, P; DiPersio, J F; Stockerl-Goldstein, K E; Vij, R

2014-11-01

High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.

A Phase II/III Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Ginger (Zingiber officinale) for Nausea Caused by Chemotherapy for Cancer: A Currently Accruing URCC CCOP Cancer Control Study.

PubMed

Hickok, Jane T; Roscoe, Joseph A; Morrow, Gary R; Ryan, Julie L

2007-09-01

Despite the widespread use of 5-HT3 receptor antagonist antiemetics such as ondansetron and granistron, up to 70% of patients with cancer receiving highly emetogenic chemotherapy agents experience postchemotherapy nausea and vomiting. Delayed postchemotherapy nausea (nausea that occurs >/= 24 hours after chemotherapy administration) and anticipatory nausea (nausea that develops before chemotherapy administration, in anticipation of it) are poorly controlled by currently available antiemetic agents. Scientific studies suggest that ginger (Zingiber officinale) might have beneficial effects on nausea and vomiting associated with motion sickness, surgery, and pregnancy. In 2 small studies of patients with cancer receiving chemotherapy, addition of ginger to standard antiemetic medication further reduced the severity of postchemotherapy nausea. This article describes a phase II/III randomized, dose-finding, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for nausea associated with chemotherapy for cancer. The study is currently being conducted by private practice oncology groups that are funded by the National Cancer Institute's Community Clinical Oncology Program and affiliated with the University of Rochester Cancer Center Community Clinical Oncology Program Research Base.

Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma.

PubMed

Geiger, Jessica L; Bauman, Julie E; Gibson, Michael K; Gooding, William E; Varadarajan, Prakash; Kotsakis, Athanasios; Martin, Daniel; Gutkind, Jorge Silvio; Hedberg, Matthew L; Grandis, Jennifer R; Argiris, Athanassios

2016-12-01

Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016. © 2016 Wiley Periodicals, Inc.

Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032

PubMed Central

Robinson, Giles W.; Orr, Brent A.; Wu, Gang; Gururangan, Sridharan; Lin, Tong; Qaddoumi, Ibrahim; Packer, Roger J.; Goldman, Stewart; Prados, Michael D.; Desjardins, Annick; Chintagumpala, Murali; Takebe, Naoko; Kaste, Sue C.; Rusch, Michael; Allen, Sariah J.; Onar-Thomas, Arzu; Stewart, Clinton F.; Fouladi, Maryam; Boyett, James M.; Gilbertson, Richard J.; Curran, Tom; Ellison, David W.; Gajjar, Amar

2015-01-01

Purpose Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Patients and Methods Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. Results A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH–MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. Conclusion Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH–MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit. PMID:26169613

A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.

PubMed

Hersh, Evan M; O'Day, Steven J; Powderly, John; Khan, Khuda D; Pavlick, Anna C; Cranmer, Lee D; Samlowski, Wolfram E; Nichol, Geoffrey M; Yellin, Michael J; Weber, Jeffrey S

2011-06-01

Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

PubMed

Ferrucci, Pier F; Minchella, Ida; Mosconi, Massimo; Gandini, Sara; Verrecchia, Francesco; Cocorocchio, Emilia; Passoni, Claudia; Pari, Chiara; Testori, Alessandro; Coco, Paola; Munzone, Elisabetta

2015-06-01

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

PubMed

Davis, Ian D; Kiers, Lynette; MacGregor, Lachlan; Quinn, Michael; Arezzo, Joseph; Green, Michael; Rosenthal, Mark; Chia, Michael; Michael, Michael; Bartley, Peter; Harrison, Leonie; Daly, Michael

2005-03-01

To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

PubMed

Reid, Marvin E; El Beshlawy, Amal; Inati, Adlette; Kutlar, Abdullah; Abboud, Miguel R; Haynes, Johnson; Ward, Richard; Sharon, Bruce; Taher, Ali T; Smith, Wally; Manwani, Deepa; Ghalie, Richard G

2014-07-01

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β(0) thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: -0.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. © 2014 Wiley Periodicals, Inc.

Safety and Efficacy of High-Dose Tamoxifen and Sulindac for Desmoid Tumor in Children: Results of a Children’s Oncology Group (COG) Phase II Study

PubMed Central

Skapek, Stephen X.; Anderson, James R.; Hill, D. Ashley; Henry, David; Spunt, Sheri L.; Meyer, William; Kao, Simon; Hoffer, Fredric A.; Grier, Holcombe E.; Hawkins, Douglas S.; Raney, R. Beverly

2015-01-01

Background Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children’s Oncology Group. Procedures Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Results Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10–18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23–0.48) and 96%, respectively. All three deaths were due to progressive DT. Conclusions Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. PMID:23281268

Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study.

PubMed

Skapek, Stephen X; Anderson, James R; Hill, D Ashley; Henry, David; Spunt, Sheri L; Meyer, William; Kao, Simon; Hoffer, Fredric A; Grier, Holcombe E; Hawkins, Douglas S; Raney, R Beverly

2013-07-01

Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. Copyright © 2012 Wiley Periodicals, Inc.

Phase II study of cisplatin/pemetrexed combined with bevacizumab followed by pemetrexed/bevacizumab maintenance therapy in patients with EGFR-wild advanced non-squamous non-small cell lung cancer.

PubMed

Fukushima, Toshirou; Wakatsuki, Yuuki; Kobayashi, Takashi; Sonehara, Kei; Tateishi, Kazunari; Yamamoto, Manabu; Masubuchi, Takeshi; Yoshiike, Fumiaki; Hirai, Kazuya; Hachiya, Tsutomu; Koizumi, Tomonobu

2018-06-01

This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type. Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged < 75 years old were enrolled in the study. The patients were treated with four cycles of cisplatin (75 mg/m 2 , day 1), pemetrexed (500 mg/m 2 , days 1), and bevacizumab (15 mg/kg, day 1), every 3 weeks, followed by pemetrexed plus bevacizumab maintenance until progression for achieving a response over stable disease after induction chemotherapy. Partial response and stable disease were observed in 35 (objective response rate: 70, 95% CI: 55.4-82.1%) and 9 patients, respectively, and 39 (78%) patients received pemetrexed plus bevacizumab maintenance therapy. Median progression-free survival and overall survival periods were 12.0 months (95% CI: 7.5-16.5 months) and 31.0 months (95% CI: 22.2-39.8 months), respectively. Grade 3 adverse events included neutropenia (14%), nausea (10%), anorexia (18%), and hypertension (8%). Coagulation disorder was observed in one patient, but all of these events were reversible and resulted in no treatment-related deaths. The combination of cisplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance therapy exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild type non-squamous NSCLC (UMIN-CTR number: UMIN000003645).

Clinically Effective Treatment of Fibromyalgia Pain With High-Definition Transcranial Direct Current Stimulation: Phase II Open-Label Dose Optimization.

PubMed

Castillo-Saavedra, Laura; Gebodh, Nigel; Bikson, Marom; Diaz-Cruz, Camilo; Brandao, Rivail; Coutinho, Livia; Truong, Dennis; Datta, Abhishek; Shani-Hershkovich, Revital; Weiss, Michal; Laufer, Ilan; Reches, Amit; Peremen, Ziv; Geva, Amir; Parra, Lucas C; Fregni, Felipe

2016-01-01

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction (P = .035) as well as improved quality of life (P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported. Registered in Clinicaltrials.gov under registry number NCT01842009. In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer.

PubMed

Fan, Yun; Huang, Zhiyu; Fang, Luo; Miao, Lulu; Gong, Lei; Yu, Haifeng; Yang, Haiyan; Lei, Tao; Mao, Weimin

2015-09-01

Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated. Eligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125 mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0 Gy per day, 5 days per week, to 30 Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Twenty patients were enrolled. The median follow-up time was 20.0 months. The overall response rate was 80.0%. The median progression-free survival time was 7.0 months (95% CI 1.2-13.2 months), and the median survival time (MST) was 14.6 months (95% CI 12.5-16.7 months). Of the 18 patients with known EGFR status, the MST was 22.0 months for those with an EGFR mutation and was 7.5 months for those with wild-type EGFR (P = 0.0001). The CSF concentration and penetration rate of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1%, respectively. No patient experienced ≥grade 4 toxicity. Icotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations.

A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma.

PubMed

McCuaig, Catherine C; Dubois, Josée; Powell, Julie; Belleville, Claude; David, Michèle; Rousseau, Elisabeth; Gendron, Roxanne; Jafarian, Fatemeh; Auger, Isabelle

2009-01-01

To explore the efficacy and safety of imiquimod 5% cream as a treatment for infantile hemangioma. Phase II, open-label, noncomparative study of imiquimod applied during 16 weeks, with posttherapy follow-up 16 weeks later (8 months total). Outpatient pediatric tertiary care referral center in Quebec, Canada. Healthy infants up to 8.8 months of age with previously untreated, nonulcerated, proliferative superficial or mixed infantile hemangioma, excluding periorbital, or perineal localization, > or =100 cm2 in size. Topical imiquimod applied three to seven times per week for 16 weeks to infantile hemangioma. Lesion area, volume, depth (Doppler ultrasound), and color (erythema), serum drug, and interferon-alpha levels. Sixteen infants (11 girls, 5 boys) with a mean age at entry of 4.1 months and mean lesion area of 32.89 cm2, and volume of 39.98 cm3 were enrolled. Two participants discontinued treatment early, one for an adverse event (crying upon application), the other because of the lack of compliance. Local skin reactions were consistent with those reported in adults. Two cases had a decrease and three had an increase in lesion parameters; otherwise no meaningful changes in lesion area, volume, or depth were observed. At the 4-month posttreatment visit, 11 of 14 subjects had improvement in erythema (marginal homogeneity test = 2.668, p = 0.008). Measured serum drug and interferon-alpha levels were low or undetectable. Treatment of infants with infantile hemangioma with imiquimod up to seven times per week for 16 weeks was generally well tolerated with low systemic exposure. Improvement was observed in hemangioma coloration, but not lesion size, suggesting effects were limited to the superficial component.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

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

Knox, S J.; Goris, M L.; Tempero, M

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m{sup 2} (mean administered dose, 106.5-10.3 mCi/m{sup 2}) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients receivedmore » biotin-DOTA-labeled with 110 mCi/m{sup 2} Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.« less

Phase II Study of Short-Course Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma

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

Minniti, Giuseppe, E-mail: Giuseppe.Minniti@ospedalesantandrea.it; Department of Neurological Sciences, Neuromed Institute, Pozzilli; Lanzetta, Gaetano

Purpose: Radiotherapy (RT) and chemotherapy may prolong survival in older patients (age {>=}70 years) with glioblastoma multiforme (GBM), although the survival benefits remain poor. This Phase II multicenter study was designed to evaluate the efficacy and safety of an abbreviated course of RT plus concomitant and adjuvant temozolomide (TMZ) in older patients with GBM. Patients and Methods: Seventy-one eligible patients 70 years of age or older with newly diagnosed GBM and a Karnofsky performance status {>=}60 were treated with a short course of RT (40 Gy in 15 fractions over 3 weeks) plus TMZ at the dosage of 75 mg/m{supmore » 2} per day followed by 12 cycles of adjuvant TMZ (150-200 mg/m{sup 2} for 5 days during each 28-day cycle). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival and toxicity. Results: The Median OS was 12.4 months, and the 1-year and 2-year OS rates were 58% and 20%, respectively. The median and 1-year rates of progression-free survival were 6 months and 20%, respectively. All patients completed the planned programme of RT. Grade 3 or 4 adverse events occurred in 16 patients (22%). Grade 3 and 4 neutropenia and/or thrombocytopenia occurred in 10 patients (15%), leading to the interruption of treatment in 6 patients (8%). Nonhematologic Grade 3 toxicity was rare, and included fatigue in 4 patients and cognitive disability in 1 patient. Conclusions: A combination of an abbreviated course of RT plus concomitant and adjuvant TMZ is well tolerated and may prolong survival in elderly patients with GBM. Future randomized studies need to evaluate the efficacy and toxicity of different schedules of RT in association with chemotherapy.« less

Gene signatures and expression of miRNAs associated with efficacy of panitumumab in a head and neck cancer phase II trial.

PubMed

Siano, Marco; Espeli, Vittoria; Mach, Nicolas; Bossi, Paolo; Licitra, Lisa; Ghielmini, Michele; Frattini, Milo; Canevari, Silvana; De Cecco, Loris

2018-07-01

Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. Cluster3 expression levels had a profile with a significant bimodal separation of samples (P =  3.08 E-13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting. Copyright © 2018 Elsevier Ltd. All rights reserved.

A mechanistic dissection of polyethylenimine mediated transfection of CHO cells: to enhance the efficiency of recombinant DNA utilization.

PubMed

Mozley, Olivia L; Thompson, Ben C; Fernandez-Martell, Alejandro; James, David C

2014-01-01

In this study, we examine the molecular and cellular interactions that underpin efficient internalization and utilization of polyethylenimine (PEI):DNA complexes (polyplexes) by Chinese Hamster Ovary (CHO) cells. Cell surface polyplex binding and internalization was a biphasic process, consisting of an initial rapid Phase (I), lasting approximately 15 min, followed by a slower second Phase (II), saturating at approximately 240 min post transfection. The second Phase accounted for the majority (60-70%) of polyplex internalization. While cell surface heparan sulphate proteoglycans (HSPGs) were rapidly cointernalized with polyplexes during Phase I, cell surface polyplex binding was not dependent on HSPGs. However, Phase II polyplex internalization and HSPG regeneration onto the surface of trypsinized cells occurred at similar rates, suggesting that the rate of recycling of HSPG-containing membrane to the plasma membrane limits Phase II internalization rate. Under optimal transfection conditions, polyplexes had a near neutral surface charge (zeta potential) and cell surface binding was dependent on hydrophobic interactions, being significantly inhibited by both chemical sequestration of cholesterol from the plasma membrane and addition of nonionic surfactant. Induced alterations in polyplex zeta potential, using ferric (III) citrate to decrease surface charge and varying PEI:DNA ratio to increase surface charge, served to inhibit polyplex binding or reduce secreted alkaline phosphatase reporter expression and cell viability, respectively. To increase polyplex hydrophobicity and internalization an alkylated derivative of PEI, propyl-PEI, was chemically synthesized. Using Design of Experiments-Response Surface Modeling to optimize the transfection process, the function of propyl-PEI was compared to that of unmodified PEI in both parental CHO-S cells and a subclone (Clone 4), which exhibited superior transgene expression via an increased resistance to polyplex cytotoxicity. The combination of propyl-PEI and Clone 4 doubled the efficiency of recombinant DNA utilization and reporter protein production. These data show that for maximal efficacy, strategies to increase polyplex internalization into cells must be used in concert with strategies to offset the inherent cytotoxicity of this process. © 2014 American Institute of Chemical Engineers.

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma.

PubMed

Hashmi, Mehmood H; Van Veldhuizen, Peter J

2010-05-01

In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies. This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website. Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21. rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing’s sarcoma

PubMed Central

Dutton, P; Love, SB; Billingham, L; Hassan, AB

2016-01-01

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency. PMID:27587590

Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?

PubMed

Kuhne, Sebastiaan; Wijtmans, Maikel; Lim, Herman D; Leurs, Rob; de Esch, Iwan J P

2011-12-01

The histamine H(3) receptor (H(3)R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H(3)R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H(3)R antagonists/inverse agonists have been extensively evaluated in the clinic. Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H(3)R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data. In all, it becomes evident that clinical evaluation of H(3)R antagonists/inverse agonists is characterized by mixed results. On one hand, Pitolisant has successfully passed several Phase II trials and seems to be the most advanced compound in the clinic now, being in Phase III. On the other hand, some compounds (e.g., PF-03654647 and MK-0249) failed at Phase II clinical level for several indications. A challenging feature in H(3)R research is the multifaceted role of the receptor at a molecular/biochemical level, which can complicate targeting by small molecules at several (pre)clinical levels. Accordingly, H(3)R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market.

Present and future treatment of advanced non-small cell lung cancer.

PubMed

Crinò, Lucio; Cappuzzo, Federico

2002-06-01

Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival. Large phase III trials comparing these second-generation cisplatin regimens indicated a substantial equivalence of new combinations, marginally improving the outcome of patients over the first-generation platinum-based regimens. Phase III trials have not yet shown dramatic advantages for either multiple-drug regimens, with nonoverlapping mechanisms of action and toxicity, or nonplatinum doublets, with efficacy and/or toxicity profiles superior to those of platinum-based chemotherapy. Chemotherapy in advanced non-small cell lung cancer has reached a plateau, and it is clear that new approaches are required. These should include prevention, screening, and early detection, and the use of novel treatments based on our understanding of the biology and molecular biology of this disease. Copyright 2002, Elsevier Science (USA). All rights reserved.

Palbociclib: A new hope in the treatment of breast cancer.

PubMed

Palanisamy, R Priyadharsini

2016-01-01

Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer. The preclinical studies with breast cancer lines were sensitive to palbociclib and the clinical trials phase I, phase II (PALOMA 1), and phase III (PALOMA 2, 3, PENTELOPE, PEARL) showed that the drug was efficacious when combined other conventional drugs for breast cancer. Palbociclib was also been tested in various other germ cell tumors, melanoma, multiple myeloma, glioblastoma multiforme etc., The major adverse effect of the drug includes hematological toxicity mainly neutropenia, gastrointestinal adverse effects.

Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

PubMed

Shak, S

1999-08-01

The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.

Using phase II data for the analysis of phase III studies: An application in rare diseases.

PubMed

Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim

2017-06-01

Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies.

PubMed

Harrison, Taylor; Miyahara, Sachiko; Lee, Anthony; Evans, Scott; Bastow, Barbara; Simpson, David; Gilron, Ian; Dworkin, Robert; Daar, Eric S; Wieclaw, Linda; Clifford, David B

2013-07-01

There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared with placebo. This study was a phase II, randomized, double-blind, placebo-controlled, four-period crossover multicenter study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. A total of 15 patients were enrolled from eight study sites and eight patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared with placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study dropout. Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed. Wiley Periodicals, Inc.

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies

PubMed Central

Harrison, Taylor; Miyahara, Sachiko; Lee, Anthony; Evans, Scott; Bastow, Barbara; Simpson, David; Gilron, Ian; Dworkin, Robert; Daar, Eric S.; Wieclaw, Linda; Clifford, David B.

2014-01-01

Objective There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared to placebo. Design This study was a phase II, randomized, double blind, placebo-controlled, four-period crossover multi-center study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. Results A total of 15 patients were enrolled from 8 study sites and 8 patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared to placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study drop-out. Conclusions Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed. PMID:23565581

A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges.

PubMed

Chen, Y H Joshua; Gesser, Richard; Luxembourg, Alain

2015-02-01

The licensed four-valent prophylactic human papillomavirus vaccine is highly efficacious in preventing cervical, vulvar, vaginal, and anal cancers and related precancers caused by human papillomavirus types 6, 11, 16, and 18. These four types account for approximately 70% of cervical cancers. A nine-valent human papillomavirus vaccine, including the four original types (6, 11, 16, and 18) plus the next five most prevalent types in cervical cancer (31, 33, 45, 52, and 58) could provide approximately 90% overall cervical cancer coverage. To expedite the nine-valent human papillomavirus vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ∼ 15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. We discuss the design rationale and implementation challenges of the outcome trial, focusing on the adaptive feature of the seamless Phase IIB/III design. Subjects were enrolled in two parts (Part A and Part B). Approximately 1240 women, 16-26 years of age, were enrolled in Part A for Phase IIB evaluation and equally randomized to one of three dose formulations of the nine-valent human papillomavirus vaccine or the four-valent human papillomavirus vaccine (active control). Based on an interim analysis of immunogenicity and safety, one dose formulation of the nine-valent human papillomavirus vaccine was selected for evaluation in the Phase III part of the study. Subjects enrolled in Part A who received the selected dose formulation of the nine-valent human papillomavirus vaccine or four-valent human papillomavirus vaccine continued to be followed up and contributed to the final efficacy and safety analyses. In addition, ∼ 13,400 women 16-26 years of age were enrolled in Part B, randomized to nine-valent human papillomavirus vaccine at the selected dose formulation or four-valent human papillomavirus vaccine, and followed for immunogenicity, efficacy, and safety. A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed four-valent human papillomavirus vaccine and the development objectives for the nine-valent human papillomavirus vaccine. Subjects enrolled in Part A who received either the selected nine-valent human papillomavirus formulation or four-valent human papillomavirus vaccine contributed ∼ 10% of person-years of follow-up due to its earlier start-thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authorities and managing changes in the assay for immunological endpoints. Application of the experience and lesson learned from this seamless adaptive design to other clinical programs may depend on case-by-case consideration. A seamless Phase IIB/III adaptive design was successfully implemented in this large outcome study. The development time of the second-generation nine-valent human papillomavirus vaccine was shortened due to improved statistical efficiency. © The Author(s) 2014.

Alginate-immobilized bentonite clay: adsorption efficacy and reusability for Cu(II) removal from aqueous solution.

PubMed

Tan, Wei Shang; Ting, Adeline Su Yien

2014-05-01

This study evaluated the use of alginate-immobilized bentonite to remove Cu(II) as an alternative to mitigate clogging problems. The adsorption efficacy (under the influence of time, pH and initial Cu(II) concentration) and reusability of immobilized-bentonite (1% w/v bentonite) was tested against plain alginate beads. Results revealed that immobilized bentonite demonstrated significantly higher sorption efficacy compared to plain alginate beads with 114.70 and 94.04 mg Cu(II) adsorbed g(-1) adsorbent, respectively. Both sorbents were comparable in other aspects where sorption equilibrium was achieved within 6 h, with optimum pH between pH 4 and 5 for adsorption, displayed maximum adsorption capacity at initial Cu(II) concentrations of 400 mg l(-1), and demonstrated excellent reusability potential with desorption greater than 90% throughout three consecutive adsorption-desorption cycles. Both sorbents also conformed to Langmuir isotherm and pseudo-second order kinetic model. Immobilized bentonite is therefore recommended for use in water treatments to remove Cu(II) without clogging the system. Copyright © 2013 Elsevier Ltd. All rights reserved.

Selecting promising treatments in randomized Phase II cancer trials with an active control.

PubMed

Cheung, Ying Kuen

2009-01-01

The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer. Due to advances in oncology therapeutics and heterogeneity in the patient population, such evaluation can be interpreted objectively only in the presence of a prospective control group of an active standard treatment. This paper deals with the design problem of Phase II selection trials in which several experimental regimens are compared to an active control, with an objective to identify an experimental arm that is more effective than the control or to declare futility if no such treatment exists. Conducting a multi-arm randomized selection trial is a useful strategy to prioritize experimental treatments for further testing when many candidates are available, but the sample size required in such a trial with an active control could raise feasibility concerns. In this study, we extend the sequential probability ratio test for normal observations to the multi-arm selection setting. The proposed methods, allowing frequent interim monitoring, offer high likelihood of early trial termination, and as such enhance enrollment feasibility. The termination and selection criteria have closed form solutions and are easy to compute with respect to any given set of error constraints. The proposed methods are applied to design a selection trial in which combinations of sorafenib and erlotinib are compared to a control group in patients with non-small-cell lung cancer using a continuous endpoint of change in tumor size. The operating characteristics of the proposed methods are compared to that of a single-stage design via simulations: The sample size requirement is reduced substantially and is feasible at an early stage of drug development.

A phase II study of combination chemotherapy with docetaxel and carboplatin for patients with advanced or metastatic non-small cell lung cancer.

PubMed

Kasahara, Kazuo; Kimura, Hideharu; Shibata, Kazuhiko; Araya, Tomoyuki; Sone, Takashi; Oribe, Yoshitaka; Furusho, Shiho; Kita, Toshiyuki; Shirasaki, Hiroki; Oribe, Yoshitaka; Yoshimi, Yuzo; Ueda, Akihito; Tachibana, Hideki; Shintani, Hiromoto; Mizuguchi, Masayuki; Nishi, Kohichi; Fujimura, Masaki; Nakao, Shinji

2006-01-01

The aim of this phase II study was to evaluate the efficacy of combination chemotherapy consisting of docetaxel and carboplatin in patients with inoperable non-small cell lung cancer (NSCLC). For this multicenter phase II study, the eligibility criteria included histologically or cytologically proven inoperable NSCLC, measurable lesions, Eastern Cooperative Oncology Group performance status (PS) 0-2, adequate organ and bone marrow functions, and written informed consent. Patients received 60 mg/m2 of docetaxel and carboplatin (target AUC 5.5) on day 1 every 3 weeks until disease progression. The primary end-point of this study was response rate and the secondary end-points were toxicities, time to progression and overall survival. A total of 40 patients were enrolled and 39 patients were eligible. A complete response and partial response were observed in 1 and 13 patients, respectively. An objective response rate was 35.9% (95% confidential interval [CI] 20.8-51.0%). The median time to progression was 5.2 months and the median overall survival was 12.0 months. The 1- and 2-year survival rates were 53.8% and 25.1%, respectively. The major toxicities were leukocytopenia and neutropenia. Grade 3 or 4 thrombocytopenia was rare and non-hematological toxicities were generally mild. Grade 3 non-hematological toxicities were observed in 6 patients (2 with nausea and vomiting, 1 with diarrhea, 1 with elevated transaminase levels, 1 with allergic reaction and 1 with edema). No grade 4 non-hematological toxicities were observed. Docetaxel and carboplatin combination chemotherapy was well tolerated and active in Japanese patients with advanced or metastatic NSCLC.

Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

PubMed

Petrou, Philip A; Cunningham, Denise; Shimel, Katherine; Harrington, Molly; Hammel, Keri; Cukras, Catherine A; Ferris, Frederick L; Chew, Emily Y; Wong, Wai T

2014-12-18

To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye. While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.). Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.

PubMed

van de Kerkhof, Peter C M; Griffiths, Christopher E M; Reich, Kristian; Leonardi, Craig L; Blauvelt, Andrew; Tsai, Tsen-Fang; Gong, Yankun; Huang, Jiaqing; Papavassilis, Charis; Fox, Todd

2016-07-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate to severe plaque psoriasis. We reviewed safety data from the secukinumab psoriasis phase II/III program. Data were pooled from 10 phase II/III secukinumab psoriasis studies. Analysis included 3993 subjects; 3430 received secukinumab, representing 2725 subject-years (SYs) of exposure. Over 52 weeks, for secukinumab 300 mg, 150 mg, and etanercept, respectively, exposure-adjusted incidence rates (IRs) per 100 SYs were comparable across treatments for total adverse events (AEs; 236.1, 239.9, and 243.4, respectively); infections (91.1, 85.3, and 93.7, respectively); serious AEs (7.4, 6.8, and 7.0, respectively); serious infections (1.4, 1.1, and 1.4, respectively); malignant or unspecified tumors (0.77, 0.97, and 0.68, respectively); and adjudicated major adverse cardiovascular events (0.42, 0.35, and 0.34, respectively). AEs were not dose-related except for nonserious, mild/moderate, skin/mucosal candidiasis (IRs 3.55, 1.85, and 1.37 for secukinumab 300 mg, 150 mg, and etanercept, respectively). There was a limited number of patients in comparator groups and the exposure to placebo was short. Secukinumab had a favorable safety profile, had no meaningful difference between the 300- and 150-mg doses and, in terms of safety, was comparable to etanercept over 52 weeks in patients with moderate to severe plaque psoriasis. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

PubMed Central

Pili, Roberto; Qin, Rui; Flynn, P.J.; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M.; Erlichman, Charles; Vaishampayan, Ulka

2013-01-01

Vascular endothelial growth factor (VEGF) is expressed in human bladder tumors. A phase II study was conducted to assess the VEGF inhibitor pazopanib in patients with metastatic, urothelial carcinoma. Nineteen patients with one prior systemic therapy were enrolled. No objective responses were observed and median progression-free survival was 1.9 months. The role of anti-VEGF therapies in urothelial carcinoma remains to be determined. Background Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Methods Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Results Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Conclusions Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. PMID:23891158

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP.

PubMed

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-05-10

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP

PubMed Central

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-01-01

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) –specific kinase inhibitor that seems to be effective against non–small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor–naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment. PMID:28296581

A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.

PubMed

Ho, Alan L; Lipson, Brynna L; Sherman, Eric J; Xiao, Han; Fury, Matthew G; Apollo, Arlyn; Seetharamu, Nagashree; Sima, Camelia S; Haque, Sofia; Lyo, John K; Sales, Roberta; Cox, Lisa; Pfister, David G

2014-06-01

Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.

EXTRA-A Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer

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

Glynne-Jones, Rob; Meadows, Helen; UCL Cancer Trials Centre, London

Purpose: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. Methods and Materials: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m{sup 2}) on Day 1 and capecitabine on each RT treatment day in two divided doses (825more » mg/m{sup 2} b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. Results: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. Conclusions: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.« less

Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

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

Kato, Ken, E-mail: kenkato@ncc.go.jp; Muro, Kei; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi

Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-weekmore » break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.« less

47 CFR 54.309 - Connect America Fund Phase II Public Interest Obligations.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 3 2014-10-01 2014-10-01 false Connect America Fund Phase II Public Interest Obligations. 54.309 Section 54.309 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON... Connect America Fund Phase II Public Interest Obligations. (a) A price cap carrier electing Phase II model...

Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs.

PubMed

Deparle, L A; Gupta, R C; Canerdy, T D; Goad, J T; D'Altilio, M; Bagchi, M; Bagchi, D

2005-08-01

DeParle L. A., Gupta R. C., Canerdy T. D., Goad J. T., D'Altilio M., Bagchi M., Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J. vet. Pharmacol. Therap.28, 385-390. In large breed dogs, arthritis is very common because of obesity, injury, aging, immune disorder, or genetic predispositions. This study was therefore undertaken to evaluate clinical efficacy and safety of undenatured type-II collagen (UC-II) in obese-arthritic dogs. Fifteen dogs in three groups received either no UC-II (Group I) or UC-II with 1 mg/day (Group II) or 10 mg/day (Group III) for 90 days. Lameness and pain were measured on a weekly basis for 120 days (90 days treatment plus 30 days post-treatment). Blood samples were assayed for creatinine and blood urea nitrogen (markers of renal injury); and alanine aminotransferase and aspartate aminotransferase (evidence of hepatic injury). Dogs receiving 1 mg or 10 mg UC-II/day for 90 days showed significant declines in overall pain and pain during limb manipulation and lameness after physical exertion, with 10 mg showed greater improvement. At either dose of UC-II, no adverse effects were noted and no significant changes were noted in serum chemistry, suggesting that UC-II was well tolerated. In addition, dogs receiving UC-II for 90 days showed increased physical activity level. Following UC-II withdrawal for a period of 30 days, all dogs experienced a relapse of overall pain, exercise-associated lameness, and pain upon limb manipulation. These results suggest that daily treatment of arthritic dogs with UC-II ameliorates signs and symptoms of arthritis, and UC-II is well tolerated as no adverse effects were noted.

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas

PubMed Central

Kilburn, Lindsay B.; Kocak, Mehmet; Schaedeli Stark, Franziska; Meneses-Lorente, Georgina; Brownstein, Carrie; Hussain, Sazzad; Chintagumpala, Murali; Thompson, Patrick A.; Gururangan, Sri; Banerjee, Anuradha; Paulino, Arnold C.; Kun, Larry; Boyett, James M.; Blaney, Susan M.

2013-01-01

Background We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas. Methods Children 3–21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m2, given twice daily, with subsequent cohorts enrolled at 650 mg/m2 and 850 mg/m2 using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles. Results Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data. Conclusions Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m2, administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030). PMID:23592571

Clinical Evaluation of a Novel Intrarectal Device for Management of Fecal Incontinence in Bedridden Patients.

PubMed

Singh, Sandeep; Bhargava, Balram; Vasantha, Padma; Bhatia, Rohit; Sharma, Hanish; Pal, Sujoy; Sahni, Peush; Makharia, Govind K

The primary objective of the study was to evaluate the safety and efficacy of a stool management kit (SMK) for containment of fecal incontinence in hospitalized bedridden patients. A single-group quasi-experimental study. Twenty bedridden adults who had at least 1 episode of fecal incontinence in the prior 24 hours participated in the study. The study setting was the neurological unit of the All India Institute of Medical Sciences in New Delhi, India. The study was carried out in 2 phases. The device was placed in situ for up to 24 hours in 10 patients during phase I of the study and up to 120 hours in an additional 10 patients during phase II. Participants were assessed for anorectal injury and peripheral device leakage on a 4- to 6-hourly basis. Sigmoidoscopy was performed to evaluate for any mucosal trauma or alteration of anorectal pathology after retrieval of the device. The device was successfully placed in all patients following the first attempt to place the device; 80% of patients retained the device until planned removal. The SMK diverted fecal matter without anal leakage in 174 (93.5%) out of 186 assessment points in a group of 20 patients. The devices remained in situ for 21 ± 0.2 and 84.5 ± 38.9 hours during phase I and phase II, respectively. None experienced anorectal bleeding, sphincter injury, or mucosal ulceration with device usage. Post-device sigmoidoscopy revealed erythema at the site of diverter placement in 2 participants. Study findings suggest that the SMK successfully diverted liquid to semiformed fecal exudate without peripheral device leakage in 93.5% of bedridden patients. No serious adverse events occurred. Additional research is needed to compare its effectiveness with that of currently available intrarectal balloon devices.

End-threaded intramedullary positive profile screw ended self-tapping pin (Admit pin) - A cost-effective novel implant for fixing canine long bone fractures.

PubMed

Chanana, Mitin; Kumar, Adarsh; Tyagi, Som Prakash; Singla, Amit Kumar; Sharma, Arvind; Farooq, Uiase Bin

2018-02-01

The current study was undertaken to evaluate the clinical efficacy of end-threaded intramedullary pinning for management of various long bone fractures in canines. This study was conducted in two phases, managing 25 client-owned dogs presented with different fractures. The technique of application of end-threaded intramedullary pinning in long bone fractures was initially standardized in 6 clinical patients presented with long bone fractures. In this phase, end-threaded pins of different profiles, i.e., positive and negative, were used as the internal fixation technique. On the basis of results obtained from standardization phase, 19 client-owned dogs clinically presented with different fractures were implanted with end-threaded intramedullary positive profile screw ended self-tapping pin in the clinical application phase. The patients, allocated randomly in two groups, when evaluated postoperatively revealed slight pin migration in Group-I (negative profile), which resulted in disruption of callus site causing delayed union in one case and large callus formation in other two cases whereas no pin migration was observed in Group-II (positive profile). Other observations in Group-I was reduced muscle girth and delayed healing time as compared to Group-II. In clinical application, phase 21 st and 42 nd day post-operative radiographic follow-up revealed no pin migration in any of the cases, and there was no bone shortening or fragment collapse in end-threaded intramedullary positive profile screw ended self-tapping pin. The end-threaded intramedullary positive profile screw ended self-tapping pin used for fixation of long bone fractures in canines can resist pin migration, pin breakage, and all loads acting on the bone, i.e., compression, tension, bending, rotation, and shearing to an extent with no post-operative complications.

Integrating ADNI Results into Alzheimer’s Disease Drug Development Programs

PubMed Central

Cummings, Jeffrey L.

2010-01-01

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer’s disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD Treatments development; this paper considers how ADNI information can be integrated in AD drug development programs. Cerebrospinal fluid (CSF) amyloid beta protein (Aβ) measures can be used in Phase I studies to detect any short term effects on Aβ levels in the CSF. Phase II studies may benefit most from biomarker measures that can inform decisions about Phase III. CSF Aβ levels, CSF total tau and phospotau measures, fluorodexoyglucose positron emission tomography (FDG PET), Pittsburgh Compound B (PIB) amyloid imaging, or magnetic resonance imaging (MRI) may be employed to select patient in enriched trials or as outcomes for specific disease-modifying interventions. Use of biomarkers may allow Phase II trials to be conducted more efficiently with smaller populations of patients or shorted treatment times. New drug applications (NDA) may include biomarker outcomes of phase III trials. ADNI patients are highly educated and are nearly all of Caucasian ethnicity limiting the generalizability of the results to other populations commonly included in global clinical trials. ADNI has inspired or collaborates with biomarker investigations worldwide and together these studies will provide biomarker information that can reduce development times and costs, improve drug safety, optimize drug efficacy, and bring new treatments to patients with or at risk for AD. PMID:20447734

Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: a phase II clinical trial.

PubMed

Glina, Sidney; Toscano, Iderpol; Gomatzky, Celso; de Góes, Plínio Moreira; Júnior, Archimedes Nardozza; Claro, Joaquim Francisco de Almeida; Pagani, Eduardo

2009-02-01

Oral treatment with phosphodiesterase type 5 inhibitor (PDE5) is considered the first-line treatment for patients with erectile dysfunction (ED). Lodenafil carbonate (LC) is a novel PDE5. This is a phase II, prospective, randomized, double-blind, and placebo controlled clinical trial of LC. Efficacy end points were International Index of Sexual Function (IIEF) erectile domain, IIEF questions 3 and 4, and Sexual Encounter Profile (SEP) questions 2 and 3, before and after the use of LC or placebo. Seventy-two men older than 18 years, with ED for at least 6 months with stable sexual relationship were enrolled. Patients were randomized to placebo or LC 80 mg, 40 mg, or 20 mg and followed for 4 weeks. IIEF erectile domain scores before and after the use of medications were (mean +/- standard deviation [SD]): placebo: 11.9 +/- 3.4 and 12.6 +/- 5.5; LC 20 mg: 15.8 +/- 4.1 and 18.9 +/- 6.6; LC 40 mg: 11.9 +/- 4.4 and 15.4 +/- 8.1; LC 80 mg: 14.2 +/- 4.7 and 22.8 +/- 6.0 (ANOVA P < 0.01). The SEP-2 scores before and after the use of medications were (Mean +/- SD): placebo: 71.0 +/- 33.1 and 51.2 +/- 43.1; LC 20 mg 70.3 +/- 34.2 and 75.5 +/- 31.5; LC 40 mg: 48.4 +/- 42.1 and 60.8 +/- 42.5; LC 80 mg: 68.6 +/- 33.5 and 89.6 +/- 26.0. The SEP-3 scores were: placebo 23.3 +/- 27.6 and 33.6 +/- 42.3; LC 20 mg: 32.3 +/- 38.9 and 51.2 +/- 41.7; LC 40 mg: 39.7 +/- 44.7 and 46.7 +/- 41.1; LC 80 mg* 17.2 +/- 29.5 and 74.3 +/- 36.4 (*P < 0.05 for difference to placebo). The drug was well tolerated. Adverse reactions were mild and self-limited and included headache, rhinitis, flushing, color visual disorders, and dyspepsia. This study showed that the dosage of 80 mg of LC was significantly more efficacious than placebo and well tolerated.

Treatment using oxaliplatin and S-1 adjuvant chemotherapy for pathological stage III gastric cancer: a multicenter phase II study (TOSA trial) protocol.

PubMed

Namikawa, Tsutomu; Maeda, Hiromichi; Kitagawa, Hiroyuki; Oba, Koji; Tsuji, Akihito; Yoshikawa, Takaki; Kobayashi, Michiya; Hanazaki, Kazuhiro

2018-02-13

Recent studies demonstrated the efficacy of S-1-based adjuvant chemotherapy administered for six months after curative surgery for stage III gastric cancer; however, it is unproven whether this type of combination chemotherapy is more effective than the standard adjuvant chemotherapy of S-1 for one year. This multicenter phase II study evaluate the efficacy and safety of adjuvant chemotherapy using S-1 plus oxaliplatin followed by S-1 for up to one year for curatively resected stage III gastric cancer in patients aged over 20 years. Treatment initially comprises oral fluoropyrimidine S-1 (80 mg/m 2 ) administered twice daily for the first 2 weeks of a 3-week cycle. On day 1 of a second 3-week cycle, patients will receive 100 mg/m 2 of intravenous oxaliplatin followed by 80 mg/m 2 of S-1 (maximum 8 cycles). Then, the patients will receive 80 mg/m 2 of S-1 daily for 4 weeks, followed by 2 weeks of no chemotherapy. This 6-week cycle will be repeated during the first year after surgery. The primary endpoint is relapse-free survival for 3 years and secondary endpoints are safety, including the incidence of adverse events, and grading of neuropathy with each treatment cycle. The planned sample size of 75 patients is appropriate for this trial. The data will be analyzed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance. In contrast to previous trials, the current study involves administration of S-1 until one year after surgery in addition to prior S-1 plus oxaliplatin, and is the first study to evaluate the safety and efficacy of S-1 plus oxaliplatin followed by S-1 for up to one year in patients with curatively resected stage III gastric cancer. This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry (UMIN-CTR) registration number, R000029656  ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029656 ). Registered January 24, 2017.

High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors.

PubMed

Spugnini, Enrico P; Buglioni, Sabrina; Carocci, Francesca; Francesco, Menicagli; Vincenzi, Bruno; Fanciulli, Maurizio; Fais, Stefano

2014-08-21

The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediated acidification of tumor microenvironment. Metronomic chemotherapy has shown efficacy in adjuvant fashion as well as in the treatment of pets with advanced disease. Moreover, we have shown in veterinary clinical settings that pre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomic chemotherapy and high dose PPIs and their responses have been matched to those of a historical control of ten patients treated with metronomic chemotherapy alone. Single arm, non randomized phase II open study, with historical control group, evaluating safety and efficacy of the combination of metronomic chemotherapy and alkalization. Twenty-four companion animals (22 dogs and 2 cats) were treated adding to their metronomic chemotherapy protocol the pump inhibitor lansoprazole at high dose, and a water alkalizer. Their responses have been evaluated by clinical and instrumental evaluation and matched to those of the control group. The protocol was overall well tolerated, with only two dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response, in the alkalized cohort, 18 out of 24 had partial or complete responses (75%), two patients had a stable disease and the remaining patients experienced no response or progressive disease. On the other hand, only one patient in the control group experienced a complete response (10%) and three other experienced short lived responses. Median time to terminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042). Patient alkalization has shown to be well tolerated and to increase tumor response to metronomic chemotherapy as well the quality of life in pets with advanced cancer. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.

A Phase II, Randomized, Double-Blind Clinical Study Evaluating the Safety, Tolerability, and Efficacy of a Topical Minocycline Foam, FMX103, for the Treatment of Facial Papulopustular Rosacea.

PubMed

Mrowietz, Ulrich; Kedem, Tal Hetzroni; Keynan, Rita; Eini, Meir; Tamarkin, Dov; Rom, Dror; Shirvan, Mitchell

2018-06-01

Our objective was to demonstrate the safety, tolerability, and efficacy of a minocycline foam, FMX103, in the treatment of moderate-to-severe facial papulopustular rosacea. This was a phase II, randomized, double-blind, multicenter study. Healthy subjects aged ≥ 18 years with moderate-to-severe rosacea that had been diagnosed ≥ 6 months previously and with ≥ 12 inflammatory facial lesions were randomized (1:1:1) to receive once-daily 1.5% FMX103, 3% FMX103, or vehicle for 12 weeks. The primary endpoint was the absolute change in inflammatory lesion count at week 12. Other assessments included grade 2 or higher Investigator's Global Assessment (IGA) improvement, IGA "clear" or "almost clear" (IGA 0/1), clinical erythema, and safety/tolerability. Safety and efficacy were evaluated at weeks 2, 4, 8, and 12, with a safety follow-up at week 16. A total of 232 subjects were randomized; 213 completed the study. At week 12, inflammatory lesion count reduction was significantly greater for the 1.5 and 3% FMX103 doses than for vehicle (21.1 and 19.1 vs. 7.8, respectively; both p < 0.001). Both doses were significantly better than vehicle for achieving grade 2 or higher IGA improvement and assessment of "clear" or "almost clear." Both doses appeared generally safe and well tolerated. In total, 11 (4.7%) subjects reported treatment-related treatment-emergent adverse events (TEAEs); all but one (eye discharge) were dermal related, and all resolved by study end. No treatment-related systemic TEAEs were reported. Four subjects discontinued the study because of TEAEs (3% FMX103, n = 3; vehicle, n = 1). Topical minocycline foam, FMX103, appeared to be an effective, safe, and well tolerated treatment for moderate-to-severe papulopustular rosacea. These results support further investigation in larger clinical trials. CLINICALTRIALS. NCT02601963.

Rotigotine transdermal patch in Chinese patients with early Parkinson's disease: A randomized, double-blind, placebo-controlled pivotal study.

PubMed

Zhang, Zhen-Xin; Shang, Hui-Fang; Hu, Xingyue; Chen, Shengdi; Zhao, Zhongxin; Du, Xinlu; Surmann, Erwin; Bauer, Lars; Asgharnejad, Mahnaz

2016-07-01

Two phase3 studies (SP512; SP513) involving mostly Caucasian patients showed that rotigotine (≤8 mg/24 h) was efficacious and welltolerated in early-stage Parkinson's disease (PD). We report results from a phase 3 study (SP0914/NCT01646268) investigating rotigotine in Chinese patients with early-stage PD. Patients were randomized 1:1 to rotigotine or placebo, titrated over 1-4 weeks, maintained at optimal/maximum dose (≤8 mg/24 h) for 24 weeks. Primary efficacy variable: change in Unified Parkinson's Disease Rating Scale (UPDRS) II + III total score from Baseline to End-of-Maintenance. Secondary variables: UPDRS II + III responders (≥20% decrease in UPDRS II + III) and changes in UPDRS II (activities of daily living [ADL]) and III (motor examination) subscores. Of 247 patients randomized, 113/124 (91.1%) rotigotine- and 107/123 (87.0%) placebo-treated patients completed the study. mean (SD) age: 59.4 (10.2) years; time since PD diagnosis: 1.01 (1.22) years, 60.7% male. Rotigotine significantly improved UPDRS II + III total score (change from Baseline LSmean [95%CI] treatment difference, -4.82 [-7.18 to -2.45]; P < 0.0001). UPDRS II + III responder rates were higher with rotigotine (42.3% vs 22.3%; P = 0.0006). UPDRS II and III subscores improved with rotigotine (both subscores: P < 0.0005 vs. placebo). Most frequent adverse events (AEs): nausea (8.9% rotigotine, 3.3% placebo), dizziness (8.1%, 5.7%), pruritus (8.1%, 4.1%), somnolence (8.1%, 3.3%), erythema (6.5%, 1.6%), and vomiting (5.6%, 1.6%). Thirteen (5.3%) patients discontinued due to AEs (6 rotigotine, 7 placebo). Rotigotine was efficacious in Chinese patients with early-stage PD, providing benefits to control of ADL and motor function. Rotigotine was generally welltolerated, with similar AEs to those observed in Caucasian patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.

PubMed

Dy, Grace K; Mandrekar, Sumithra J; Nelson, Garth D; Meyers, Jeffrey P; Adjei, Araba A; Ross, Helen J; Ansari, Rafat H; Lyss, Alan P; Stella, Philip J; Schild, Steven E; Molina, Julian R; Adjei, Alex A

2013-01-01

The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small-cell lung cancer. A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095). The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.

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.

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.

Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.

PubMed

Chawla, Sant P; Cranmer, Lee D; Van Tine, Brian A; Reed, Damon R; Okuno, Scott H; Butrynski, James E; Adkins, Douglas R; Hendifar, Andrew E; Kroll, Stew; Ganjoo, Kristen N

2014-10-10

TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. In this open-label phase II study, TH-302 300 mg/m(2) was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m(2) on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity. PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088). © 2014 by American Society of Clinical Oncology.

Isac Sc-Linac Phase-II Helium Refrigerator Commissioning and First Operational Experience at Triumf

NASA Astrophysics Data System (ADS)

Sekachev, I.; Kishi, D.; Laxdal, R. E.

2010-04-01

ISAC Phase-II is an upgrade of the radioactive isotope superconducting linear accelerator, SC-linac, at TRIUMF. The Phase-I section of the accelerator, medium-beta, is operational and is cooled with a 600 W helium refrigerator, commissioned in March 2005. An identical refrigerator is being used with the Phase-II segment of the accelerator; which is now under construction. The second refrigerator has been commissioned and tested with the Phase-I section of the linac and is used for Phase-II linac development, including new SC-cavity performance tests. The commissioning of the Phase-II refrigeration system and recent operational experience is presented.

Potential Psychiatric Uses for MDMA.

PubMed

Yazar-Klosinski, B B; Mithoefer, M C

2017-02-01

Phase II trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of posttraumatic stress disorder (PTSD), with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as the US Food and Drug Administration (FDA) Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches. © 2016, The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

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

[Crataegus Special Extract WS 1442. Assessment of objective effectiveness in patients with heart failure (NYHA II)].

PubMed

Weikl, A; Assmus, K D; Neukum-Schmidt, A; Schmitz, J; Zapfe, G; Noh, H S; Siegrist, J

1996-08-30

In a multicenter, placebo-controlled double-blind study, the efficacy of the Crataegus-Specialextrakt WS 1442 in patients with NYHA stage II cardiac insufficiency was investigated. A total of 136 patients with this diagnosis were admitted to the study and, following a 2-week run-in phase, treated with Crataegus-Specialextract or placebo over a period of 8 weeks. The primary target parameter was the change in the difference of the pressure, heart rate product (systolic blood pressure x heart rate/100) (PHRP 50 W load vs. rest) measured at the beginning and end of treatment. On the basis of this variable, a clear improvement in the performance of the heart was shown in the group receiving the test substance, while the condition of the placebo group progressively worsened. The therapeutic difference between the groups was statistically significant. The positive result for the objective efficacy parameter was confirmed by a statistically obvious superiority of Crataegus in the patient's own assessment of improvement in the main symptoms (reduced performance, shortness of breath, ankle edema etc.). In addition, active treatment led, in comparison with placebo, to a considerably better quality of life for the patient, in particular with respect to mental well-being. The tolerability of the active substance proved to be very good-as shown by comprehensive laboratory investigations and the recording of undesirable events. All in all, the results of the present clinical investigation confirm those of previous studies showing that Crataegus-Specialextrakt WS 1442 is an effective and low-risk phytotherapeutic form of treatment in patients with NYHA II cardiac insufficiency.

Management of high risk metastatic prostate cancer: the case for novel therapies.

PubMed

Brand, Timothy C; Tolcher, Anthony W

2006-12-01

We reviewed the results of preliminary studies of select novel agents for metastatic prostate cancer and discuss the potential benefit of these agents for earlier stage disease, eg biochemically recurrent prostate cancer with high risk features. Available data on select investigational immunotherapies as well as endothelin-A receptor antagonists and survivin inhibitors were obtained and reviewed through PubMed searches, conference proceedings and unpublished proprietary information, when available. A large number of promising agents are in varying stages of development. Phase III results have been reported for the endothelin-A receptor antagonist atrasentan. Several immunotherapies are currently in phase II/III trials, namely the GM-CSF transduced tumor cell vaccine GVAX, the prostatic acid phosphatase loaded dendritic cell vaccine Provenge and the prostate specific antigen expressing poxvirus vaccine PROSTVAC-VF. Another immunotherapy, the prostate specific membrane antigen immunoconjugate MLN2704 (Millennium Pharmaceuticals, Cambridge, Massachusetts), is in phase I/II study. The first clinical inhibitors of survivin are in early phase I studies. Several of these agents, including atrasentan, have shown statistically significant but modest effects in the advanced disease setting in which they have been studied. Clinical trial design with these novel therapies presents particular challenges since most of these agents may induce disease stabilization rather than disease regression. There is a risk of false-negative results and failure to recognize a potentially efficacious agent if these cytostatic agents are studied only in men with advanced, heavily pretreated disease in whom life expectancy is measured in months. We advocate the early referral and enrollment of men with high risk prostate cancer in clinical trials.

A Randomized Phase II Dose-Response Exercise Trial among Colon Cancer Survivors: Purpose, Study Design, Methods, and Recruitment Results

PubMed Central

Brown, Justin C.; Troxel, Andrea B.; Ky, Bonnie; Damjanov, Nevena; Zemel, Babette S.; Rickels, Michael R.; Rhim, Andrew D.; Rustgi, Anil K.; Courneya, Kerry S.; Schmitz, Kathryn H.

2016-01-01

Background Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the COURAGE trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. Methods/Results The primary objective of the COURAGE trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min·wk−1) and high-dose (300 min·wk−1) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1,433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (P<0.001) and randomization onto the study protocol (P<0.001). No other demographic, clinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. Discussion The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors. PMID:26970181

Randomized controlled dissemination study of community-to-clinic navigation to promote CRC screening: Study design and implications.

PubMed

Larkey, Linda; Szalacha, Laura; Herman, Patricia; Gonzalez, Julie; Menon, Usha

2017-02-01

Regular screening facilitates early diagnosis of colorectal cancer (CRC) and reduction of CRC morbidity and mortality. Screening rates for minorities and low-income populations remain suboptimal. Provider referral for CRC screening is one of the strongest predictors of adherence, but referrals are unlikely among those who have no clinic home (common among poor and minority populations). This group randomized controlled study will test the effectiveness of an evidence based tailored messaging intervention in a community-to-clinic navigation context compared to no navigation. Multicultural, underinsured individuals from community sites will be randomized (by site) to receive CRC screening education only, or education plus navigation. In Phase I, those randomized to education plus navigation will be guided to make a clinic appointment to receive a provider referral for CRC screening. Patients attending clinic appointments will continue to receive navigation until screened (Phase II) regardless of initial arm assignment. We hypothesize that those receiving education plus navigation will be more likely to attend clinic appointments (H1) and show higher rates of screening (H2) compared to those receiving education only. Phase I group assignment will be used as a control variable in analysis of screening follow-through in Phase II. Costs per screening achieved will be evaluated for each condition and the RE-AIM framework will be used to examine dissemination results. The novelty of our study design is the translational dissemination model that will allow us to assess the real-world application of an efficacious intervention previously tested in a randomized controlled trial. Copyright © 2016. Published by Elsevier Inc.

Apatinib alone or combined with radiotherapy in metastatic prostate cancer: Results from a pilot, multicenter study.

PubMed

Zhao, Feng; Tian, Wei; Zeng, Ming; Xia, Jianling; Hu, Honglin; Hao, Xinbao; Han, Liangfu; Liu, Hao; He, Yangke; Zhu, Xueqiang; Liang, Liang; Ao, Rui; Wei, Min; Deng, Lili; Wei, Yuquan

2017-12-19

To study safety and efficacy of apatinib in combination of radiotherapy in patients with symptomatic bony disease prostate cancer(SBPC), based on the potential synergistic antitumor activity between apatinib and Radiation Therapy (RT). In phase I dose escalation part, 18 patients received apatinib dose at 250 mg every other day, 250 mg daily and 500 mg daily. In phase II part, the 250 mg daily cohorts were expanded to 20 patients in combination of RT (6 Gy/fraction, 5 fraction in total), one patient lost followed up and excluded the study, comparing with RT alone cohort with 10 patients, ratio of RT to RT + apatinib was 1 to 2. Evaluations included adverse events (AEs), prostate specific antigen (PSA) changes, radiographic evaluation and pain relief. In phase I study, common apatinib-related AEs (arAEs) were fatigue, anorexia, hand foot syndrome, proteinuria, and hypertension (HTN). Grade 3arAEs included HTN, proteinuria, liver dysfunction. In phase II study, combination apatinib with RT cohorts, AEs events increased comparing with either apatinib alone or RT alone; at the same time, combination cohorts showed PSA declines of ≥50% in 12 patients, and stable disease in 6 patients. Combination cohorts had pain control significantly improved in both level and duration comparing with RT alone. In SBPC patients, apatinib at less than 500 mg daily dose as mono-therapy had tolerable toxicity. Apatinib at dose of 250 mg daily in combining with RT synergized pain control, the overall AEs were manageable. Further studies are needed in large sample size future trials.

78 FR 76789 - Additional Connect America Fund Phase II Issues

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-19

... inspection and copying during normal business hours in the FCC Reference Information Center, Portals II, 445... Phase I to Phase II. 2. Timing of Phase II Support Disbursements. In the USF/ICC Transformation Order... language in paragraph 180 of the USF/ICC Transformation Order. We now seek to more fully develop the record...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2014 CFR

2014-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2013 CFR

2013-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

48 CFR 1852.219-81 - Limitation on subcontracting-SBIR Phase II program.

Code of Federal Regulations, 2012 CFR

2012-10-01

... subcontracting-SBIR Phase II program. 1852.219-81 Section 1852.219-81 Federal Acquisition Regulations System... CLAUSES Texts of Provisions and Clauses 1852.219-81 Limitation on subcontracting—SBIR Phase II program. As prescribed in 1819.7302(b), insert the following clause: Limitation on Subcontracting—SBIR Phase II Program...

Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells?

PubMed

Kalunian, K C

2016-09-01

Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti-interferon-α monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher and corticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-α monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to ≤7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab-treated patients and influenza rates were increased in anifrolumab-treated patients. Anifrolumab is currently in pivotal phase III studies. Data appear to support the concept that targeting type I interferon in SLE patients associates with clinical efficacy and safety. Further data are forthcoming from ongoing phase III clinical trials of anifrolumab. Other drug development efforts should be considered that target plasmacytoid dendritic cells and toll like receptors given the effects these components have on interferon production. © The Author(s) 2016.

The herpes zoster subunit vaccine.

PubMed

Cunningham, Anthony L

2016-01-01

Herpes zoster (HZ) causes severe pain and rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN). HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age related or other causes of decreased T cell immunity. A concentrated live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 5-8 years. The new HZ subunit (HZ/su or Shingrix) vaccine combines a key surface VZV glycoprotein (E) with T cell boosting adjuvant (AS01B). It is highly efficacious in protection (97%) against HZ in immunocompetent subjects, with no decline in advancing age and protection maintained for >3 years. Phase I-II trials showed safety and similar immunogenicity in severely immunocompromised patients. Local injection site pain and swelling can be severe in a minority (9.5%) but is transient (2 days). The HZ/su vaccine appears very promising in immunocompetent patients in the ZoE-50 controlled trial. The unblinding of the current ZoE-50 trial and publication of results from the accompanying ZoE-70 trial will reveal more about its mechanism of action and its efficacy against PHN, particularly in subjects >70 years. Phase III trial results in immunocompromised patients are eagerly awaited.

Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients.

PubMed

Kaku, Kohei

2017-11-01

Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM. Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors. Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.

Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

PubMed Central

Welker, Martin-Walter; Trojan, Joerg

2013-01-01

Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety. PMID:24204170

Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials

PubMed Central

Halperin, Daniel M.; Lee, J. Jack; Dagohoy, Cecile Gonzales; Yao, James C.

2015-01-01

Purpose Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies. Methods We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies. Results In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer. Conclusion Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies. PMID:26261263

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual.

PubMed

Massett, Holly A; Mishkin, Grace; Rubinstein, Larry; Ivy, S Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A; Abrams, Jeffrey S

2016-11-15

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397. ©2016 American Association for Cancer Research.

Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy.

PubMed

Santarpia, Mariacarmela; Liguori, Alessia; Karachaliou, Niki; Gonzalez-Cao, Maria; Daffinà, Maria Grazia; D'Aveni, Alessandro; Marabello, Grazia; Altavilla, Giuseppe; Rosell, Rafael

2017-01-01

The discovery of epidermal growth factor receptor ( EGFR ) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR -mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR . Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I-III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR -mutated NSCLC patients.

A brain-computer interface based cognitive training system for healthy elderly: a randomized control pilot study for usability and preliminary efficacy.

PubMed

Lee, Tih-Shih; Goh, Siau Juinn Alexa; Quek, Shin Yi; Phillips, Rachel; Guan, Cuntai; Cheung, Yin Bun; Feng, Lei; Teng, Stephanie Sze Wei; Wang, Chuan Chu; Chin, Zheng Yang; Zhang, Haihong; Ng, Tze Pin; Lee, Jimmy; Keefe, Richard; Krishnan, K Ranga Rama

2013-01-01

Cognitive decline in aging is a pressing issue associated with significant healthcare costs and deterioration in quality of life. Previously, we reported the successful use of a novel brain-computer interface (BCI) training system in improving symptoms of attention deficit hyperactivity disorder. Here, we examine the feasibility of the BCI system with a new game that incorporates memory training in improving memory and attention in a pilot sample of healthy elderly. This study investigates the safety, usability and acceptability of our BCI system to elderly, and obtains an efficacy estimate to warrant a phase III trial. Thirty-one healthy elderly were randomized into intervention (n = 15) and waitlist control arms (n = 16). Intervention consisted of an 8-week training comprising 24 half-hour sessions. A usability and acceptability questionnaire was administered at the end of training. Safety was investigated by querying users about adverse events after every session. Efficacy of the system was measured by the change of total score from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after training. Feedback on the usability and acceptability questionnaire was positive. No adverse events were reported for all participants across all sessions. Though the median difference in the RBANS change scores between arms was not statistically significant, an effect size of 0.6SD was obtained, which reflects potential clinical utility according to Simon's randomized phase II trial design. Pooled data from both arms also showed that the median change in total scores pre and post-training was statistically significant (Mdn = 4.0; p<0.001). Specifically, there were significant improvements in immediate memory (p = 0.038), visuospatial/constructional (p = 0.014), attention (p = 0.039), and delayed memory (p<0.001) scores. Our BCI-based system shows promise in improving memory and attention in healthy elderly, and appears to be safe, user-friendly and acceptable to senior users. Given the efficacy signal, a phase III trial is warranted. ClinicalTrials.gov NCT01661894.

Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy

PubMed Central

Santarpia, Mariacarmela; Liguori, Alessia; Karachaliou, Niki; Gonzalez-Cao, Maria; Daffinà, Maria Grazia; D’Aveni, Alessandro; Marabello, Grazia; Altavilla, Giuseppe; Rosell, Rafael

2017-01-01

The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I–III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients. PMID:28860885

Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson's Disease: A Post Hoc Analysis.

PubMed

Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

2016-04-02

Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson's disease (PD). To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as "Selegiline+Rotigotine" and "Selegiline+Placebo". Outcome measures included change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. 130 patients were evaluable for efficacy analyses ("Selegiline+Rotigotine": 84, "Selegiline+Placebo": 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: -4.89 [-7.87 to -1.91], p = 0.0015; for UPDRS II+III: -5.76 [-9.71 to -1.82], p = 0.0045). Higher proportion of patients in the "Selegiline+Rotigotine" group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD.

Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson’s Disease: A Post Hoc Analysis

PubMed Central

Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

2016-01-01

Background: Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson’s disease (PD). Objective: To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. Methods: In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as “Selegiline+Rotigotine” and “Selegiline+Placebo”. Outcome measures included change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. Results: 130 patients were evaluable for efficacy analyses (“Selegiline+Rotigotine”: 84, “Selegiline+Placebo”: 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: –4.89 [–7.87 to –1.91], p = 0.0015; for UPDRS II+III: –5.76 [–9.71 to –1.82], p = 0.0045). Higher proportion of patients in the “Selegiline+Rotigotine” group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. Conclusions: In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD. PMID:27061066

Overview of current immunotherapeutic strategies for glioma

PubMed Central

Calinescu, Anda-Alexandra; Kamran, Neha; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro Ricardo; Castro, Maria Graciela

2015-01-01

In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints. PMID:26598957

Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies.

PubMed

Burgos-Vargas, Ruben; Cardiel, Mario; Xibillé, Daniel; Pacheco-Tena, César; Pascual-Ramos, Virginia; Abud-Mendoza, Carlos; Mahgoub, Ehab; Rahman, Mahboob; Fan, Haiyun; Rojo, Ricardo; García, Erika; Santana, Karina

2017-05-25

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Vilazodone for the Treatment of Depression: An Update

PubMed Central

Wang, Sheng-Min; Han, Changsu; Lee, Soo-Jung; Patkar, Ashwin A.; Masand, Prakash S

2016-01-01

Vilazodone is a novel antidepressant having a selective serotonin (5-HT) reuptake inhibitor and 5-HT1A receptor partial agonist profile, so it has been regarded as a serotonin partial agonist-reuptake inhibitor (SPARI). We aimed to provide Vilazodone's clinical implications mainly by reviewing published clinical trials. Vilazodone has been speculated to have three potential benefits including faster onset of action, greater efficacy, and better tolerability owning to its SPARI properties. However, no studies conducted so far have directly proven the above speculations. Five initial phase II trials failed to distinguish vilazodone from placebo in the treatment of MDD, but 4 randomized clinical trials (RCT), 3 post-hoc or pooled analysis, 1 long-term open label study, and a meta-analysis showed vilazodone's superior efficacy over placebo. The studies also showed vilazodone is generally safe and tolerable. However, diarrhea, nausea, headache, dizziness, dry mouth, and insomnia warrant close attention in clinical practice because they have been constantly noted throughout the clinical studies. 2 RCTs recently documented the efficacy and safety of vilazodone in patients with generalized anxiety disorder, which could be a start of broadening vilazodone's usage or FDA approval in diverse anxiety disorders. PMID:27231672

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

PubMed Central

Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Markert, James M; Waters, Alicia M; Gillespie, George Yancey; Beierle, Elizabeth A; Friedman, Gregory K

2015-01-01

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors. PMID:26436135

Improvement of the Pharmacokinetics and In Vivo Antibacterial Efficacy of a Novel Type IIa Topoisomerase Inhibitor by Formulation in Liposomes

PubMed Central

Newman, Joseph; Goteti, Kosalaram; Beaudoin, Marie-Eve; Harrison, Rane; Hopkins, Sussie; Agrawal, Nikunj; Rivin, Olga

2013-01-01

Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials. The free (i.e., nonliposomal) compound has broad-spectrum MICs but suboptimal pharmacokinetics in rats and mice, characterized by a high volume of distribution and rapid clearance. The liposomal formulation of the compound had essentially unchanged MICs but greatly reduced volume of distribution and clearance in rats and mice. In an in vivo mouse model of Staphylococcus aureus infection of one thigh, the liposomal compound localized preferentially to the infected thigh, whereas the free compound showed no preference for the infected versus the uninfected thigh. Most importantly, the liposomal compound had enhanced efficacy at clearing the infection compared with the free compound. Delivery of this class of compounds as liposomal formulations may offer clinical advantages compared with free compounds. PMID:23877679

Enhanced Night Visibility Series, Volume XII : Overview of Phase II and Development of Phase III Experimental Plan

DOT National Transportation Integrated Search

2005-12-01

This volume provides an overview of the six studies that compose Phase II of the Enhanced Night Visibility project and the experimental plan for its third and final portion, Phase III. The Phase II studies evaluated up to 12 vision enhancement system...

Pharmacotherapy of amphetamine-type stimulant dependence: an update.

PubMed

Brensilver, Matthew; Heinzerling, Keith G; Shoptaw, Steven

2013-09-01

Methamphetamine- or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy. A review of randomised controlled trials of pharmacotherapies for methamphetamine- or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported. Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline and men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy. Problems in Phase II trials, including high dropout rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from preclinical and early phases of the medication development process for selecting better pharmacotherapy candidates. After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine- or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers. © 2013 Australasian Professional Society on Alcohol and other Drugs.

Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups.

PubMed

Allison, Annabel; Edwards, Tansy; Omollo, Raymond; Alves, Fabiana; Magirr, Dominic; E Alexander, Neal D

2015-11-16

Visceral leishmaniasis (VL) is a parasitic disease transmitted by sandflies and is fatal if left untreated. Phase II trials of new treatment regimens for VL are primarily carried out to evaluate safety and efficacy, while pharmacokinetic data are also important to inform future combination treatment regimens. The efficacy of VL treatments is evaluated at two time points, initial cure, when treatment is completed and definitive cure, commonly 6 months post end of treatment, to allow for slow response to treatment and detection of relapses. This paper investigates a generalization of the triangular design to impose a minimum sample size for pharmacokinetic or other analyses, and methods to estimate efficacy at extended follow-up accounting for the sequential design and changes in cure status during extended follow-up. We provided R functions that generalize the triangular design to impose a minimum sample size before allowing stopping for efficacy. For estimation of efficacy at a second, extended, follow-up time, the performance of a shrinkage estimator (SHE), a probability tree estimator (PTE) and the maximum likelihood estimator (MLE) for estimation was assessed by simulation. The SHE and PTE are viable approaches to estimate an extended follow-up although the SHE performed better than the PTE: the bias and root mean square error were lower and coverage probabilities higher. Generalization of the triangular design is simple to implement for adaptations to meet requirements for pharmacokinetic analyses. Using the simple MLE approach to estimate efficacy at extended follow-up will lead to biased results, generally over-estimating treatment success. The SHE is recommended in trials of two or more treatments. The PTE is an acceptable alternative for one-arm trials or where use of the SHE is not possible due to computational complexity. NCT01067443 , February 2010.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

PubMed

Cohen, Ezra E W; Davis, Darren W; Karrison, Theodore G; Seiwert, Tanguy Y; Wong, Stuart J; Nattam, Sreenivasa; Kozloff, Mark F; Clark, Joseph I; Yan, Duen-Hwa; Liu, Wen; Pierce, Carolyn; Dancey, Janet E; Stenson, Kerstin; Blair, Elizabeth; Dekker, Allison; Vokes, Everett E

2009-03-01

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia.

PubMed

Meaney, Calvin J; Beccari, Mario V; Yang, Yang; Zhao, Jiwei

2017-04-01

To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. A systematic review and meta-analysis of phase II and III clinical trial data was completed. Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis. Significant heterogeneity was found in the meta-analysis with an I 2 value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%). Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia. © 2017 Pharmacotherapy Publications, Inc.

Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia

PubMed Central

Meaney, Calvin J.; Beccari, Mario V.; Yang, Yang; Zhao, Jiwei

2017-01-01

Objective To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. Design A systematic review and meta-analysis of phase II and III clinical trial data was completed. Patients or Participants Eight studies (2 phase II and 4 phase III trials with 2 subgroup analyses) were included in the qualitative analysis whereas six studies (2 phase II and 4 phase III trials) were included in the meta-analysis. Measurements and Results There was significant heterogeneity in the meta-analysis with an I2 value ranging from 80.6–99.6%. A random-effects meta-analysis was applied for all endpoints. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, there was a significant −0.70mEq/L (95% confidence interval [CI] −0.48 to −0.91mEq/L) change in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was −0.36mEq/L (range of standard deviation: 0.07 to 0.30). The primary endpoint for ZS-9-- change in potassium at 48 hours-- was −0.67mEq/L (95% CI −0.45 to −0.89mEq/L). By 1 hour after ZS-9 administration, change in potassium was −0.17mEq/L (95% CI −0.05 to −0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with adverse effects of urinary tract infections (1.1%) and edema (0.9%). Conclusion Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary endpoint of this meta-analysis. Given the adverse effect profile and the observed time dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia. PMID:28122118

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

PubMed

Lopez Lopez, C; Caputo, A; Liu, F; Riviere, M E; Rouzade-Dominguez, M-L; Thomas, R G; Langbaum, J B; Lenz, R; Reiman, E M; Graf, A; Tariot, P N

2017-01-01

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Efficacy of a novel swallowing exercise program for chronic dysphagia in long-term head and neck cancer survivors.

PubMed

Kraaijenga, Sophie A C; Molen, Lisette van der; Stuiver, Martijn M; Takes, Robert P; Al-Mamgani, Abrahim; Brekel, Michiel W M van den; Hilgers, Frans J M

2017-10-01

The efficacy of rehabilitative exercises for chronic dysphagia treatment in head and neck cancer survivors has not been studied extensively and is ambiguous. A prospective clinical phase II study using an intensive strength training program was carried out in 17 head and neck cancer survivors with chronic dysphagia. Both swallow and nonswallow exercises were performed for 6-8 weeks with a newly developed tool allowing for progressive muscle overload, including chin tuck, jaw opening, and effortful swallow exercises. Outcome parameters were feasibility, compliance, and parameters for effect. Feasibility in terms of the program completion rate was 88%. Compliance with the exercises was 97%. After the training period, chin tuck, jaw opening, and anterior tongue strength had substantially improved. All but 1 patient reported to benefit from the exercises. Feasibility and compliance were high. Some objective and subjective effects of progressive load on muscle strength and swallowing function could be demonstrated. © 2017 Wiley Periodicals, Inc.

Change of motion and localization of cholesterol molecule during L(alpha)-H(II) transition.

PubMed Central

Hayakawa, E; Naganuma, M; Mukasa, K; Shimozawa, T; Araiso, T

1998-01-01

Formation of the inverted hexagonal (H(II)) phase from the lamellar (L(alpha)) phase of bovine brain-extracted phosphatidylcholine (BBPC) and phosphatidylethanolamine (BBPE) was investigated using 31P-NMR with or without cholesterol. When the ratio of BBPC to BBPE was 1:1, the H(II) formation was observed in the presence of 33 mol% cholesterol (i.e., BBPC:BBPE:cholesterol = 1:1:1) at 47 degrees C. The fraction of the H(II) phase in the BBPC/BBPE/cholesterol system could be controlled by the addition of dioleoylglycerol. The change of molecular motion of cholesterol affected by the H(II) formation was measured at various ratios of the L(alpha) to H(II) phase with the time-resolved fluorescence depolarization method, using dehydroergosterol as a fluorescent probe. It is observed that the motion of cholesterol became vigorous in the mixture state of the L(alpha) and the H(II) phases compared to that in the L(alpha) or the H(II) phase only. These facts show that cholesterol has the strong ability to induce the H(II) phase, probably by special molecular motion, which includes change of its location from the headgroup area to the acyl-chain area. PMID:9533700

Comparative study of therapeutic response to baclofen vs tolperisone in spasticity.

PubMed

Agarwal, Saurabh; Patel, Tejas; Shah, Nehal; Patel, Bhoomika M

2017-03-01

Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord. Some of the more common conditions associated with spasticity include spinal cord injury, cerebral palsy, and post-stroke syndrome. In this study we compared the efficacy and safety of baclofen vs tolperisone in spasticity. One hundred fifty patients with cerebral palsy or post stroke or spinal cord injury associated spasticity were enrolled in present study. Group I comprised of Seventy-five patients receiving baclofen and group II comprised of 75 patients receiving tolperisone. For efficacy measurement 4 evaluation methods were used, 1) Modified Ashworth Scale for muscle tone, 2) Medical research council scale for muscle strength and 3) Barthel Index for functional outcome 4) Coefficient of efficacy. In efficacy evaluation, both groups showed significant improvement in muscle tone, muscle strength and functional outcome at week 6 (Group I, 1.55±0.053, 2.79+0.032, 59.31±1.32; Group II, 1.57±0.053, 3.04±0.032, 73±1.32 respectively). In between the group analysis, there was no significant difference in muscle tone improvement in both the groups after 6 weeks (Group I, 1.055±0.053 vs Group II, 1.57±0.053, p>0.05). Group II showed non-significant but greater improvement in muscle strength (Week 6; Group I, 2.79±0.032 vs Group II, 3.04±0.032, p>0.07). Improvement in functional outcomes was greater in group II as compared to group I (Group I, 59.31±1.32 vs Group II, 73±1.32, p<0.05). Overall efficacy coefficient was greater for group II (3.6) as compared to group I (2.3). Baclofen showed more side effects compared to tolperisone in, asthenia being the most frequent. Tolperisone offers greater improvement in activities of daily living compared to baclofen. Tolperisone is more tolerable drug as compared to baclofen. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Flight Test of the F/A-18 Active Aeroelastic Wing Airplane

NASA Technical Reports Server (NTRS)

Voracek, David

2007-01-01

A viewgraph presentation of flight tests performed on the F/A active aeroelastic wing airplane is shown. The topics include: 1) F/A-18 AAW Airplane; 2) F/A-18 AAW Control Surfaces; 3) Flight Test Background; 4) Roll Control Effectiveness Regions; 5) AAW Design Test Points; 6) AAW Phase I Test Maneuvers; 7) OBES Pitch Doublets; 8) OBES Roll Doublets; 9) AAW Aileron Flexibility; 10) Phase I - Lessons Learned; 11) Control Law Development and Verification & Validation Testing; 12) AAW Phase II RFCS Envelopes; 13) AAW 1-g Phase II Flight Test; 14) Region I - Subsonic 1-g Rolls; 15) Region I - Subsonic 1-g 360 Roll; 16) Region II - Supersonic 1-g Rolls; 17) Region II - Supersonic 1-g 360 Roll; 18) Region III - Subsonic 1-g Rolls; 19) Roll Axis HOS/LOS Comparison Region II - Supersonic (open-loop); 20) Roll Axis HOS/LOS Comparison Region II - Supersonic (closed-loop); 21) AAW Phase II Elevated-g Flight Test; 22) Region I - Subsonic 4-g RPO; and 23) Phase II - Lessons Learned

Installation Restoration Program. Phase II--Confirmation/Quantification. Stage 1.

DTIC Science & Technology

1985-03-01

four phases. Phase I, Initial Assessment/ Records Search, is designed to identify possible hazardous waste contami- nated sites and potential...7 71 -. - - IL’ -, 1% 33 AihlIII Is 33 n~iL t iiC UII! ii CL C LU 1-3, Phase II, Confirmation and Quantification, is designed to confirm the...additional monitoring data upon which design of mitigative actions are based. In Phase III, Technology Base Development, appropriate technology is selected and

Installation Restoration Program. Phase II: Stage 1 Problem Confirmation Study, Duluth International Airport, Duluth, Minnesota.

DTIC Science & Technology

1984-10-01

8 iii "i t-. Table of Contents (cont.) Section Title Page -APPENDIX A Acronyms, Definitions, Nomenclature and Units of Measure B Scope of Work, Task...Identification/Records Search Phase II - Problem Confirmation and Quantification Phase III - Technology Base Development Phase IV - Corrective Action Only...Problem Identification/Records Search Phase II - Problem Confirmation and Quantification Phase III - Technology Base Development Phase IV - Corrective

Uterine cavity lavage: adding FISH to conventional cytogenetics for embryonic sexing and diagnosing common chromosomal aberrations.

PubMed

Ishai, D; Amiel, A; Diukman, R; Cogan, O; Lichtenstein, Z; Abramovici, H; Fejgin, M D

1995-10-01

This study was undertaken to examine the efficacy for early prenatal diagnosis of uterine cavity lavage at the level of the internal os and to assess the rate of maternal contamination. In phase I, uterine cavity lavage was performed in 38 women scheduled for pregnancy termination between 6 and 12 weeks. In addition to short- and long-term cultures, one-colour FISH (fluorescence in situ hybridization) with Y and X probes was used for fetal sexing. Two-colour FISH was used in all known male fetuses for the assessment of maternal contamination. In phase II, lavage was performed on 16 women. Fetal sex was diagnosed with direct labelled X and Y probes and common numerical chromosomal aberration was attempted with 18 and 21 direct labelled probes. Fetal sexing was successful in all cases in phases I and II. Out of 34 patients in which tissue was obtained, only FISH was done in six. Long-term cell cultures were successful in the other 28 cases, but complete karyotyping in 19 (56 per cent). No chromosomal aberration was found with the direct labelled probes 18 and 21 in FISH. Maternal contamination was assessed to be 5-10 per cent. This simple and easy-to-master technique is very effective in obtaining fetal cells early in pregnancy for genetic diagnosis, especially by FISH. However, the safety of the procedure must be tested in ongoing pregnancies.

SOME DESIGN ISSUES IN PHASE 2B VERSUS PHASE 3 PREVENTION TRIALS FOR TESTING EFFICACY OF PRODUCTS OR CONCEPTS

PubMed Central

Gilbert, Peter B.

2009-01-01

SUMMARY After one or more Phase 2 trials show that a candidate preventive vaccine induces immune responses that putatively protect against an infectious disease for which there is no licensed vaccine, the next step is to evaluate the efficacy of the candidate. The trial-designer faces the question of what is the optimal size of the initial efficacy trial? Part of the answer will entail deciding between a large Phase 3 licensure trial or an intermediate-sized Phase 2b screening trial, the latter of which may be designed to directly contribute to the evidence-base for licensing the candidate, or, to test a scientific concept for moving the vaccine field forward, acknowledging that the particular candidate will never be licensable. Using the HIV vaccine field as a case study, we describe distinguishing marks of Phase 2b and Phase 3 prevention efficacy trials, and compare the expected utility of these trial types using Pascal’s decision-theoretic framework. By integrating values/utilities on (1) Correct or incorrect conclusions resulting from the trial; (2) Timeliness of obtaining the trial results; (3) Precision for estimating the intervention effect; and (4) Resources expended; this decision framework provides a more complete approach to selecting the optimal efficacy trial size than a traditional approach that is based primarily on power calculations. Our objective is to help inform the decision-process for planning an initial efficacy trial design. PMID:20419758

Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies.

PubMed

Fleischmann, Roy; Kremer, Joel; Tanaka, Yoshiya; Gruben, David; Kanik, Keith; Koncz, Tamas; Krishnaswami, Sriram; Wallenstein, Gene; Wilkinson, Bethanie; Zwillich, Samuel H; Keystone, Edward

2016-12-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1-30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose-dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient-reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies. © 2016 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

A Tailored Web-Based Psycho-Educational Intervention for Cancer Patients and Their Family Caregivers

PubMed Central

Northouse, Laurel; Schafenacker, Ann; Barr, Kathryn L.C.; Katapodi, Maria; Yoon, Hyojin; Brittain, Kelly; Song, Lixin; Ronis, David L.; An, Larry

2014-01-01

Background Most programs addressing psychosocial concerns of cancer survivors are in-person programs that are expensive to deliver, have limited availability, and seldom deal with caregivers’ concerns. Objective This study examined the feasibility of translating an efficacious nurse-delivered program (FOCUS Program) for patients and their caregivers to a tailored, dyadic web-based format. Specific aims were to: (i) test the preliminary effects of the web-based intervention on patient and caregiver outcomes, (ii) examine participants’ program satisfaction, and (iii) determine the feasibility of using a web-based delivery format. Intervention/Methods A Phase II feasibility study was conducted with cancer patients (lung, breast, colorectal, prostate) and their family caregivers (N=38 dyads). The web-based intervention provided information and support tailored to the unique characteristics of each patient, caregiver, and their dyadic relationship. Primary outcomes were emotional distress and quality of life (QOL). Secondary outcomes were benefits of illness/caregiving, communication, support, and self-efficacy. Analyses included descriptive statistics and repeated measures ANOVA. Results Dyads had a significant decrease in emotional distress, increase in QOL, and perceived more benefits of illness/caregiving. Caregivers also had significant improvement in self-efficacy. There were no changes in communication. Participants were satisfied with program usability, but recommended additional content. Conclusions It was possible to translate a clinician-delivered program to a web-based format that was easy to use and had positive effects on dyadic outcomes. Implications for Practice The web-based program is a promising way to provide psychosocial care to more patients and caregivers using fewer personnel. It needs further testing in a larger RCT. PMID:24945270

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17.

PubMed

Kishnani, Priya S; Heller, James H; Spiridigliozzi, Gail A; Lott, Ira; Escobar, Luis; Richardson, Sharon; Zhang, Richard; McRae, Thomas

2010-12-01

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated. © 2010 Wiley-Liss, Inc.

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

PubMed

Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-07-13

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Circulating heregulin level is associated with the efficacy of patritumab combined with erlotinib in patients with non-small cell lung cancer.

PubMed

Yonesaka, Kimio; Hirotani, Kenji; von Pawel, Joachim; Dediu, Mircea; Chen, Shuquan; Copigneaux, Catherine; Nakagawa, Kazuhiko

2017-03-01

Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib. Serum was obtained from participants prior to treatment (n=202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed. sHRG level was various (-1346-11,772pg/mL). Participants were divided into the sHRG-high or -low subgroups at the concentration defining near the third quartile, 980pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n=46, hazard ratio 0.42 [0.19-0.96], p=0.0327). In contrast, the HRG-low subgroup (n=148) had no improvement in PFS with patritumab. sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature

PubMed Central

Masumori, Naoya

2013-01-01

Imidafenacin is an antimuscarinic agent with high affinity for the M3 and M1 muscarinic receptor subtypes and low affinity for the M2 subtype, and is used to treat overactive bladder. Several animal studies have demonstrated that imidafenacin has organ selectivity for the bladder over the salivary glands, colon, heart, and brain. In Phase I studies in humans, the approximately 2.9-hour elimination half-life of imidafenacin was shorter than that of other antimuscarinics such as tolterodine and solifenacin. Imidafenacin was approved for clinical use in overactive bladder in Japan in 2007 after a randomized, double-blind, placebo-controlled Phase II study and a propiverine-controlled Phase III study conducted in Japanese patients demonstrated that imidafenacin 0.1 mg twice daily was clinically effective for treating overactive bladder and was not inferior to propiverine for reduction of episodes of incontinence, with a better safety profile than propiverine. Several short-term clinical studies have demonstrated that imidafenacin also improves sleep disorders, nocturia, and nocturia-related quality of life. In addition, it is speculated that addon therapy with imidafenacin is beneficial for men with benign prostatic hyperplasia whose overactive bladder symptoms are not controlled by alpha-1 adrenoceptor antagonists. No cognitive impairment or influence of imidafenacin on the QTc interval has been observed. Although there have been very few relevant long-term clinical studies, the available information suggests the long-term efficacy, safety, and tolerability of imidafenacin, with less frequent severe adverse events, such as dry mouth and constipation. In addition, imidafenacin can be used safely for a long time even for cognitively vulnerable elderly patients with symptoms of overactive bladder. Thus, it is highly likely that imidafenacin is safe, efficacious, and tolerable to control symptoms of overactive bladder even over the long term. However, it remains unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese. PMID:23390360

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

PubMed Central

Santarpia, Mariacarmela; Daffinà, Maria Grazia; D’Aveni, Alessandro; Marabello, Grazia; Liguori, Alessia; Giovannetti, Elisa; Karachaliou, Niki; Gonzalez Cao, Maria; Rosell, Rafael; Altavilla, Giuseppe

2017-01-01

The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations. PMID:28740365

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

A second generation human haplotype map of over 3.1 million SNPs.

PubMed

Frazer, Kelly A; Ballinger, Dennis G; Cox, David R; Hinds, David A; Stuve, Laura L; Gibbs, Richard A; Belmont, John W; Boudreau, Andrew; Hardenbol, Paul; Leal, Suzanne M; Pasternak, Shiran; Wheeler, David A; Willis, Thomas D; Yu, Fuli; Yang, Huanming; Zeng, Changqing; Gao, Yang; Hu, Haoran; Hu, Weitao; Li, Chaohua; Lin, Wei; Liu, Siqi; Pan, Hao; Tang, Xiaoli; Wang, Jian; Wang, Wei; Yu, Jun; Zhang, Bo; Zhang, Qingrun; Zhao, Hongbin; Zhao, Hui; Zhou, Jun; Gabriel, Stacey B; Barry, Rachel; Blumenstiel, Brendan; Camargo, Amy; Defelice, Matthew; Faggart, Maura; Goyette, Mary; Gupta, Supriya; Moore, Jamie; Nguyen, Huy; Onofrio, Robert C; Parkin, Melissa; Roy, Jessica; Stahl, Erich; Winchester, Ellen; Ziaugra, Liuda; Altshuler, David; Shen, Yan; Yao, Zhijian; Huang, Wei; Chu, Xun; He, Yungang; Jin, Li; Liu, Yangfan; Shen, Yayun; Sun, Weiwei; Wang, Haifeng; Wang, Yi; Wang, Ying; Xiong, Xiaoyan; Xu, Liang; Waye, Mary M Y; Tsui, Stephen K W; Xue, Hong; Wong, J Tze-Fei; Galver, Luana M; Fan, Jian-Bing; Gunderson, Kevin; Murray, Sarah S; Oliphant, Arnold R; Chee, Mark S; Montpetit, Alexandre; Chagnon, Fanny; Ferretti, Vincent; Leboeuf, Martin; Olivier, Jean-François; Phillips, Michael S; Roumy, Stéphanie; Sallée, Clémentine; Verner, Andrei; Hudson, Thomas J; Kwok, Pui-Yan; Cai, Dongmei; Koboldt, Daniel C; Miller, Raymond D; Pawlikowska, Ludmila; Taillon-Miller, Patricia; Xiao, Ming; Tsui, Lap-Chee; Mak, William; Song, You Qiang; Tam, Paul K H; Nakamura, Yusuke; Kawaguchi, Takahisa; Kitamoto, Takuya; Morizono, Takashi; Nagashima, Atsushi; Ohnishi, Yozo; Sekine, Akihiro; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Deloukas, Panos; Bird, Christine P; Delgado, Marcos; Dermitzakis, Emmanouil T; Gwilliam, Rhian; Hunt, Sarah; Morrison, Jonathan; Powell, Don; Stranger, Barbara E; Whittaker, Pamela; Bentley, David R; Daly, Mark J; de Bakker, Paul I W; Barrett, Jeff; Chretien, Yves R; Maller, Julian; McCarroll, Steve; Patterson, Nick; Pe'er, Itsik; Price, Alkes; Purcell, Shaun; Richter, Daniel J; Sabeti, Pardis; Saxena, Richa; Schaffner, Stephen F; Sham, Pak C; Varilly, Patrick; Altshuler, David; Stein, Lincoln D; Krishnan, Lalitha; Smith, Albert Vernon; Tello-Ruiz, Marcela K; Thorisson, Gudmundur A; Chakravarti, Aravinda; Chen, Peter E; Cutler, David J; Kashuk, Carl S; Lin, Shin; Abecasis, Gonçalo R; Guan, Weihua; Li, Yun; Munro, Heather M; Qin, Zhaohui Steve; Thomas, Daryl J; McVean, Gilean; Auton, Adam; Bottolo, Leonardo; Cardin, Niall; Eyheramendy, Susana; Freeman, Colin; Marchini, Jonathan; Myers, Simon; Spencer, Chris; Stephens, Matthew; Donnelly, Peter; Cardon, Lon R; Clarke, Geraldine; Evans, David M; Morris, Andrew P; Weir, Bruce S; Tsunoda, Tatsuhiko; Mullikin, James C; Sherry, Stephen T; Feolo, Michael; Skol, Andrew; Zhang, Houcan; Zeng, Changqing; Zhao, Hui; Matsuda, Ichiro; Fukushima, Yoshimitsu; Macer, Darryl R; Suda, Eiko; Rotimi, Charles N; Adebamowo, Clement A; Ajayi, Ike; Aniagwu, Toyin; Marshall, Patricia A; Nkwodimmah, Chibuzor; Royal, Charmaine D M; Leppert, Mark F; Dixon, Missy; Peiffer, Andy; Qiu, Renzong; Kent, Alastair; Kato, Kazuto; Niikawa, Norio; Adewole, Isaac F; Knoppers, Bartha M; Foster, Morris W; Clayton, Ellen Wright; Watkin, Jessica; Gibbs, Richard A; Belmont, John W; Muzny, Donna; Nazareth, Lynne; Sodergren, Erica; Weinstock, George M; Wheeler, David A; Yakub, Imtaz; Gabriel, Stacey B; Onofrio, Robert C; Richter, Daniel J; Ziaugra, Liuda; Birren, Bruce W; Daly, Mark J; Altshuler, David; Wilson, Richard K; Fulton, Lucinda L; Rogers, Jane; Burton, John; Carter, Nigel P; Clee, Christopher M; Griffiths, Mark; Jones, Matthew C; McLay, Kirsten; Plumb, Robert W; Ross, Mark T; Sims, Sarah K; Willey, David L; Chen, Zhu; Han, Hua; Kang, Le; Godbout, Martin; Wallenburg, John C; L'Archevêque, Paul; Bellemare, Guy; Saeki, Koji; Wang, Hongguang; An, Daochang; Fu, Hongbo; Li, Qing; Wang, Zhen; Wang, Renwu; Holden, Arthur L; Brooks, Lisa D; McEwen, Jean E; Guyer, Mark S; Wang, Vivian Ota; Peterson, Jane L; Shi, Michael; Spiegel, Jack; Sung, Lawrence M; Zacharia, Lynn F; Collins, Francis S; Kennedy, Karen; Jamieson, Ruth; Stewart, John

2007-10-18

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

Webcam delivery of the Camperdown Program for adolescents who stutter: a phase II trial.

PubMed

Carey, Brenda; O'Brian, Sue; Lowe, Robyn; Onslow, Mark

2014-10-01

This Phase II clinical trial examined stuttering adolescents' responsiveness to the Webcam-delivered Camperdown Program. Sixteen adolescents were treated by Webcam with no clinic attendance. Primary outcome was percentage of syllables stuttered (%SS). Secondary outcomes were number of sessions, weeks and hours to maintenance, self-reported stuttering severity, speech satisfaction, speech naturalness, self-reported anxiety, self-reported situation avoidance, self-reported impact of stuttering, and satisfaction with Webcam treatment delivery. Data were collected before treatment and up to 12 months after entry into maintenance. Fourteen participants completed the treatment. Group mean stuttering frequency was 6.1 %SS (range, 0.7-14.7) pretreatment and 2.8 %SS (range, 0-12.2) 12 months after entry into maintenance, with half the participants stuttering at 1.2 %SS or lower at this time. Treatment was completed in a mean of 25 sessions (15.5 hr). Self-reported stuttering severity ratings, self-reported stuttering impact, and speech satisfaction scores supported %SS outcomes. Minimal anxiety was evident either pre- or post-treatment. Individual responsiveness to the treatment varied, with half the participants showing little reduction in avoidance of speech situations. The Webcam service delivery model was appealing to participants, although it was efficacious and efficient for only half. Suggestions for future stuttering treatment development for adolescents are discussed.

Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation.

PubMed

Cheung, Ka Lung; Khor, Tin Oo; Kong, Ah-Ng

2009-01-01

Accumulating evidence from epidemiologic and clinical studies indicates that chronic inflammatory disorders harbor an increased risk of cancer development. Curcumin (CUR) has been strongly linked to the anti-inflammatory effect. On the other hand, isothiocyanates such as sulforaphane (SFN) and phenethyl isothiocyanate (PEITC) are strong phase-II detoxifying/antioxidant enzymes inducer. Therefore it is interesting to see if combination of these drugs can inhibit inflammation with higher combined efficacies. We used nitric oxide (NO) assay to assess the synergism of the different combinations of CUR, SFN and PEITC. The inflammatory markers, e.g. iNOS, COX-2, prostaglandin E2 (PGE2), tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels were determined using RT-PCR, Western blot and ELISA assays. We report that combination of PEITC + SFN or CUR + SFN has a synergistic effect in down-regulating inflammation markers like TNF, IL-1, NO, PGE2. The synergism is probably due to the synergistic induction of phase II/antioxidant enzymes including heme-oxygenase1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1). Our data suggest that CUR + SFN and PEITC + SFN combinations could be more effective than used alone in preventing inflammation and possibly its associated diseases including cancer.

Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation

PubMed Central

Snowden, J A; Saccardi, R; Allez, M; Ardizzone, S; Arnold, R; Cervera, R; Denton, C; Hawkey, C; Labopin, M; Mancardi, G; Martin, R; Moore, J J; Passweg, J; Peters, C; Rabusin, M; Rovira, M; van Laar, J M; Farge, D

2012-01-01

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized. PMID:22002489

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

Randomized Phase II Trial of High-Dose Melatonin and Radiation Therapy for RPA Class 2 Patients With Brain Metastases (RTOG 0119)

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

Berk, Lawrence; Berkey, Brian; Rich, Tyvin

Purpose: To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients. Methods and Materials: RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8-9 AM) or in the evening (8-9 PM). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon.more » Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured. Results: Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months. Conclusions: High-dose melatonin did not show any beneficial effect in this group of patients.« less

A phase II study of preoperative mFOLFOX6 with short-course radiotherapy in patients with locally advanced rectal cancer and liver-only metastasis.

PubMed

Kim, Kyung Hwan; Shin, Sang Joon; Cho, Min Soo; Ahn, Joong Bae; Jung, Minkyu; Kim, Tae Il; Park, Young Suk; Kim, Hoguen; Kim, Nam Kyu; Koom, Woong Sub

2016-02-01

To evaluate the efficacy and safety of upfront mFOLFOX6 followed by short-course radiotherapy (SCRT) and surgery in patients with locally advanced rectal cancer and liver-only metastases. This single-arm phase II study involved 32 patients. mFOLFOX6 was administered for four cycles followed by SCRT and another four cycles of mFOLFOX6. Surgery was performed 4-6 weeks after the last chemotherapy cycle. The primary endpoint was complete (R0) resection rate. Secondary endpoints were response rate, progression-free survival (PFS), overall survival (OS), and complication rates. Surgical resection of the rectum and liver was performed in 25 patients (78%) and R0 resection was achieved in 20 patients (63%). Local tumor downstaging was observed in 54% of patients. Median OS and PFS were 38 and 9 months, respectively. One patient discontinued treatment due to toxicity and no treatment-related deaths occurred. Patients who progressed after 4 cycles of mFOLFOX6 were less likely to receive resection. This regimen was safe and effective in inducing local tumor response and achieving R0 resection in this patient population. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Relationship between Occurrence Timing of Dispensing Errors and Subsequent Danger to Patients under the Situation According to the Classification of Drugs by Efficacy.

PubMed

Tsuji, Toshikazu; Nagata, Kenichiro; Kawashiri, Takehiro; Yamada, Takaaki; Irisa, Toshihiro; Murakami, Yuko; Kanaya, Akiko; Egashira, Nobuaki; Masuda, Satohiro

2016-01-01

There are many reports regarding various medical institutions' attempts at the prevention of dispensing errors. However, the relationship between occurrence timing of dispensing errors and subsequent danger to patients has not been studied under the situation according to the classification of drugs by efficacy. Therefore, we analyzed the relationship between position and time regarding the occurrence of dispensing errors. Furthermore, we investigated the relationship between occurrence timing of them and danger to patients. In this study, dispensing errors and incidents in three categories (drug name errors, drug strength errors, drug count errors) were classified into two groups in terms of its drug efficacy (efficacy similarity (-) group, efficacy similarity (+) group), into three classes in terms of the occurrence timing of dispensing errors (initial phase errors, middle phase errors, final phase errors). Then, the rates of damage shifting from "dispensing errors" to "damage to patients" were compared as an index of danger between two groups and among three classes. Consequently, the rate of damage in "efficacy similarity (-) group" was significantly higher than that in "efficacy similarity (+) group". Furthermore, the rate of damage is the highest in "initial phase errors", the lowest in "final phase errors" among three classes. From the results of this study, it became clear that the earlier the timing of dispensing errors occurs, the more severe the damage to patients becomes.

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

PubMed Central

Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

2016-01-01

Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug’s impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow. PMID:27478824

Centrifuge workers study. Phase II, completion report

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

Wooten, H.D.

1994-09-01

Phase II of the Centrifuge Workers Study was a follow-up to the Phase I efforts. The Phase I results had indicated a higher risk than expected among centrifuge workers for developing bladder cancer when compared with the risk in the general population for developing this same type of cancer. However, no specific agent could be identified as the causative agent for these bladder cancers. As the Phase II Report states, Phase I had been limited to workers who had the greatest potential for exposure to substances used in the centrifuge process. Phase II was designed to expand the survey tomore » evaluate the health of all employees who had ever worked in Centrifuge Program Departments 1330-1339 but who had not been interviewed in Phase I. Employees in analytical laboratories and maintenance departments who provided support services for the Centrifuge Program were also included in Phase II. In December 1989, the Oak Ridge Associated Universities (ORAU), now known as Oak Ridge Institute for Science and Education (ORISE), was contracted to conduct a follow-up study (Phase II). Phase H of the Centrifuge Workers Study expanded the survey to include all former centrifuge workers who were not included in Phase I. ORISE was chosen because they had performed the Phase I tasks and summarized the corresponding survey data therefrom.« less

Thinking Styles and University Self-Efficacy Among Deaf, Hard-of-Hearing, and Hearing Students.

PubMed

Cheng, Sanyin; Zhang, Li-Fang; Hu, Xiaozhong

2016-01-01

This study explores how students' thinking styles are related to their university self-efficacy, by administering the Thinking Styles Inventory-Revised II and the University Self-Efficacy Scale to 366 deaf or hard-of-hearing (DHH) and 467 hearing university students in mainland China. Results showed that, among all participants, those with Type I styles (i.e., more creativity-generating, less structured, and cognitively more complex) had higher levels of university self-efficacy. At the same time, DHH students with Type II styles (i.e., more norm-favoring, more structured, and cognitively more simplistic) had lower levels of university self-efficacy. The contributions, limitations, and implications of the present research are discussed. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Development of an orphan drug to treat a genetic disease: the paradigm of agalsidase beta].

PubMed

Germain, Dominique P; Benistan, Karelle

2007-03-01

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.

ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention

PubMed Central

Roncon, Loris; Azzarito, Michele; Becattini, Cecilia; Bongarzoni, Amedeo; Casazza, Franco; Cuccia, Claudio; D’Agostino, Carlo; Rugolotto, Matteo; Vatrano, Marco; Vinci, Eugenio; Fenaroli, Paride; Formigli, Dario; Silvestri, Paolo; Nardi, Federico; Vedovati, Maria Cristina; Scherillo, Marino

2017-01-01

Abstract The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the ‘double drug single dose’ approach or with ‘single drug double dose’; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer. PMID:28751847

Development and Preliminary Validation of the Collective Efficacy Questionnaire for Sports

ERIC Educational Resources Information Center

Short, Sandra E.; Sullivan, Philip; Feltz, Deborah L.

2005-01-01

This study presents the development and preliminary validation of the Collective Efficacy Questionnaire for Sports (CEQS). The study was conducted in 3 phases. In Phase 1, a 42-item questionnaire was developed and tested with 271 college-aged student-athletes. An exploratory factor analysis revealed 5 collective efficacy factors with 27 items…

Efficacy and reusability of alginate-immobilized live and heat-inactivated Trichoderma asperellum cells for Cu (II) removal from aqueous solution.

PubMed

Tan, Wei Shang; Ting, Adeline Su Yien

2012-11-01

Cu(II) removal efficacies of alginate-immobilized Trichoderma asperellum using viable and non-viable forms were investigated with respect to time, pH, and initial Cu(II) concentrations. The reusability potential of the biomass was determined based on sorption/desorption tests. Cu(II) biosorption by immobilized heat-inactivated T. asperellum cells was the most efficient, with 134.22mg Cu(II) removed g(-1) adsorbent, compared to immobilized viable cells and plain alginate beads (control) with 105.96 and 94.04mg Cu(II) adsorbed g(-1) adsorbent, respectively. Immobilized non-viable cells achieved equilibrium more rapidly within 4h. For all biosorbents, optimum pH for Cu(II) removal was between pH 4 and 5. Reusability of all biosorbents were similar, with more than 90% Cu(II) desorbed with HCl. These alginate-immobilized cells can be applied to reduce clogging and post-separation process incurred from use of suspended biomass. Copyright © 2012 Elsevier Ltd. All rights reserved.

Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia.

PubMed

Galinkin, J L; Fazi, L M; Cuy, R M; Chiavacci, R M; Kurth, C D; Shah, U K; Jacobs, I N; Watcha, M F

2000-12-01

Many children are restless, disoriented, and inconsolable immediately after bilateral myringotomy and tympanosotomy tube placement (BMT). Rapid emergence from sevoflurane anesthesia and postoperative pain may increase emergence agitation. The authors first determined serum fentanyl concentrations in a two-phase study of intranasal fentanyl. The second phase was a prospective, placebo-controlled, double-blind study to determine the efficacy of intranasal fentanyl in reducing emergence agitation after sevoflurane or halothane anesthesia. In phase 1, 26 children with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled for BMT received intranasal fentanyl, 2 microg/kg, during a standardized anesthetic. Serum fentanyl concentrations in blood samples drawn at emergence and at postanesthesia care unit (PACU) discharge were determined by radioimmunoassay. In phase 2, 265 children with ASA physical status I or II were randomized to receive sevoflurane or halothane anesthesia along with either intranasal fentanyl (2 microg/kg) or saline. Postoperative agitation, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, and satisfaction of PACU nurses and parents with the anesthetic technique were evaluated. In phase 1, the mean fentanyl concentrations at 10 +/- 4 min (mean +/- SD) and 34 +/- 9 min after administering intranasal fentanyl were 0.80 +/- 0.28 and 0.64 +/- 0.25 ng/ml, respectively. In phase 2, the incidence of severe agitation, highest CHEOPS scores, and heart rate in the PACU were decreased with intranasal fentanyl. There were no differences between sevoflurane and halothane in these measures and in times to hospital discharge. The incidence of postoperative vomiting, hypoxemia, and slow respiratory rates were not increased with fentanyl. Serum fentanyl concentrations after intranasal administration exceed the minimum effective steady state concentration for analgesia in adults. The use of intranasal fentanyl during halothane or sevoflurane anesthesia for BMT is associated with diminished postoperative agitation without an increase in vomiting, hypoxemia, or discharge times.

Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date.

PubMed

Chong, Julio T; Oh, William K; Liaw, Bobby C

2018-01-01

Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo.

The efficacy of three objective systems for identifying beef cuts that can be guaranteed tender.

PubMed

Wheeler, T L; Vote, D; Leheska, J M; Shackelford, S D; Belk, K E; Wulf, D M; Gwartney, B L; Koohmaraie, M

2002-12-01

The objective of this study was to determine the accuracy of three objective systems (prototype BeefCam, colorimeter, and slice shear force) for identifying guaranteed tender beef. In Phase I, 308 carcasses (105 Top Choice, 101 Low Choice, and 102 Select) from two commercial plants were tested. In Phase II, 400 carcasses (200 rolled USDA Select and 200 rolled USDA Choice) from one commercial plant were tested. The three systems were evaluated based on progressive certification of the longissimus as "tender" in 10% increments (the best 10, 20, 30%, etc., certified as "tender" by each technology; 100% certification would mean no sorting for tenderness). In Phase I, the error (percentage of carcasses certified as tender that had Warner-Bratzler shear force of > or = 5 kg at 14 d postmortem) for 100% certification using all carcasses was 14.1%. All certification levels up to 80% (slice shear force) and up to 70% (colorimeter) had less error (P < 0.05) than 100% certification. Errors in all levels of certification by prototype BeefCam (13.8 to 9.7%) were not different (P > 0.05) from 100% certification. In Phase I, the error for 100% certification for USDA Select carcasses was 30.7%. For Select carcasses, all slice shear force certification levels up to 60% (0 to 14.8%) had less error (P < 0.05) than 100% certification. For Select carcasses, errors in all levels of certification by colorimeter (20.0 to 29.6%) and by BeefCam (27.5 to 31.4%) were not different (P > 0.05) from 100% certification. In Phase II, the error for 100% certification for all carcasses was 9.3%. For all levels of slice shear force certification less than 90% (for all carcasses) or less than 80% (Select carcasses), errors in tenderness certification were less than (P < 0.05) for 100% certification. In Phase II, for all carcasses or Select carcasses, colorimeter and prototype BeefCam certifications did not significantly reduce errors (P > 0.05) compared to 100% certification. Thus, the direct measure of tenderness provided by slice shear force results in more accurate identification of "tender" beef carcasses than either of the indirect technologies, prototype BeefCam, or colorimeter, particularly for USDA Select carcasses. As tested in this study, slice shear force, but not the prototype BeefCam or colorimeter systems, accurately identified "tender" beef.

Anticancer activity and tissue distribution of platinum (II) complex with lignin-derived polymer of benzene-poly-carboxylic acids.

PubMed

Solovyev, Nikolay D; Fedoros, Elena I; Drobyshev, Evgenii J; Ivanenko, Natalya B; Pigarev, Sergey E; Tyndyk, Margarita L; Anisimov, Vladimir N; Vilpan, Yury A; Panchenko, Andrey V

2017-09-01

Platinum-containing antineoplastic agents with physiologically active ligands seem to be a promising direction in anticancer drug design. PDBA is a novel promising antineoplastic agent, containing polymer ligand of natural origin (international patent WO2013/143549 A1). Polymer ligand of PDBA has a highly functionalised polyphenolic backbone, which exerts its own pharmacological effect via immune modulation and regulation of gene expression. PDBA is a cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands (approximate bulk formula C 83 H 70 N 2 O 27 Pt). The agent is being evaluated in Phase II controlled clinical trials in metastatic breast cancer patients. In the present study, tissue distribution and tumour growth inhibition effects of PDBA, cisplatin and carboplatin were compared in SHR female mice, bearing inoculated solid Ehrlich carcinoma. The agents were administered subcutaneously every second day for the period of 10days (5 injections) at 62.5mg/kg, 3.0mg/kg and 18.5mg/kg for PDBA, cisplatin and carboplatin, respectively. Experimental animals were sacrificed on the Days 11, 16 and 23 after the inoculation of the tumour. The doses of all studied drugs were selected to obtain similar antitumour efficacy with ca. 50% growth inhibition of the Ehrlich tumour at the end of the study. The efficacy of a single platinum reactive moiety [cis-diammineplatinum(II)] was shown to be the highest for cisplatin, followed by PDBA and finally carboplatin. However, the toxicity of PDBA was considerably lower than that of carboplatin and especially cisplatin. The drugs were mainly distributed in lungs, kidneys, liver, spleen and tumour tissue. PDBA showed quite high accumulation in the tumour tissue, possibly, owing to the effect of the lignin-derived ligand. Copyright © 2016 Elsevier GmbH. All rights reserved.

Efficacy and safety of neoadjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate for T3 or T4 stage II/III rectal cancer: the FACT trial.

PubMed

Koike, Junichi; Funahashi, Kimihiko; Yoshimatsu, Kazuhiko; Yokomizo, Hajime; Kan, Hayato; Yamada, Takeshi; Ishida, Hideyuki; Ishibashi, Keiichiro; Saida, Yoshihisa; Enomoto, Toshiyuki; Katsumata, Kenji; Hisada, Masayuki; Hasegawa, Hirotoshi; Koda, Keiji; Ochiai, Takumi; Sakamoto, Kazuhiro; Shiokawa, Hiroyuki; Ogawa, Shimpei; Itabashi, Michio; Kameoka, Shingo

2017-03-01

A multicenter phase II clinical study was performed in patients with T3 or T4 stage II/III rectal cancer to evaluate the efficacy and safety of neoadjuvant chemotherapy with 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6). Patients received four 2-week cycles of mFOLFOX6 therapy (oxaliplatin at 85 mg/m 2  + leucovorin at 200 mg/m 2  + fluorouracil as a 400 mg/m 2 bolus followed by infusion of 2400 mg/m 2 over 46 h, all on Day 1). They were evaluated by computed tomography after completion of the fourth cycle. If there was no disease progression, two additional cycles were administered and then surgery was performed. Adjuvant chemotherapy was generally administered for 6 months using appropriate regimens at the discretion of the physician. mFOLFOX6 therapy was given to 52 patients with locally advanced rectal cancer. The preoperative response rate was 48.8% and the operation rate was 80.8%. Serious adverse events of Grade 3-4 were neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The R0 resection rate, pathologic complete response rate, and sphincter preservation rate were 91.0, 11.9, and 73.8%, respectively. Postoperative complications were tolerable. The present results suggested that neoadjuvant therapy with mFOLFOX6 is safe and effective, representing a reasonable treatment option for locally advanced rectal cancer.

Testing phase-specific self-efficacy beliefs in the context of dietary behaviour change.

PubMed

Ochsner, Sibylle; Scholz, Urte; Hornung, Rainer

2013-03-01

Self-efficacy is an important predictor of health behaviour change. Within the health action process approach (HAPA; Schwarzer, 2008), motivational and volitional self-efficacy can be distinguished. Motivational self-efficacy is assumed to serve as predictor of intention formation whereas volitional self-efficacy should be relevant for behaviour change. This study examined these assumptions in a sample with overweight and obese individuals. Moreover, we tested whether behavioural intentions moderate the association between volitional self-efficacy and behaviour. Overall, 373 overweight and obese individuals completed a baseline and six months later a follow-up questionnaire on HAPA variables and dietary behaviour. A factor analysis confirmed the phase-specific separation of self-efficacy. Motivational self-efficacy emerged as predictor for behavioural intentions over and above other HAPA variables after six months, whereas volitional self-efficacy did not. Volitional self-efficacy interacted with intention in the prediction of behaviour, indicating that volitional self-efficacy is only beneficial for individuals with high levels of intentions. The results provide evidence for the phase-specific distinction of self-efficacy in the context of dietary change in an overweight or obese sample. Thus, differentiating between motivational and volitional self-efficacy beliefs should be considered when developing future interventions of dietary change. © 2012 The Authors. Applied Psychology: Health and Well-Being © 2012 The International Association of Applied Psychology.

Review of nemonoxacin with special focus on clinical development

PubMed Central

Qin, Xiaohua; Huang, Haihui

2014-01-01

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone with remarkably enhanced in vitro activity against a wide variety of clinically relevant pathogens, especially gram-positive bacteria, including multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. It has a low propensity for selecting resistant pathogens than fluoroquinolones, since bacteria become resistant to nemonoxacin only when three different mutations occur in their quinolone resistance-determining regions. Nemonoxacin shows greater efficacy than most of the widely used fluoroquinolones in the murine model of systemic, pulmonary, or ascending urinary tract infection. Nemonoxacin has a sound PK profile in healthy volunteers. It rapidly reaches maximum concentration Cmax 1–2 hours after oral administration in the fasting state and has a relatively long elimination half-life of more than 10 hours, which is similar to fluoroquinolones. Approximately 60%–75% of the administered dose is excreted in unchanged form via kidneys over 24–72 hours. Phase II and III studies of oral nemonoxacin and Phase II studies of intravenous nemonoxacin have been completed in patients with community-acquired pneumonia (CAP), before which the Phase I studies of oral and intravenous nemonoxacin indicated sound tolerance and safety with healthy volunteers. The published results demonstrate that an oral dose of either 500 mg or 750 mg nemonoxacin once daily for 7 days is as effective and safe as levofloxacin 500 mg once daily for 7 days. Nemonoxacin is well-tolerated in patients with CAP. The most common adverse events of oral administration are observed in the gastrointestinal and nervous system, the incidence of which is similar to levofloxacin treatment. The Phase III studies of intravenous nemonoxacin for treating CAP and oral nemonoxacin for diabetic foot infection has been registered with promising outcomes to be expected. PMID:25045247

Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date.

PubMed

Crotti, Chiara; Raimondo, Maria Gabriella; Becciolini, Andrea; Biggioggero, Martina; Favalli, Ennio Giulio

2017-01-01

The introduction of biological therapies into clinical practice has dramatically modified the natural history of chronic inflammatory diseases, such as rheumatoid arthritis (RA). RA is a systemic autoimmune disease that causes articular damage and has a great negative impact on patients' quality of life. Despite the wide spectrum of available biological treatments, ~30% of RA patients are still unresponsive, resulting in high disability and increased morbidity and mortality. In the last few decades, the scientific knowledge on RA pathogenesis vastly improved, leading to the identification of new proinflammatory molecules as potential therapeutic targets. Several in vitro and in vivo studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), known to be a hematopoietic factor, is also one of the proinflammatory cytokines involved in macrophage activation, crucial for the pathogenic network of RA. Mavrilimumab, a human monoclonal antibody targeting the subunit α of GM-CSF receptor, was recently developed as a competitive antagonist of GM-CSF pathway and successfully adopted in human trials for mild to moderate RA. Mavrilimumab phase I and phase II studies reported an overall good efficacy and safety profile of the drug, and these encouraging results promoted the initiation of worldwide phase III studies. In particular, 158-week results of phase II trials did not show long-term lung toxicity, addressing the major concern about this target of pulmonary alveolar proteinosis development. However, further clinical studies conducted in larger RA populations are needed to confirm these promising results. This review summarizes the biological role of GM-CSF in RA and the preclinical and clinical data on mavrilimumab and other monoclonal antibodies targeted on this pathway as an alternative therapeutic option in RA patients who are unresponsive to conventional biological drugs.

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

PubMed Central

Trippett, Tanya M.; Herzog, Cynthia; Whitlock, James A.; Wolff, Johannes; Kuttesch, John; Bagatell, Rochelle; Hunger, Stephen P.; Boklan, Jessica; Smith, Amy A.; Arceci, Robert J.; Katzenstein, Howard M.; Harbison, Christopher; Zhou, Xiaofei; Lu, Haolan; Langer, Christiane; Weber, Martin; Gore, Lia

2009-01-01

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m2) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m2/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m2 weekly plus irinotecan 16 mg/m2/d (pediatric) or 20 mg/m2/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen. PMID:19770383

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

Vaccination: a novel strategy for inhibiting the renin-angiotensin-aldosterone system.

PubMed

Gradman, Alan H; Pinto, Rehka

2008-12-01

Immunologic approaches to renin-angiotensin-aldosterone system (RAAS) inhibition have been studied for more than 50 years. In animal models, vaccination against renin was effective but resulted in fatal autoimmune renal disease; vaccines directed at small peptides including angiotensin I and II and a segment of the AT(1) receptor reduced blood pressure (BP) without causing autoimmune disease. In humans, angiotensin I vaccination did not reduce BP. More promising is the AngQb vaccine, which uses an immunization technology involving conjugation of angiotensin II to virus-like particles. In a phase 2 trial, hypertensive patients vaccinated with 300 microg showed a difference of 9.0/4.0 mm Hg from baseline in mean daytime ambulatory BP after 14 weeks (P = 0.015 for systolic BP, P = 0.064 for diastolic BP), and a marked reduction in early morning BP. No serious adverse events were attributed to vaccine administration. Although questions remain regarding efficacy and safety, RAAS immunization represents an innovative and promising approach to hypertension treatment.

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs

PubMed Central

Charles-Schoeman, Christina; Burmester, Gerd; Nash, Peter; Zerbini, Cristiano A F; Soma, Koshika; Kwok, Kenneth; Hendrikx, Thijs; Bananis, Eustratios; Fleischmann, Roy

2016-01-01

Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. Trial registration numbers (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385). PMID:26275429

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs.

PubMed

Charles-Schoeman, Christina; Burmester, Gerd; Nash, Peter; Zerbini, Cristiano A F; Soma, Koshika; Kwok, Kenneth; Hendrikx, Thijs; Bananis, Eustratios; Fleischmann, Roy

2016-07-01

Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385). 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/

The efficacy and safety of Baoji Tablets for treating common cold with summer-heat and dampness syndrome: study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background Despite the high incidence and the economic impact of the common cold, there are still no effective therapeutic options available. Although traditional Chinese medicine (TCM) is widely used in China to treat the common cold, there is still a lack of high-quality clinical trials. This article sets forth the protocol for a high-quality trial of a new TCM drug, Baoji Tablets, which is designed to treat the common cold with summer-heat and dampness syndrome (CCSDS). The trial is evaluating both the efficacy and safety of Baoji Tablets. Methods/design This study is designed as a multicenter, phase II, parallel-group, double-blind, double-dummy, randomized and placebo-controlled trial. A total of 288 patients will be recruited from four centers. The new tablets group are administered Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. The old pills group are administered dummy Baoji Tablets 0.9 g and Baoji Pills 3.7 g. The placebo control group are administered dummy Baoji Tablets 0.9 g and dummy Baoji Pills 3.7 g. All drugs are taken three times daily for 3 days. The primary outcome is the duration of all symptoms. Secondary outcomes include the duration of primary and secondary symptoms, changes in primary and secondary symptom scores and cumulative symptom score at day 4, as well as an evaluation of treatment efficacy. Discussion This is the first multicenter, double-blind, double-dummy, randomized and placebo-controlled trial designated to treat CCSDS in an adult population from China. It will establish the basis for a scientific and objective assessment of the efficacy and safety of Baoji Tablets for treating CCSDS, and provide evidence for a phase III clinical trial. Trial registration This study is registered with the Chinese Clinical Trial Registry. The registration number is ChiCTR-TRC-13003197. PMID:24359521

Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or Poor-Risk Germ Cell Tumors

PubMed Central

Hu, James; Dorff, Tanya B.; Lim, Kristina; Patil, Sujata; Woo, Kaitlin M.; Carousso, Maryann; Hughes, Amanda; Sheinfeld, Joel; Bains, Manjit; Daneshmand, Siamak; Ketchens, Charlene; Bajorin, Dean F.; Bosl, George J.; Quinn, David I.; Motzer, Robert J.

2016-01-01

Purpose Paclitaxel, ifosfamide, and cisplatin (TIP) achieved complete responses (CRs) in two thirds of patients with advanced germ cell tumors (GCTs) who relapsed after first-line chemotherapy with cisplatin and etoposide with or without bleomycin. We tested the efficacy of first-line TIP in patients with intermediate- or poor-risk disease. Patients and Methods In this prospective, multicenter, single-arm phase II trial, previously untreated patients with International Germ Cell Cancer Collaborative Group poor-risk or modified intermediate-risk GCTs received four cycles of TIP (paclitaxel 240 mg/m2 over 2 days, ifosfamide 6 g/m2 over 5 days with mesna support, and cisplatin 100 mg/m2 over 5 days) once every 3 weeks with granulocyte colony-stimulating factor support. The primary end point was the CR rate. Results Of the first 41 evaluable patients, 28 (68%) achieved a CR, meeting the primary efficacy end point. After additional accrual on an extension phase, total enrollment was 60 patients, including 40 (67%) with poor risk and 20 (33%) with intermediate risk. Thirty-eight (68%) of 56 evaluable patients achieved a CR and seven (13%) achieved partial responses with negative markers (PR-negative) for a favorable response rate of 80%. Five of seven achieving PR-negative status had seminoma and therefore did not undergo postchemotherapy resection of residual masses. Estimated 3-year progression-free survival and overall survival rates were 72% (poor risk, 63%; intermediate risk, 90%) and 91% (poor risk, 87%; intermediate risk, 100%), respectively. Grade 3 to 4 toxicities consisted primarily of reversible hematologic or electrolyte abnormalities, including neutropenic fever in 18%. Conclusion TIP demonstrated efficacy as first-line therapy for intermediate- and poor-risk GCTs with an acceptable safety profile. Given higher rates of favorable response, progression-free survival, and overall survival compared with prior first-line studies, TIP warrants further study in this population. PMID:27185842

47 CFR 69.727 - Regulatory relief.

Code of Federal Regulations, 2010 CFR

2010-10-01

... customer. (b) Phase II relief. Upon satisfaction of the Phase II triggers specified in §§ 69.709(c) or 69... Pricing Flexibility § 69.727 Regulatory relief. (a) Phase I relief. Upon satisfaction of the Phase I... similarly situated customers; and (ii) The price cap LEC excludes all contract tariff offerings from price...

Ribozyme Targeting the Novel Fusion Junction of EGFRvIII in Breast Cancer

DTIC Science & Technology

2003-07-01

targeting the novel junction of EGFRvyII. * Demonstrate the therapeutic efficacy of an anti-EGFRvIll hammerhead ribozyme targeting the endogenous...first demonstration of the therapeutic efficacy of an anti-EGFRvlII hammerhead ribozyme targeting the endogenous EGFRvAII expression against human...202-687-7505.designed and generated a tumor specific hammerhead ribozyme E-mail: Tangc@georgetown.edu targeted to the novel fusion junction of

Conducting efficacy trials in children with MDR-TB: what is the rationale and how should they be done?

PubMed

Seddon, J A; Weld, E D; Schaaf, H S; Garcia-Prats, A J; Kim, S; Hesseling, A C

2018-05-01

Paediatric anti-tuberculosis treatment trials have traditionally been limited to Phase I/II studies evaluating the drug pharmacokinetics and safety in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly being recognised that, in some circumstances, efficacy trials are required in children. The current treatment for children with multidrug-resistant tuberculosis (MDR-TB) is long and toxic; shorter, safer regimens, using novel agents, require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will be, this presents a unique challenge in children. Recruiting only these children would, however, limit the generalisability of such a trial, as in reality the majority of children with TB do not have bacteriologically confirmed disease. Given the good existing treatment outcomes with current routine regimens for children with MDR-TB, conducting a superiority trial may not be the optimal design. Demonstrating non-inferiority of efficacy, but superiority with regard to safety, would be an alternative strategy. Using standardised control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens would make interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.

Comparison of African American and Caucasian Caregiver Self-Efficacy.

PubMed

Easom, Leisa; Cotter, Ellen; Ramos, Angel

2018-03-01

Self-efficacy influences one's behavior and can determine the degree to which one is motivated to take action. The current study explores changes in caregiver self-efficacy pre- and post-participation in a Resources for Enhancing Alzheimer's Caregiver Health (REACH II) program, a multi-component intervention aimed at caregivers of individuals with Alzheimer's disease. The study specifically compared this construct in African American and Caucasian populations, which may give indications of how to empower dementia caregivers and whether REACH II is culturally sensitive and thus, an important component to examine. Nurses are the connection between families and community resources and must serve as referral sources to programs that work. Although African American and Caucasian caregivers showed comparable rates of increase in self-efficacy, African American caregivers started and ended at higher rates of self-efficacy for obtaining respite and overall self-efficacy. Applications of the results and directions for future research are discussed. [Journal of Gerontological Nursing, 44(3), 16-21.]. Copyright 2018, SLACK Incorporated.

47 CFR 90.769 - Construction and implementation of Phase II nationwide licenses.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Use of Frequencies in the 220-222 MHz Band Policies Governing the Licensing and Use of Phase II Ea, Regional and Nationwide Systems § 90.769 Construction and implementation of Phase II nationwide licenses...

Efficacy of the organic-certified insecticide Diatect II against the boll weevil (Anthonomus grandis) in cotton.

PubMed

Sappington, Thomas W

2002-10-01

The efficacy of the organic insecticide Diatect II against boll weevil (Anthonomus grandis Boheman) in cotton (Gossypium hirsutum L) in the Lower Rio Grande Valley of Texas were assessed in small-plot field trials and greenhouse cage tests using azinphos-methyl treatments as a standard for comparison. Plastic sheets were placed in the furrows of the treated plots to retrieve boll weevils which dropped from the plants after being killed by the insecticides. Samples of live weevils taken by a tractor-mounted vacuum sampler revealed a modest, but significant, reduction in boll weevil populations in Diatect II plots. However, samples of dead weevils indicated that this reduction was due to movement of weevils out of the plots rather than to mortality. This interpretation is supported by greenhouse cage studies, where mortality in Diatect II treated cages was no greater than that in untreated control cages. The effects of insecticide treatments in small plots can be confounded easily and quickly by interplot movement of target insects. Although the relative effects of various compounds can usually be assessed by sampling the populations in plots soon after treatment, the best measure of efficacy is obtained by directly sampling insects that have died in the plot. This parameter is insulated from the effects of interplot movement, unless the toxicant is slow to immobilize the target insect. Taken together, our results indicate little efficacy by Diatect II against boll weevil under our test conditions.

Barriers to participation in a phase II cardiac rehabilitation programme.

PubMed

Mak, Y M W; Chan, W K; Yue, C S S

2005-12-01

To identify barriers to participation in a phase II cardiac rehabilitation programme and measures that may enhance participation. Prospective study. Regional hospital, Hong Kong. Cardiac patients recruited for a phase I cardiac rehabilitation programme from July 2002 to January 2003. Reasons for not participating in a phase II cardiac rehabilitation programme. Of the 193 patients recruited for a phase I cardiac rehabilitation programme, 152 (79%) patients, with a mean age of 70.3 years (standard deviation, 11.9 years), did not proceed to phase II programme. Eleven (7%) deaths occurred before commencement of phase II and 74 (49%) patients were considered physically unfit. Reasons for the latter included fractures, pain, or degenerative changes in the lower limbs (24%), and co-morbidities such as cerebrovascular accident (19%), chronic renal failure (11%), congestive heart failure (9%), and unstable angina (8%). Phase II rehabilitation was postponed until after completion of scheduled cardiac interventions in 13% of patients. Failure of physicians to arrange the pre-phase II exercise stress test as per protocol was reported in 7% of patients. Other reasons were reported: work or time conflicts (16%), non-compliance with cardiac treatment (5%), financial constraints (4%), self-exercise (3%), fear after exercise stress testing (3%), and patients returning to their original cardiologists for treatment (3%). A significant (79%) proportion of patients did not proceed to a phase II cardiac rehabilitation programme for a variety of reasons. These included physical unfitness, work or time conflicts, and need to attend scheduled cardiac interventions. Further studies are required to determine how to overcome obstacles to cardiac rehabilitation.

Efficacy and safety of collagenase clostridium histolyticum in the treatment of proximal interphalangeal joints in dupuytren contracture: combined analysis of 4 phase 3 clinical trials.

PubMed

Badalamente, Marie A; Hurst, Lawrence C; Benhaim, Prosper; Cohen, Brian M

2015-05-01

To examine the results of proximal interphalangeal (PIP) joint contractures from 4 phase 3 clinical trials of collagenase clostridium histolyticum (CCH) injection for Dupuytren contracture. Patients enrolled in Collagenase Option for Reduction of Dupuytren I/II and JOINT I/II with one or more PIP joint contractures (20° to 80°) received CCH 0.58 mg/0.20 mL or placebo (Collagenase Option for Reduction of Dupuytren I/II only) injected directly into a palpable cord. The percentage of PIP joints achieving clinical success (0° to 5° of full extension), clinical improvement (50% or more reduction in baseline contracture), and range of motion improvement at 30 days after the first and last CCH injections was assessed. The PIP joint contractures were classified into low (40° or less) and high (more than 40°) baseline severity. Adverse events were recorded. A total of 506 adults (mean age, 63 ± 10 y; 80% male) received 1,165 CCH injections in 644 PIP joint cords (mean, 1.6 injections/cord). Most patients (60%) received 1 injection, with 24%, 16%, and 1% receiving 2, 3, and 4 injections, respectively. Clinical success and clinical improvement occurred in 27% and 49% of PIP joints after one injection and in 34% and 58% after the last injection. Patients with lower baseline severity showed greater improvement and response was comparable between fingers, as were improvements in range of motion. Adverse events occurring in more than 10% of patients were peripheral edema (58%), contusion (38%), injection site hemorrhage (23%), injection site pain (21%), injection site swelling (16%), and tenderness (13%). This incidence was consistent with data reported in phase 3 trials. Two tendon ruptures occurred. No further ruptures occurred after a modified injection technique was adopted. Collagenase clostridium histolyticum was effective and well tolerated in the short term in patients with Dupuytren PIP joint contractures. Therapeutic II. Copyright © 2015 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF).

PubMed

Pang, Peter S; Butler, Javed; Collins, Sean P; Cotter, Gad; Davison, Beth A; Ezekowitz, Justin A; Filippatos, Gerasimos; Levy, Phillip D; Metra, Marco; Ponikowski, Piotr; Teerlink, John R; Voors, Adriaan A; Bharucha, David; Goin, Kathleen; Soergel, David G; Felker, G Michael

2017-08-07

Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

NLX-P101, an adeno-associated virus gene therapy encoding glutamic acid decarboxylase, for the potential treatment of Parkinson's disease.

PubMed

Diaz-Nido, Javier

2010-07-01

Parkinson's disease (PD) is a neurodegenerative disease affecting nigrostriatal dopaminergic neurons. Dopamine depletion in the striatum leads to functional changes in several deep brain nuclei, including the subthalamic nucleus (STN), which becomes disinhibited and perturbs the control of body movement. Although there is no cure for PD, some pharmacological and surgical treatments can significantly improve the functional ability of patients, particularly in the early stages of the disease. Among neurodegenerative diseases, PD is a particularly suitable target for gene therapy because the neuropathology is largely confined to a relatively small region of the brain. Neurologix Inc is developing NLX-P101 (AAV2-GAD), an adeno-associated viral vector encoding glutamic acid decarboxylase (GAD), for the potential therapy of PD. As GAD potentiates inhibitory neurotransmission from the STN, sustained expression of GAD in the STN by direct delivery of NLX-P101 decreases STN overactivation. This procedure was demonstrated to be a safe and efficient method of reducing motor deficits in animal models of PD. A phase I clinical trial has demonstrated that NLX-P101 was safe and indicated the efficacy of this approach in patients with PD. Results from an ongoing phase II clinical trial of NLX-P101 are awaited to establish the clinical efficacy of this gene therapy.

A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension.

PubMed

Rakugi, Hiromi; Shimizu, Kohei; Nishiyama, Yuya; Sano, Yuhei; Umeda, Yuusuke

2018-06-01

Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long-term safety and BP (office and home), respectively. Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension.

A randomized, double-blind, crossover, placebo-controlled comparative clinical trial of arginine aspartate plus adenosine monophosphate for the intermittent treatment of male erectile dysfunction.

PubMed

Neuzillet, Y; Hupertan, V; Cour, F; Botto, H; Lebret, T

2013-03-01

Efficacy and safety of l-arginine aspartate 8 g combined with 200 mg of adenosine monophosphate (AA) with placebo (PL) alone for intermittent treatment of mild-to-moderate erectile dysfunction (ED) were compared. The study design was a double-blind, PL-controlled, two-way crossover randomized clinical trial with 26 patients. Efficacy was assessed by International Index of Erectile Function (IIEF) and two additional validated questionnaires [the Erection Hardness Score (EHS) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). During each crossover period, separated by a 2-week wash-out period, drugs were administered orally, 1-2 h before sexual intercourse. Primary endpoint was a change in the IIEF. Secondary endpoints were patient and investigator assessments of treatment success. Investigators' and patients' assessment of efficacy was significantly improved by the combination vs. PL (p = 0.01 and p = 0.04 respectively]. EHS and EDITS questionnaires were both improved by the combination (p = 0.015 and p = 0.017 respectively). There was no significant difference in terms of tolerance between AA and PL or severe adverse events. ED patients demonstrated significant improvements in all IIEF domains with the exception of the Sexual Desire and Orgasmic Domains when treated with AA compared with PL. This pilot phase II study showed that the on-demand oral administration at a high dosage of l-arginine aspartate-adenosine monophosphate combination may be effective in patients with mild-to-moderate ED, is very well tolerated and could be tested as a safe first-line therapy in a larger size phase III study. © 2012 American Society of Andrology and European Academy of Andrology.

FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study.

PubMed

Tedesco-Silva, Helio; Szakaly, Peter; Shoker, Ahmed; Sommerer, Claudia; Yoshimura, Norio; Schena, Francesco Paolo; Cremer, Malika; Hmissi, Abdel; Mayer, Hartmut; Lang, Philippe

2007-10-15

FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC). This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone. The primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. The primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P=NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2: 51.7 ml/min, P=0.039 vs. Group 3: 62.5 ml/min). Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.

Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

PubMed

Mahalingam, Devalingam; Mita, Monica; Sarantopoulos, John; Wood, Leslie; Amaravadi, Ravi K; Davis, Lisa E; Mita, Alain C; Curiel, Tyler J; Espitia, Claudia M; Nawrocki, Steffan T; Giles, Francis J; Carew, Jennifer S

2014-08-01

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

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

Miyazaki, Masaya, E-mail: mmiyazak@gunma-u.ac.jp; Arai, Yasuaki; Myoui, Akira

PurposeThis multicenter prospective study was conducted to evaluate the safety and efficacy of percutaneous radiofrequency ablation (RFA) for painful osteoid osteoma (OO).Materials and MethodsPatients with OO (femur: n = 17, tibia: n = 2, humerus: n = 1, rib: n = 1) were enrolled and treated with RFA. In phase I, nine patients were evaluated for safety. In phase II, 12 patients were accrued, and an intent-to-treat analysis was performed on all patients. The primary endpoint was to evaluate the treatment safety. The secondary endpoint was to evaluate the efficacy for pain relief by the visual analogue scale (VAS) at 4 weeks after RFA. Treatment efficacy was classified as significantlymore » effective (SE) when VAS score decreased by ≥5 or score was <2, moderately effective when VAS score decreased by <5–≥2 and score was ≥2, and not effective (NE) when VAS score decreased by <2 or score was increased. Cases where the need for analgesics increased after treatment were also NE.ResultsRFA procedures were completed in all patients. Minor adverse effects (AEs) were observed as 4.8–14.3 % in 12 patients, and no major AEs were observed. Mean VAS score was 7.1 before treatment, 1.6 at 1 week, 0.3 at 4 weeks, and 0.2 at 3 months. All procedures were classified as SE. Pain recurrence was not noted in any patient during follow-up (mean: 15.1 months).ConclusionRFA is a safe, highly effective, and fast-acting treatment for painful extraspinal OO. Future studies with a greater number of patients are needed.« less

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.

PubMed

Duran, Marta; Pérez, Eulàlia; Abanades, Sergio; Vidal, Xavier; Saura, Cristina; Majem, Margarita; Arriola, Edurne; Rabanal, Manel; Pastor, Antoni; Farré, Magí; Rams, Neus; Laporte, Joan-Ramon; Capellà, Dolors

2010-11-01

Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV. Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response. Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups. Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial. © 2010 Department of Health, Generalitat of Catalonia. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

Sundstrand’s Precision Metal Forming Cell. Industrial Modernization Incentive Program (IMIP). Phase 2

DTIC Science & Technology

1991-03-01

1-2 1.4 CONCLUSIONS AND RECOMMENDATIONS ....................... 1-2 20. PHASE II MANAGEMENT PLAN...2-1 2.1 PROGRAM MANAGEMENT ................................... 2-1 2.2 IM IP TEAM...Barbier, reference Section 2.0 (Phase II Management Plan), is complete and this report provides the results of the Phase II study. 1.2 OBJECTIVES The

What Works in Oklahoma Schools: A Comprehensive Needs Assessment of Oklahoma Schools. Phase II State Report

ERIC Educational Resources Information Center

Marzano Research Laboratory, 2010

2010-01-01

Phase II provides a more detailed examination of classroom variables important to achievement in Oklahoma schools. Where Phase I addressed all nine of the Oklahoma essential elements using survey data, Phase II focuses on what occurs in Oklahoma classrooms primarily using data from principal interviews, classroom observations (on-site), and video…

Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.

PubMed

Karoui, Mehdi; Rullier, Anne; Luciani, Alain; Bonnetain, Franck; Auriault, Marie-Luce; Sarran, Antony; Monges, Geneviève; Trillaud, Hervé; Le Malicot, Karine; Leroy, Karen; Sobhani, Iradj; Bardier, Armelle; Moreau, Marie; Brindel, Isabelle; Seitz, Jean François; Taieb, Julien

2015-07-10

In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery. PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial. NCT01675999 (ClinicalTrials.gov).

Biweekly cetuximab in combination with FOLFOX-4 in the first-line treatment of wild-type KRAS metastatic colorectal cancer: final results of a phase II, open-label, clinical trial (OPTIMIX-ACROSS Study).

PubMed

Fernandez-Plana, Julen; Pericay, Carlos; Quintero, Guillermo; Alonso, Vicente; Salud, Antonieta; Mendez, Miguel; Salgado, Mercedes; Saigi, Eugeni; Cirera, Luis

2014-11-22

This phase II study aims to evaluate the efficacy and safety of biweekly cetuximab in combination with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) as first-line treatment of metastatic wild-type KRAS colorectal cancer. Previously untreated patients with wild-type KRAS tumours received biweekly cetuximab (500 mg/m2 on day 1) plus FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on days 1 and 2, and fluorouracil as a 400 mg/m2 bolus followed by a 22-hour 600 mg/m2 infusion on day 1 and 2). Treatment was continued until disease progression, onset of unacceptable toxicities, metastases surgery, or discontinuation request. The primary endpoint was ORR. The intention-to-treat population included 99 patients with a median age of 64.1 years (range, 34-82). The ORR was 60.6% (95% CI, 50.3% to 70.3%). The median follow-up was 17.8 months; the median OS and PFS were 20.8 and 10.1 months, respectively. Metastases from colorectal cancer were surgically resected in 26 (26.3%) patients, with complete resection achieved in 18 (69.2%) patients. Median PFS and OS in patients undergoing metastatic resection were 12.6 and 29.5 months, respectively. The most common grade 3-4 toxicities were neutropenia (32.3%), acne-like rash (15.2%) and diarrhoea (11.1%). The efficacy of the biweekly combination of cetuximab with FOLFOX-4 in patients with wild-type KRAS tumours supports the administration of cetuximab in a dosing regimen more convenient for patients and healthcare providers. The activity of the biweekly administration is similar to what has been reported for the weekly regimen. Reported toxicity was also consistent with the known toxicity profile of weekly cetuximab. EudraCT Number 200800690916.

Use of penile extender device in the treatment of penile curvature as a result of Peyronie's disease. Results of a phase II prospective study.

PubMed

Gontero, Paolo; Di Marco, Massimiliano; Giubilei, Gianluca; Bartoletti, Riccardo; Pappagallo, Giovanni; Tizzani, Alessandro; Mondaini, Nicola

2009-02-01

Pilot experiences have suggested that tension forces exerted by a penile extender may reduce penile curvature as a result of Peyronie's disease. To test this hypothesis in a Phase II study using a commonly marketed brand of penile extender. Peyronie's disease patients with a curvature not exceeding 50 degrees with mild or no erectile dysfunction (ED) were eligible. Fifteen patients were required to test the efficacy of the device assuming an effect size of >0.8, consistent with an "important" reduction in penile curvature. Changes in penile length over baseline and erectile function (EF) domain scores of the International Index of Erectile Function (IIEF) constituted secondary end points. Patients were counselled on the use of the penile extender for at least 5 hours per day for 6 months. Photographic pictures of the erect penis and measurements were carried out at baseline, at 1, 3, 6, and 12 months (end of study). The IIEF-EF domain scores were administered at baseline and at the end of study. Treatment satisfaction was assessed at end of study using a nonvalidated institutional 5-item questionnaire. Penile curvature decreased from an average of 31 degrees to 27 degrees at 6 months without reaching the effect size (P = 0.056). Mean stretched and flaccid penile length increased by 1.3 and 0.83 cm, respectively at 6 months. Results were maintained at 12 months. Overall treatment results were subjectively scored as acceptable in spite of curvature improvements, which varied from "no change" to "mild improvement." In our study, the use of a penile extender device provided only minimal improvements in penile curvature but a reasonable level of patient satisfaction, probably attributable to increased penile length. The selection of patients with a stabilized disease, a penile curvature not exceeding 50 degrees, and no severe ED may have led to outcomes underestimating the potential efficacy of the treatment.

Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer.

PubMed

Yokota, Tomoya; Kato, Ken; Hamamoto, Yasuo; Tsubosa, Yasuhiro; Ogawa, Hirofumi; Ito, Yoshinori; Hara, Hiroki; Ura, Takashi; Kojima, Takashi; Chin, Keisho; Hironaka, Shuichi; Kii, Takayuki; Kojima, Yasushi; Akutsu, Yasunori; Matsushita, Hisayuki; Kawakami, Kentaro; Mori, Keita; Nagai, Yushi; Asami, Chika; Kitagawa, Yuko

2016-11-22

The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30-40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer

PubMed Central

Yokota, Tomoya; Kato, Ken; Hamamoto, Yasuo; Tsubosa, Yasuhiro; Ogawa, Hirofumi; Ito, Yoshinori; Hara, Hiroki; Ura, Takashi; Kojima, Takashi; Chin, Keisho; Hironaka, Shuichi; Kii, Takayuki; Kojima, Yasushi; Akutsu, Yasunori; Matsushita, Hisayuki; Kawakami, Kentaro; Mori, Keita; Nagai, Yushi; Asami, Chika; Kitagawa, Yuko

2016-01-01

Background: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. Methods: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30–40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). Results: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. Conclusions: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus. PMID:27811857

Nemolizumab in moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study.

PubMed

Kabashima, Kenji; Furue, Masutaka; Hanifin, Jon M; Pulka, Grazyna; Wollenberg, Andreas; Galus, Ryszard; Etoh, Takafumi; Mihara, Ryosuke; Nakano, Miwa; Ruzicka, Thomas

2018-05-09

Nemolizumab, an anti-interleukin-31 receptor A monoclonal antibody, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (Part A) (NCT01986933). To assess long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week double-blind extension (Part B). During Part B, patients continued previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B endpoints included percentage improvement from baseline in pruritus visual analogue scale (VAS) and dermatitis scores (including Eczema Area and Severity Index [EASI]). Overall, 216/264 patients completed Part A and 191 entered Part B; 131 completed Part B. In 153 patients randomized to nemolizumab in Part A, improvement from baseline in pruritus VAS was maintained/increased from Week 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at Week 64: -73.0, -89.6, -74.7, and -79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to Week 64 (percent change in EASI score: -68.5, -75.8, -78.9, and -69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83-89% had ≥1 adverse event, with no new safety concerns identified. Nemolizumab for up to 64 weeks was efficacious and, overall, well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy. Copyright © 2018. Published by Elsevier Inc.

Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebo-controlled, phase II study.

PubMed

Seino, Yutaka; Sasaki, Takashi; Fukatsu, Atsushi; Sakai, Soichi; Samukawa, Yoshishige

2014-07-01

Luseogliflozin is a novel sodium glucose cotransporter 2 inhibitor for type 2 diabetes mellitus (T2DM) treatment. An exploratory Phase II study was conducted to assess the efficacy and safety of several doses of luseogliflozin in Japanese T2DM patients. Japanese T2DM patients aged 20-74 years with hemoglobin A1c (HbA1c) of 6.9-10.5%, fasting plasma glucose (FPG) ≥126 mg/dL and on diet therapy were randomized in a double-blind manner to receive luseogliflozin (0.5, 2.5, or 5 mg) or placebo once daily for 12 weeks (n = 61, 61, 61, and 56, respectively). The primary endpoint was the change in HbA1c from baseline to end of treatment. Other endpoints included FPG, 2 h postprandial plasma glucose (PPG) in a meal tolerance test (MTT), and body weight. Drug safety was also assessed. Japan Pharmaceutical Information Center (identifier: JapicCTI-090908). Changes in HbA1c from baseline to end of treatment were -0.36, -0.62, and -0.75% in the 0.5, 2.5, and 5 mg luseogliflozin groups, respectively, versus +0.06% in the placebo group (all P < 0.001). The reductions in FPG and 2 h-PPG in the MTT were also significantly greater in the luseogliflozin groups (all P < 0.01) without increases in insulin levels from baseline. Luseogliflozin reduced body weight at all doses. There were no significant differences in the incidences of adverse events among groups. Most adverse events were mild in severity. There were no serious adverse events. Although this was a small-scale study with a short duration, all tested doses of luseogliflozin significantly improved glycemic control, reduced body weight, and were well tolerated in Japanese T2DM patients over the 12-week treatment period.

Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.

PubMed

Rini, B I; Melichar, B; Fishman, M N; Oya, M; Pithavala, Y K; Chen, Y; Bair, A H; Grünwald, V

2015-07-01

In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor. © 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.

Efficacy and Safety of Low-Dose-Rate Endorectal Brachytherapy as a Boost to Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Distal Rectal Cancer: A Phase-II Clinical Trial

PubMed Central

Omidvari, Shapour; Zohourinia, Shadi; Ansari, Mansour; Ghahramani, Leila; Zare-Bandamiri, Mohammad; Mosalaei, Ahmad; Ahmadloo, Niloofar; Pourahmad, Saeedeh; Nasrolahi, Hamid; Hamedi, Sayed Hasan

2015-01-01

Purpose Despite advances in rectal cancer treatment over the last decade, local control and risk of late side effects due to external beam radiation therapy (EBRT) remain as concerns. The present study aimed to investigate the efficacy and the safety of low-dose-rate endorectal brachytherapy (LDRBT) as a boost to neoadjuvant chemoradiation for use in treating locally advanced distal rectal adenocarcinomas. Methods This phase-II clinical trial included 34 patients (as the study arm) with newly diagnosed, locally advanced (clinical T3-T4 and/or N1/N2, M0) lower rectal cancer. For comparative analysis, 102 matched patients (as the historical control arm) with rectal cancer were also selected. All the patients were treated with LDRBT (15 Gy in 3 fractions) and concurrent chemoradiation (45-50.4 Gy). Concurrent chemotherapy consisted of oxaliplatin 130 mg/m2 intravenously on day 1 plus oral capecitabine 825 mg/m2 twice daily during LDRBT and EBRT. Results The study results revealed a significant differences between the study arm and the control arm in terms in the pathologic tumor size (2.1 cm vs. 3.6 cm, P = 0.001), the pathologic tumor stage (35% T3-4 vs. 65% T3-4, P = 0.003), and the pathologic complete response (29.4% vs. 11.7%, P < 0.028). Moreover, a significantly higher dose of EBRT (P = 0.041) was found in the control arm, and a longer time to surgery was observed in the study arm (P < 0.001). The higher rate of treatment-related toxicities, such as mild proctitis and anemia, in the study arm was tolerable and easily manageable. Conclusion A boost of LDRBT can optimize the pathologic complete response, with acceptable toxicities, in patients with distal rectal cancer. PMID:26361613

Efficacy and Safety of Low-Dose-Rate Endorectal Brachytherapy as a Boost to Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Distal Rectal Cancer: A Phase-II Clinical Trial.

PubMed

Omidvari, Shapour; Zohourinia, Shadi; Ansari, Mansour; Ghahramani, Leila; Zare-Bandamiri, Mohammad; Mosalaei, Ahmad; Ahmadloo, Niloofar; Pourahmad, Saeedeh; Nasrolahi, Hamid; Hamedi, Sayed Hasan; Mohammadianpanah, Mohammad

2015-08-01

Despite advances in rectal cancer treatment over the last decade, local control and risk of late side effects due to external beam radiation therapy (EBRT) remain as concerns. The present study aimed to investigate the efficacy and the safety of low-dose-rate endorectal brachytherapy (LDRBT) as a boost to neoadjuvant chemoradiation for use in treating locally advanced distal rectal adenocarcinomas. This phase-II clinical trial included 34 patients (as the study arm) with newly diagnosed, locally advanced (clinical T3-T4 and/or N1/N2, M0) lower rectal cancer. For comparative analysis, 102 matched patients (as the historical control arm) with rectal cancer were also selected. All the patients were treated with LDRBT (15 Gy in 3 fractions) and concurrent chemoradiation (45-50.4 Gy). Concurrent chemotherapy consisted of oxaliplatin 130 mg/m(2) intravenously on day 1 plus oral capecitabine 825 mg/m(2) twice daily during LDRBT and EBRT. The study results revealed a significant differences between the study arm and the control arm in terms in the pathologic tumor size (2.1 cm vs. 3.6 cm, P = 0.001), the pathologic tumor stage (35% T3-4 vs. 65% T3-4, P = 0.003), and the pathologic complete response (29.4% vs. 11.7%, P < 0.028). Moreover, a significantly higher dose of EBRT (P = 0.041) was found in the control arm, and a longer time to surgery was observed in the study arm (P < 0.001). The higher rate of treatment-related toxicities, such as mild proctitis and anemia, in the study arm was tolerable and easily manageable. A boost of LDRBT can optimize the pathologic complete response, with acceptable toxicities, in patients with distal rectal cancer.

Efficacy of gamification-based smartphone application for weight loss in overweight and obese adolescents: study protocol for a phase II randomized controlled trial

PubMed Central

Timpel, Patrick; Cesena, Fernando Henpin Yue; da Silva Costa, Christiane; Soldatelli, Matheus Dorigatti; Gois, Emanuel; Castrillon, Eduardo; Díaz, Lina Johana Jaime; Repetto, Gabriela M.; Hagos, Fanah; Castillo Yermenos, Raul E.; Pacheco-Barrios, Kevin; Musallam, Wafaa; Braid, Zilda; Khidir, Nesreen; Romo Guardado, Marcela; Roepke, Roberta Muriel Longo

2018-01-01

Background: Overweight and obesity are significant public health concerns that are prevalent in younger age cohorts. Preventive or therapeutic interventions are difficult to implement and maintain over time. On the other hand, the majority of adolescents in the United States have a smartphone, representing a huge potential for innovative digitized interventions, such as weight loss programs delivered via smartphone applications. Although the number of available smartphone applications is increasing, evidence for their effectiveness in weight loss is insufficient. Therefore, the proposed study aims to assess the efficacy of a gamification-based smartphone application for weight loss in overweight and obese adolescents. The trial is designed to be a phase II, single-centre, two-arm, triple-blinded, randomized controlled trial (RCT) with a duration of 6 months. Method: The intervention consists of a smartphone application that provides both tracking and gamification elements, while the control arm consists of an identically designed application solely with tracking features of health information. The proposed trial will be conducted in an urban primary care clinic of an academic centre in the United States of America, with expertise in the management of overweight and obese adolescents. Eligible adolescents will be followed for 6 months. Changes in body mass index z score from baseline to 6 months will be the primary outcome. Secondary objectives will explore the effects of the gamification-based application on adherence, as well as anthropometric, metabolic and behavioural changes. A required sample size of 108 participants (54 participants per group) was calculated. Discussion: The benefits of the proposed study include mid-term effects in weight reduction for overweight and obese adolescents. The current proposal will contribute to fill a gap in the literature on the mid-term effects of gamification-based interventions to control weight in adolescents. This trial is a well-designed RCT that is in line with the Consolidated Standards of Reporting Trials statement. PMID:29854386

Efficacy of gamification-based smartphone application for weight loss in overweight and obese adolescents: study protocol for a phase II randomized controlled trial.

PubMed

Timpel, Patrick; Cesena, Fernando Henpin Yue; da Silva Costa, Christiane; Soldatelli, Matheus Dorigatti; Gois, Emanuel; Castrillon, Eduardo; Díaz, Lina Johana Jaime; Repetto, Gabriela M; Hagos, Fanah; Castillo Yermenos, Raul E; Pacheco-Barrios, Kevin; Musallam, Wafaa; Braid, Zilda; Khidir, Nesreen; Romo Guardado, Marcela; Roepke, Roberta Muriel Longo

2018-06-01

Overweight and obesity are significant public health concerns that are prevalent in younger age cohorts. Preventive or therapeutic interventions are difficult to implement and maintain over time. On the other hand, the majority of adolescents in the United States have a smartphone, representing a huge potential for innovative digitized interventions, such as weight loss programs delivered via smartphone applications. Although the number of available smartphone applications is increasing, evidence for their effectiveness in weight loss is insufficient. Therefore, the proposed study aims to assess the efficacy of a gamification-based smartphone application for weight loss in overweight and obese adolescents. The trial is designed to be a phase II, single-centre, two-arm, triple-blinded, randomized controlled trial (RCT) with a duration of 6 months. The intervention consists of a smartphone application that provides both tracking and gamification elements, while the control arm consists of an identically designed application solely with tracking features of health information. The proposed trial will be conducted in an urban primary care clinic of an academic centre in the United States of America, with expertise in the management of overweight and obese adolescents. Eligible adolescents will be followed for 6 months. Changes in body mass index z score from baseline to 6 months will be the primary outcome. Secondary objectives will explore the effects of the gamification-based application on adherence, as well as anthropometric, metabolic and behavioural changes. A required sample size of 108 participants (54 participants per group) was calculated. The benefits of the proposed study include mid-term effects in weight reduction for overweight and obese adolescents. The current proposal will contribute to fill a gap in the literature on the mid-term effects of gamification-based interventions to control weight in adolescents. This trial is a well-designed RCT that is in line with the Consolidated Standards of Reporting Trials statement.