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Sample records for deutschoesterreichischen phase ii-studie

  1. Final Report on Phase II; Study of Academic Library Consortia.

    ERIC Educational Resources Information Center

    Cuadra, Carlos A.; And Others

    Phase II involves a case-study analysis of 15 selected consortia to help determine the usefulness and effectiveness of academic library consortia. The two major products resulting from the project are the "Directory of Academic Library Consortia" and the "Guidelines for the Development of Academic Library Consortia." The Phase II report presents…

  2. Mercury Phase II Study - Mercury Behavior in Salt Processing Flowsheet

    SciTech Connect

    Jain, V.; Shah, H.; Bannochie, C. J.; Wilmarth, W. R.

    2016-07-25

    Mercury (Hg) in the Savannah River Site Liquid Waste System (LWS) originated from decades of canyon processing where it was used as a catalyst for dissolving the aluminum cladding of reactor fuel. Approximately 60 metric tons of mercury is currently present throughout the LWS. Mercury has long been a consideration in the LWS, from both hazard and processing perspectives. In February 2015, a Mercury Program Team was established at the request of the Department of Energy to develop a comprehensive action plan for long-term management and removal of mercury. Evaluation was focused in two Phases. Phase I activities assessed the Liquid Waste inventory and chemical processing behavior using a system-by-system review methodology, and determined the speciation of the different mercury forms (Hg+, Hg++, elemental Hg, organomercury, and soluble versus insoluble mercury) within the LWS. Phase II activities are building on the Phase I activities, and results of the LWS flowsheet evaluations will be summarized in three reports: Mercury Behavior in the Salt Processing Flowsheet (i.e. this report); Mercury Behavior in the Defense Waste Processing Facility (DWPF) Flowsheet; and Mercury behavior in the Tank Farm Flowsheet (Evaporator Operations). The evaluation of the mercury behavior in the salt processing flowsheet indicates, inter alia, the following: (1) In the assembled Salt Batches 7, 8 and 9 in Tank 21, the total mercury is mostly soluble with methylmercury (MHg) contributing over 50% of the total mercury. Based on the analyses of samples from 2H Evaporator feed and drop tanks (Tanks 38/43), the source of MHg in Salt Batches 7, 8 and 9 can be attributed to the 2H evaporator concentrate used in assembling the salt batches. The 2H Evaporator is used to evaporate DWPF recycle water. (2) Comparison of data between Tank 21/49, Salt Solution Feed Tank (SSFT), Decontaminated Salt Solution Hold Tank (DSSHT), and Tank 50 samples suggests that the total mercury as well as speciated

  3. A phase II study of axitinib in advanced neuroendocrine tumors

    PubMed Central

    Strosberg, J R; Cives, M; Hwang, J; Weber, T; Nickerson, M; Atreya, C E; Venook, A; Kelley, R K; Valone, T; Morse, B; Coppola, D; Bergsland, E K

    2016-01-01

    Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5 mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29 months, we observed a median PFS of 26.7 months (95% CI, 11.4–35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4–45.3), and the median TTF was 9.6 months (95% CI, 5.5–12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients. PMID:27080472

  4. Phase I-II study of isotopic immunoglobulin therapy for primary liver cancer

    SciTech Connect

    Ettinger, D.S.; Order, S.E.; Wharam, M.D.; Parker, M.K.; Klein, J.L.; Leichner, P.K.

    1982-02-01

    A phase I-II study of isotopic immunoglobulin therapy was performed in 18 patients with primary liver cancer; 14 were evaluable for toxicity. The patients received a dose of 37-157 millicuries of 131I-labeled antibody. The dose-limiting factor appears to be hematologic toxicity, especially thrombocytopenia. An objective antitumor effect was seen in six of nine patients who were evaluable for response. Present results suggest that further clinical studies with isotopic immunoglobulin are indicated.

  5. Designing phase II studies in cancer with time-to-event endpoints.

    PubMed

    Owzar, Kouros; Jung, Sin-Ho

    2008-01-01

    The primary clinical endpoint in many phase II studies in cancer is a time-to-event outcome subject to potential censoring. The decision in favor of abandoning or continuing investigation of the protocol regimen is typically based on the amount of statistical evidence suggesting an improvement compared to a given historical control. The primary statistical endpoint would typically be the median of the time-to-event distribution of the clinical endpoint. For the purpose of sample size or power calculations, software implementing parametric and nonparametric median tests, is freely available. The main assumptions are those of Exponential survival and a Uniform right-censoring mechanism. The performance of the parametric and nonparametric methods is compared to that of using a binomial endpoint based on dichotomizing the event time at a clinically relevant landmark. As sufficient details on the various methods and related designs for phase II clinical design with survival endpoints are provided, this article should also serve as a comparative reference on these three methods for designing phase II studies in cancer with time-to-event endpoints. The statistical performance, by virtue of considering the type I and II error rates, of the three methods is compared by carrying out a comprehensive simulation study. The parametric method may fail to control the type I error rate if the underlying survival distribution is not Exponential, while the nonparametric method may fail to control the type I error rate as the sample sizes for phase II studies are typically small. Both of these methods may be sensitive to the distribution of the censoring variable. The results provided in this article are mostly discussed in the framework of specific examples and by using specific implementations of the tests. As such the results may not be universally generalizable. The recommended method has some drawbacks if patients are censored before the landmark of interest. A method that should

  6. [Phase II study of decarbazine (DTIC) in malignant melanoma. DTIC Research Group].

    PubMed

    Ishihara, K

    1986-05-01

    A phase II study of DTIC was carried out with a response rate (CR and PR) of 24.2%. Metastases to liver, lymph nodes and subcutaneous tissues were susceptible to the drug. Most of the adverse reactions observed were upper gastrointestinal symptoms such as nausea in 15.4%, vomiting in 5.8% and anorexia in 3.8%. Alterations in white blood cells, red blood cells or platelets exceeding Grade 2 were not observed. As for biochemistry, GOT was increased in 25.0% and GPT in 28.2%. However, these were mild and transient changes, disappearing in 3 to 4 weeks. The results seem to reproduce those of various U.S. group studies.

  7. Phase II study of bevacizumab and preoperative chemoradiation for esophageal adenocarcinoma

    PubMed Central

    Bains, Manjit S.; Park, Do Joong; Janjigian, Yelena Y.; Rusch, Valerie W.; Rizk, Nabil P.; Yoon, Sam S.; Millang, Brittanie; Capanu, Marinela; Goodman, Karyn A.; Ilson, David H.

    2016-01-01

    Background A standard-of-care for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma is pre-operative chemoradiation. Elevated levels of vascular endothelial growth factor (VEGF) have been associated with worse outcomes following chemoradiation and anti-VEGF therapies can potentiate radiation efficacy. Methods In this single-arm phase II study, we added bevacizumab to induction chemotherapy and concurrent chemoradiation with cisplatin/irinotecan for locally advanced esophageal and GEJ adenocarcinomas. Results Thirty-three patients were enrolled, with all evaluable. All tumors involved the GEJ and 67% were node-positive by endoscopic ultrasound (EUS) and imaging. Twenty-eight patients completed chemoradiation and 26 patients underwent surgery (25 R0 resections). Toxicities were not clearly increased. The pathologic complete response (pCR) rate was 15%. Median progression-free survival (PFS) and overall survival (OS) were 15.1 and 30.5 months respectively. Higher baseline VEGF-A levels were associated with a trend toward improved OS (not reached vs. 21.0 months, P=0.11). Response on positron emission tomography (PET) scan after induction chemotherapy was predictive of PFS and showed trends toward improved OS and pCR rate. Conclusions The addition of bevacizumab to chemoradiation was not associated with clear worsening of toxicities but also led to no improvement in outcomes, when compared to a prior phase II study of 55 patients. Higher baseline VEGF-A levels correlated with a trend toward improved survival and might be used to stratify or select patients for future studies incorporating this or similar agents. PET scan to assess response following induction chemotherapy and change chemotherapy in non-responders during chemoradiation is the subject of a fully-accrued national trial (NCT01333033). PMID:28078107

  8. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients.

    PubMed Central

    Lissoni, P.; Paolorossi, F.; Tancini, G.; Ardizzoia, A.; Barni, S.; Brivio, F.; Maestroni, G. J.; Chilelli, M.

    1996-01-01

    Preliminary data would suggest that the pineal hormone, melatonin (MLT), may enhance tamoxifen (TMX) anti-tumour efficacy. Both MLT and TMX have been used as single agents in the palliative treatment of metastatic neoplasms, other than the classical hormone-dependent tumours, without, however, any clear efficacy. On this basis, a phase II study with TMX plus MLT has been performed in untreatable metastatic solid tumour patients. The study included 25 metastatic solid tumour patients other than breast cancer and prostate cancer (six unknown primary tumour; four melanoma; four uterine cervix carcinoma; five pancreatic cancer; three hepatocarcinoma; two ovarian cancer; one non-small-cell lung cancer), for whom no other effective standard therapy was available, because of poor clinical conditions, no response to previous chemotherapies and/or chemotherapy-resistant tumours. Both drugs were given orally every day until disease progression (TMX, 20 mg day-1 at noon; MLT, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS. PMID:8912546

  9. Potential clinical applications of epothilones: a review of phase II studies.

    PubMed

    Larkin, J M G; Kaye, S B

    2007-07-01

    Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment. This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design. Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin. The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens.

  10. A pilot phase II study of capecitabine in advanced or recurrent breast cancer.

    PubMed

    Saeki, Toshiaki; Kimura, Tsunehito; Toi, Masakazu; Taguchi, Tetsuo

    2006-01-01

    A pilot phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent regimen of capecitabine (Xeloda) in patients with advanced or recurrent breast cancer. A total of 23 patients who had received no more than one prior chemotherapy regimen received oral 828 mg/m2 capecitabine twice daily for 3 weeks followed by a 1-week rest period. The response to capecitabine was evaluated in 22 patients (one patient ineligible). The overall response rate was 45.5% (95% CI, 24.4-67.8%), including 1 complete response (4.5%) and 9 patients with partial response (40.9%). A further 7 patients (31.8%) had stable disease. The median duration of response was 7.2 months (range, 3.0-15.8 months) and the median time to progression was 6.4 months (95% CI, 4.1-15.1 months). Treatment-related adverse events >or= grade 3 were observed in 7 patients (30.1%). Intermittent capecitabine therapy (828 mg/m(2) twice daily for 3 weeks followed by a 1-week rest period) was shown to be effective and well tolerated as second-line treatment for advanced or recurrent breast cancer. The Japanese regimen is worthy of further study in larger numbers of patients in phase II / III clinical trials.

  11. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors.

    PubMed

    Kulke, Matthew H; Bergsland, Emily K; Ryan, David P; Enzinger, Peter C; Lynch, Thomas J; Zhu, Andrew X; Meyerhardt, Jeffrey A; Heymach, John V; Fogler, William E; Sidor, Carolyn; Michelini, Ann; Kinsella, Kate; Venook, Alan P; Fuchs, Charles S

    2006-08-01

    Endostatin is a 20-kd proteolytic fragment of collagen XVIII that, in preclinical studies, has been shown to have antiangiogenic and antitumor activity. Both preclinical and human phase I studies of recombinant human endostatin (rhEndostatin) suggested activity in neuroendocrine tumors, which are known to be hypervascular. We therefore performed a multicenter phase II study of rhEndostatin in patients with carcinoid or pancreatic neuroendocrine tumors. Forty-two patients with advanced pancreatic endocrine tumors or carcinoid tumors were treated with rhEndostatin administered as a bid subcutaneous injection at a starting dose of 60 mg/m2/d. Steady-state trough levels were obtained after 6 weeks of therapy; patients who did not achieve a target therapeutic level of 300 ng/mL underwent dose escalation to 90 mg/m2/d. Patients were observed for evidence of toxicity, response, and survival. rhEndostatin was associated with minimal toxicity. However, among 40 patients assessable for radiologic response, none experienced partial response to therapy, as defined by WHO criteria. The median steady-state trough level achieved after dose escalation was 331 ng/mL, within the postulated therapeutic range. Treatment with rhEndostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors.

  12. Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study.

    PubMed Central

    Goey, S. H.; Eggermont, A. M.; Punt, C. J.; Slingerland, R.; Gratama, J. W.; Oosterom, R.; Oskam, R.; Bolhuis, R. L.; Stoter, G.

    1995-01-01

    mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x 10(6) IU day-1 using the present treatment schedule. Images Figure 1 PMID:7577483

  13. A Phase I-II Study of Postoperative Capecitabine-Based Chemoradiotherapy in Gastric Cancer

    SciTech Connect

    Jansen, Edwin; Crosby, Tom D.L.; Dubbelman, Ria; Bartelink, Harry; Verheij, Marcel

    2007-12-01

    Background: The Intergroup 0116 randomized study showed that postoperative 5-fluorouracil-based chemoradiotherapy improved locoregional control and overall survival in patients with gastric cancer. We hypothesized that these results could be improved further by using a more effective, intensified, and convenient chemotherapy schedule. Therefore, this Phase I-II dose-escalation study was performed to determine the maximal tolerated dose and toxicity profile of postoperative radiotherapy combined with concurrent capecitabine. Patients and Methods: After recovery from surgery for adenocarcinoma of the gastroesophageal junction or stomach, all patients were treated with capecitabine monotherapy, 1,000 mg/m{sup 2} twice daily for 2 weeks. After a 1-week treatment-free interval, patients received capecitabine (650-1,000 mg/m{sup 2} orally twice daily 5 days/week) in a dose-escalation schedule combined with radiotherapy on weekdays for 5 weeks. Radiotherapy was delivered to a total dose of 45 Gy in 25 fractions to the gastric bed, anastomoses, and regional lymph nodes. Results: Sixty-six patients were treated accordingly. Two patients went off study before or shortly after the start of chemoradiotherapy because of progressive disease. Therefore, 64 patients completed treatment as planned. During the chemoradiotherapy phase, 4 patients developed four items of Grade III dose-limiting toxicity (3 patients in Dose Level II and 1 patient in Dose Level IV). The predefined highest dose of capecitabine, 1,000 mg/m{sup 2} twice daily orally, was tolerated well and, therefore, considered safe for further clinical evaluation. Conclusions: This Phase I-II study shows that intensified chemoradiotherapy with daily capecitabine is feasible in postoperative patients with gastroesophageal junction and gastric cancer.

  14. Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer.

    PubMed

    D'Agostino, G; Ferrandina, G; Ludovisi, M; Testa, A; Lorusso, D; Gbaguidi, N; Breda, E; Mancuso, S; Scambia, G

    2003-10-06

    In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m(-2), was administered on day 1 by 60' i.v. infusion, followed by GEM, 1000 mg m(-2), given by 30' i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1-17.7), 16 partial responses (23.9%, 95% CI: 13.7-34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1-50.5) and 18 progressions (26.9%, 95% CI: 16.3-37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9-39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7-62.7). A total of 443 courses are evaluable for toxicity. Grade 3-4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).

  15. A phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gall bladder cancer.

    PubMed

    Sharma, Atul; Mohanti, Bidhu; Raina, Vinod; Shukla, Nootan; Pal, Sujoy; Dwary, Amit; Deo, Surya; Sahni, Peush; Garg, Pramod; Thulkar, Sanjay; DattaGupta, Siddhartha; Rath, Goura

    2010-02-01

    There is a need for effective chemotherapy protocols for gall bladder cancer (GBC). Gemcitabine has antitumor activity in pancreatic cancer. Oxaliplatin is effective in GI cancers. Based on evidence of synergy between these two, we designed this study to evaluate efficacy of this combination in unresectable GBC. Unresectable GBC was enrolled for single center phase II study. Drugs gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 IV infusion (Oxigem) on days 1 and 8 every 3 weeks for a maximum of six cycles or unacceptable toxicity which ever was earlier. Fifty patients were enrolled and analysis was restricted to 48 who were treated. Median age was 50 years and 31 patients were females. CR 3 (6.2%), PR 7 (15%), SD 17 (35.4%), and PD 18. One had complete pathological response. Median OS and PFS were 7.5 and 3 months, respectively. OS in responders was 10.5 versus 4 months in non-responders (p<0.0000). Eleven patients (23%) survived for a year or more. There was no toxic death and grade III/IV toxicity seen in 10 (22%) patients: diarrhea 3, vomiting 2, neutropenia and thrombocytopenia 5 patients. This combination of Oxigem effective in unresectable GBC. It may even induce complete pathological response. One-year survival was 20%. There is a need for controlled trial to assess efficacy of this combination.

  16. Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma

    PubMed Central

    Oki, Yasuhiro; Fanale, Michelle; Romaguera, Jorge; Fayad, Luis; Fowler, Nathan; Copeland, Amanda; Samaniego, Felipe; Kwak, Larry W.; Neelapu, Sattva; Wang, Michael; Feng, Lei; Younes, Anas

    2017-01-01

    Summary We conducted a phase II study of the AKT inhibitor, MK2206 in patients with relapsed or refractory lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma. MK-2206 was administered orally at 200 mg once weekly in 28-d cycles up to 12 cycles in the absence of progression or significant toxicity. The dose was adjusted based on tolerance. A total of 59 patients were enrolled. The final doses patients received were 300 mg (n = 33), 250 mg (n = 2), 200 mg (n = 16) and 135 mg (n = 8). Based on intent-to-treat analysis, objective response was observed in 8 (14%) patients (2 complete response and 6 partial response), with median response duration of 5.8 months. The overall response rate was 20% in 25 patients with classical Hodgkin lymphoma. Rash was the most common toxicity (any grade 53%, Grade 3 in 15%) and was observed in a dose-dependent manner. The correlative cytokine analysis showed paradoxical increase in several cytokines, which may be explained by negative feedback mechanism induced by the on-target effect of AKT inhibitor. Our data demonstrate that MK2206 has a favourable safety profile with a modest activity in patients with relapsed Hodgkin lymphoma. The future studies should explore mechanism-based combinations (clinicaltrials.gov NCT01258998). PMID:26213141

  17. Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma.

    PubMed

    Oki, Yasuhiro; Fanale, Michelle; Romaguera, Jorge; Fayad, Luis; Fowler, Nathan; Copeland, Amanda; Samaniego, Felipe; Kwak, Larry W; Neelapu, Sattva; Wang, Michael; Feng, Lei; Younes, Anas

    2015-11-01

    We conducted a phase II study of the AKT inhibitor, MK2206 in patients with relapsed or refractory lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma. MK-2206 was administered orally at 200 mg once weekly in 28-d cycles up to 12 cycles in the absence of progression or significant toxicity. The dose was adjusted based on tolerance. A total of 59 patients were enrolled. The final doses patients received were 300 mg (n = 33), 250 mg (n = 2), 200 mg (n = 16) and 135 mg (n = 8). Based on intent-to-treat analysis, objective response was observed in 8 (14%) patients (2 complete response and 6 partial response), with median response duration of 5·8 months. The overall response rate was 20% in 25 patients with classical Hodgkin lymphoma. Rash was the most common toxicity (any grade 53%, Grade 3 in 15%) and was observed in a dose-dependent manner. The correlative cytokine analysis showed paradoxical increase in several cytokines, which may be explained by negative feedback mechanism induced by the on-target effect of AKT inhibitor. Our data demonstrate that MK2206 has a favourable safety profile with a modest activity in patients with relapsed Hodgkin lymphoma. The future studies should explore mechanism-based combinations (clinicaltrials.gov NCT01258998). © 2015 John Wiley & Sons Ltd.

  18. Phase II study of mifepristone (RU486) in refractory ovarian cancer.

    PubMed

    Rocereto, T F; Saul, H M; Aikins, J A; Paulson, J

    2000-06-01

    A phase II study of Mifepristone (RU486) was conducted in patients with ovarian cancer whose tumors were resistant to cisplatin and paclitaxel, alone or in combination. Forty-four patients were accrued into this study. All had ovarian cancer that had become resistant to cisplatin and paclitaxel. Patients received Mifepristone 200 mg orally on a daily basis. Patients were followed by tumor size or CA-125 levels when there was no measurable disease. A dose reduction of Mifepristone was to occur in the event of grade 3/4 hematologic, GI, or liver toxicity, creatinine >2.5%, and grade 4 peripheral neuropathy. Thirty-four patients were evaluable for response. Nine (26.5%) of these patients had a response to Mifepristone. Three(9%) patients had a complete response, and six (17.5%), a partial response. The response of one patient in each group was measured by CA-125 levels while the remainder had measurable disease. The response lasted 1 to 4 months in all but one patient. One patient continues to respond after more than 3 years. The major toxic effect was a rash and this was the major reason patients were removed from the study. Mifepristone has activity against ovarian cancer resistant to cisplatin and paclitaxel. The drug is well tolerated. Further studies need to be performed when this drug becomes more widely available in the United States. Copyright 2000 Academic Press.

  19. 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.

  20. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy.

    PubMed

    Choy, Edwin; Butrynski, James E; Harmon, David C; Morgan, Jeffrey A; George, Suzanne; Wagner, Andrew J; D'Adamo, David; Cote, Gregory M; Flamand, Yael; Benes, Cyril H; Haber, Daniel A; Baselga, Jose M; Demetri, George D

    2014-11-05

    Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (-9% and -11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant

  1. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma.

    PubMed

    Kalpathy-Cramer, Jayashree; Chandra, Vyshak; Da, Xiao; Ou, Yangming; Emblem, Kyrre E; Muzikansky, Alona; Cai, Xuezhu; Douw, Linda; Evans, John G; Dietrich, Jorg; Chi, Andrew S; Wen, Patrick Y; Stufflebeam, Stephen; Rosen, Bruce; Duda, Dan G; Jain, Rakesh K; Batchelor, Tracy T; Gerstner, Elizabeth R

    2017-02-01

    Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24-72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.

  2. Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study

    PubMed Central

    Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Muzikansky, Alona; Sheehan, Susan; Regan, Eileen; Vasudev, Eamala; Knowles, Michelle; Fuchs, Charles S.; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.

    2013-01-01

    Purpose We performed a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK) and biomarkers for cediranib. Results Cediranib treatment resulted in an estimated 3-month-PFS rate of 77% [60%, 99%]. Median PFS was 5.3 [3.5,9.7] months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 [7.5–13.6] months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%) and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not appear to affect the steady-state PK of cediranib. Exploratory studies suggested pro-angiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. PMID:23362324

  3. Phase II study of vinorelbine monotherapy in anthracycline and taxane pre-treated metastatic breast cancer.

    PubMed

    Seo, Hee Yeon; Lee, Hyun Joo; Woo, Ok Hee; Park, Kyong Hwa; Woo, Sang Uk; Yang, Dae Sik; Kim, Ae-Ree; Lee, Jae-Bok; Lee, Eun Sook; Kim, Yeul Hong; Kim, Jun Suk; Seo, Jae Hong

    2011-04-01

    We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assessed after every two cycles of treatment. All of the patients had previously been treated with anthracyclines and taxanes. A total of 26 patients were enrolled in this study between April 2004 and August 2009. The median age of the patients was 47 years (range, 37 to 71 years), and 80.8% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Out of 24 evaluable patients, five partial responses were observed, giving an overall response rate of 20.8%, with a median response duration of 2.8 months. The median time to progression was 3.7 months (range, 0.5 to 22.6 months), and median overall survival duration was 10.4 months (range, 1.3 to 57.6 months). The major toxicities observed were neutropenia, anemia and peripheral neuropathy. Grade 3 or 4 hematologic toxicities included neutropenia in 18 patients (69.2%) and anemia in four patients (15.3%). Grade 1 or 2 peripheral neuropathy was observed in 11 patients (42.3%), however there were no cases of grade 3 or 4 peripheral neuropathy. The results of this study indicate that vinorelbine monotherapy was feasible regimen with manageable toxicities in patients with metastatic breast cancer who were previously exposed to anthracyclines and taxanes.

  4. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas

    PubMed Central

    Karajannis, Matthias A.; Legault, Geneviève; Fisher, Michael J.; Milla, Sarah S.; Cohen, Kenneth J.; Wisoff, Jeffrey H.; Harter, David H.; Goldberg, Judith D.; Hochman, Tsivia; Merkelson, Amanda; Bloom, Michael C.; Sievert, Angela J.; Resnick, Adam C.; Dhall, Girish; Jones, David T. W.; Korshunov, Andrey; Pfister, Stefan M.; Eberhart, Charles G.; Zagzag, David; Allen, Jeffrey C.

    2014-01-01

    Background Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA. Methods Key eligibility criteria included age ≥2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m2/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available. Results Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1–31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma. Conclusions Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction. PMID:24803676

  5. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study

    PubMed Central

    André, T; Reyes-Vidal, J M; Fartoux, L; Ross, P; Leslie, M; Rosmorduc, O; Clemens, M R; Louvet, C; Perez, N; Mehmud, F; Scheithauer, W

    2008-01-01

    Advanced biliary tract carcinomas (BTCs) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) has shown promising activity in this setting. This international phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTC received gemcitabine 1000 mg m−2 (day 1) and oxaliplatin 100 mg m−2 (day 2), every 2 weeks. Seventy patients were enroled; 72.9% had metastatic disease. Sixty-seven patients were treated. There were 10 confirmed partial responses (14.9%; 95% confidence interval (CI), 7.4–25.7%) in the treated population (RECIST). Twenty-four patients (35.8 %) had stable disease. The objective response rate was 20.5% in patients with non-gallbladder cancers (9/44 patients) and 4.3% in patients with gallbladder cancers (1/23). Median overall survival for the intent-to-treat population was 8.8 months (95% CI, 6.9–11.1%) and progression-free survival was 3.4 months (95% CI, 2.5–4.6%). Grade 3/4 toxicities included thrombocytopenia (14.9% of patients), alanine aminotransferase elevation (13.4%), anaemia (10.4%), neutropenia (11.9%) and pain (11.9%). In this study, GEMOX demonstrated activity in non-gallbladder carcinoma, but poor activity in gallbladder carcinoma. GEMOX is well tolerated in advanced BTCs. PMID:19238628

  6. Topotecan is active against Wilms' tumor: results of a multi-institutional phase II study.

    PubMed

    Metzger, Monika L; Stewart, Clinton F; Freeman, Burgess B; Billups, Catherine A; Hoffer, Fredric A; Wu, Jianrong; Coppes, Max J; Grant, Ronald; Chintagumpala, Murali; Mullen, Elizabeth A; Alvarado, Carlos; Daw, Najat C; Dome, Jeffrey S

    2007-07-20

    A phase II study was conducted to evaluate the activity and safety of topotecan in pediatric patients with recurrent Wilms' tumor. Patients with favorable histology Wilms' tumor (FHWT) and recurrence after at least one salvage chemotherapy regimen or with anaplastic histology Wilms' tumor (AHWT) in first or subsequent recurrence were eligible. Patients were stratified according to histology, with statistical considerations based on the FHWT stratum. Topotecan was administered intravenously over 30 minutes for 5 days on 2 consecutive weeks. Treatment dosages were adjusted to achieve a target area under the curve (AUC) of 80 +/- 10 ng/mL*h. Tumor responses were measured after two cycles of treatment. Thirty-seven patients (26 patients with FHWT) were enrolled and received a total of 94 cycles of topotecan (range, one to six cycles). The median topotecan dosage required to achieve the target AUC was 1.8 mg/m2 (range, 0.7 to 3.2 mg/m2). Of 25 assessable patients with FHWT, 12 had partial response (PR), six had stable disease (SD), and seven had progressive disease (PD), for an overall response rate of 48% (95% CI, 27.8% to 68.7%). Of 11 assessable patients with AHWT, two had PR, one had SD, and eight had PD. The main toxicities were grade 3 and 4 neutropenia (median duration, 13 days) and thrombocytopenia (median duration, 7.5 days). Topotecan administered on a protracted schedule is active against recurrent FHWT. Inclusion of topotecan in front-line clinical trials for patients with recurrent Wilms' tumor should be considered.

  7. Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study.

    PubMed

    Boscaro, M; Bertherat, J; Findling, J; Fleseriu, M; Atkinson, A B; Petersenn, S; Schopohl, J; Snyder, P; Hughes, G; Trovato, A; Hu, K; Maldonado, M; Biller, B M K

    2014-08-01

    In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76% of patients and normalized UFC in 17%. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56% of the 18 patients had lower UFC than at core baseline and 22% had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.

  8. Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

    PubMed Central

    de Groot, John F.; Lamborn, Kathleen R.; Chang, Susan M.; Gilbert, Mark R.; Cloughesy, Timothy F.; Aldape, Kenneth; Yao, Jun; Jackson, Edward F.; Lieberman, Frank; Robins, H. Ian; Mehta, Minesh P.; Lassman, Andrew B.; DeAngelis, Lisa M.; Yung, W.K. Alfred; Chen, Alice; Prados, Michael D.; Wen, Patrick Y.

    2011-01-01

    Purpose Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. Patients and Methods Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. Results The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. Conclusion Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma. PMID:21606416

  9. Phase II study of magnesium sulfate in acute organophosphate pesticide poisoning.

    PubMed

    Basher, A; Rahman, S H; Ghose, A; Arif, S M; Faiz, M A; Dawson, A H

    2013-01-01

    Acute organophosphorus (OP) poisoning is relatively common and a major cause of death from poisoning in developing countries. Magnesium has been shown to be of benefit in animal models. We conducted a phase II study of bolus doses of (MgSO4) in 50 patients with acute organophosphate poisoning. Patients eligible for inclusion had ingested OP and had cholinergic symptoms consistent with moderate or severe poisoning. All patients received standard care of atropinization titrated to control muscarinic symptoms and pralidoxime. The trial was run in 4 sequential groups of patients. Participants in each group received a different total dose of MgSO4 (20%) administered as intermittent bolus doses infused over 10-15 min or placebo. There was one control patient for every 4 patients who received MgSO4. Group A (16 patients) received a total of 4 gm MgSO4 as a single bolus, group B (8 patients) received 8 gm (in two 4 gm doses q4H), group C (8 patients) received 12 gm (in three 4 gm doses q4H) group D (8 patients) received 16 gm (in four 4 gm doses q4H) and control (10 patients) received placebo). Patients were closely monitored for any adverse reaction like significant clinical neuromuscular disturbance and respiratory depression. No adverse reactions to magnesium were observed. The 24 hour urinary magnesium concentration were statistically different between 16 gm (234.74 ± 74.18 mg/dl) and control (118.06 ± 30.76 mg/dl) (p = 0.019), while it was much lower than the 80% of the intravenous magnesium load. Six patients died in control group compared to 3 in 4 gm, 2 in 8 gm and 1 in 12 gm group. There was no mortality in 16 gm group. Magnesium was well tolerated in this study. Larger studies are required to examine for efficacy.

  10. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

    PubMed Central

    Nowak, A K; Byrne, M J; Williamson, R; Ryan, G; Segal, A; Fielding, D; Mitchell, P; Musk, A W; Robinson, B W S

    2002-01-01

    Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2–69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m−2 i.v. day 1 and gemcitabine 1000 mg m−2 i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20–46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life. British Journal of Cancer (2002) 87, 491–496. doi:10.1038/sj.bjc.6600505 www.bjcancer.com © 2002 Cancer Research UK PMID:12189542

  11. A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma.

    PubMed

    Dillon, Patrick M; Petroni, Gina R; Horton, Bethany J; Moskaluk, Christopher A; Fracasso, Paula M; Douvas, Michael G; Varhegyi, Nikole; Zaja-Milatovic, Snjezana; Thomas, Christopher Y

    2017-08-01

    Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC.Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints.Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment (P < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on (18)FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib.Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138-45. ©2017 AACR. ©2017 American Association for Cancer Research.

  12. A phase I/II study of the protease inhibitor indinavir in children with HIV infection.

    PubMed

    Mueller, B U; Sleasman, J; Nelson, R P; Smith, S; Deutsch, P J; Ju, W; Steinberg, S M; Balis, F M; Jarosinski, P F; Brouwers, P; Mistry, G; Winchell, G; Zwerski, S; Sei, S; Wood, L V; Zeichner, S; Pizzo, P A

    1998-07-01

    Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

  13. Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study.

    PubMed

    Recchia, Francesco; Candeloro, Giampiero; Desideri, Giovambattista; Necozione, Stefano; Recchia, Cornelia O C; Cirulli, Vincenzo; Rea, Silvio

    2012-08-01

    Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile.

  14. Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study

    PubMed Central

    Recchia, Francesco; Candeloro, Giampiero; Desideri, Giovambattista; Necozione, Stefano; Recchia, Cornelia O C; Cirulli, Vincenzo; Rea, Silvio

    2012-01-01

    Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m2 and docetaxel 75 mg/m2 were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile. PMID:23342258

  15. Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition

    PubMed Central

    Carvajal, Richard D.; Lawrence, Donald P.; Weber, Jeffrey S.; Gajewski, Thomas F.; Gonzalez, Rene; Lutzky, Jose; O’Day, Steven J.; Hamid, Omid; Wolchok, Jedd D.; Chapman, Paul B.; Sullivan, Ryan J.; Teitcher, Jerrold B.; Ramaiya, Nikhil; Giobbie-Hurder, Anita; Antonescu, Cristina R.; Heinrich, Michael C.; Bastian, Boris C.; Corless, Christopher L.; Fletcher, Jonathan A.; Hodi, F. Stephen

    2016-01-01

    Purpose Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases is unknown. Experimental Design We conducted a phase II study of nilotinib 400 mg BID in two cohorts of patients with melanomas harboring KIT mutations or amplification: A) those refractory or intolerant to a prior KIT inhibitor; and B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression and overall survival. A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in Cohorts A and B, respectively. Results Twenty patients were enrolled and 19 treated (11-Cohort A; 8-Cohort B). Three patients on Cohort A (27%; 95% CI, 8% – 56%) and 1 on Cohort B (12.5%; 90% CI, 0.6% – 47%) achieved the primary endpoint. Two partial responses were observed in Cohort A (18.2%, 90% CI, 3% – 47%); none were observed in Cohort B. The median time-to-progression and overall survival was 3·3 (90% CI, 2.1 – 3.9 months) and 9.1 months (90% CI, 4.3 – 14.2 months), respectively, in all treated patients. Conclusion Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT altered melanoma with brain metastasis is limited. PMID:25695690

  16. Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition.

    PubMed

    Carvajal, Richard D; Lawrence, Donald P; Weber, Jeffrey S; Gajewski, Thomas F; Gonzalez, Rene; Lutzky, Jose; O'Day, Steven J; Hamid, Omid; Wolchok, Jedd D; Chapman, Paul B; Sullivan, Ryan J; Teitcher, Jerrold B; Ramaiya, Nikhil; Giobbie-Hurder, Anita; Antonescu, Cristina R; Heinrich, Michael C; Bastian, Boris C; Corless, Christopher L; Fletcher, Jonathan A; Hodi, F Stephen

    2015-05-15

    Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited. ©2015 American Association for Cancer Research.

  17. REFINEMENT OF THE NEPHELINE DISCRIMINATOR: RESULTS OF A PHASE II STUDY

    SciTech Connect

    Fox, K; Tommy Edwards, T

    2008-11-21

    Twenty five glass compositions were selected for a Phase II study to assess the potential for reducing the conservatism in the nepheline discriminator. The glass compositions were restricted to regions that fell within the validation ranges of the DWPF PCCS models. In addition, the liquidus temperature model was used to restrict the glass compositions so that they could all be melted at the same temperature. The nepheline discriminator was used to force the glass compositions into regions where nepheline formation was predicted to occur. The glasses were fabricated in the laboratory and characterized for crystallization and chemical durability after both quenching and slow cooling. Chemical analysis showed that the fabricated glasses met the target compositions. Nepheline was identified in one of the quenched glasses and several of the CCC glasses. There was no clear relationship between the types of crystallization that occurred in a particular glass and its location on the Al{sub 2}O{sub 3}-Na{sub 2}O-SiO{sub 2} ternary diagram. A partitioning algorithm was used to identify trends in crystallization behavior based on glass composition. Generally, for the CCC glasses MnO influenced the crystallization of spinels and B{sub 2}O{sub 3} and SiO{sub 2} influenced the crystallization of nepheline. Measured durability responses varied from acceptable to unacceptable depending on the glass composition and type and extent of crystallization that occurred. It was not possible to identify any linear effects of composition on chemical durability performance for this set of study glasses. The results were not sufficient to recommend modification of the current nepheline discriminator at this time. It is recommended that the next series of experiments continue to focus not only on compositional regions where the PCCS models are considered applicable (i.e., the model validation ranges), but also be restricted to compositional regions where acceptable glasses are predicted to be

  18. Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

    ClinicalTrials.gov

    2016-03-04

    Chronic Phase Chronic Myeloid Leukemia; Accelerated Phase Chronic Myeloid Leukemia; Blastic Phase Chronic Myeloid Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Resistant to Tyrosine Kinase Inhibitor Therapy

  19. Phase I/II Study of Temozolomide Plus Nimustine Chemotherapy for Recurrent Malignant Gliomas: Kyoto Neuro-oncology Group

    PubMed Central

    AOKI, Tomokazu; ARAKAWA, Yoshiki; UEBA, Tetsuya; ODA, Masashi; NISHIDA, Namiko; AKIYAMA, Yukinori; TSUKAHARA, Tetsuya; IWASAKI, Koichi; MIKUNI, Nobuhiro; MIYAMOTO, Susumu

    2017-01-01

    The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS. PMID:27725524

  20. Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer.

    PubMed

    Tolaney, Sara M; Tan, Sally; Guo, Hao; Barry, William; Van Allen, Eliezer; Wagle, Nikhil; Brock, Jane; Larrabee, Katherine; Paweletz, Cloud; Ivanova, Elena; Janne, Pasi; Overmoyer, Beth; Wright, John J; Shapiro, Geoffrey I; Winer, Eric P; Krop, Ian E

    2015-10-01

    MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.

  1. A Phase II Study of RO4929097 Gamma-Secretase Inhibitor in Metastatic Melanoma: SWOG 0933

    PubMed Central

    Lee, Sylvia M.; Moon, James; Redman, Bruce G.; Chidiac, Tarek; Flaherty, Lawrence E.; Zha, Yuanyuan; Othus, Megan; Ribas, Antoni; Sondak, Vernon K.

    2014-01-01

    Background Aberrant Notch activation confers a proliferative advantage onto many human tumors, including melanoma. This phase II trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, on the progression-free and overall survival of patients with advanced melanoma. Methods Chemotherapy-naïve patients with metastatic melanoma of cutaneous or unknown origin were treated with RO4929097 at a dose of 20 mg orally daily, 3 consecutive days per week. A two-step accrual design was used, with an interim analysis on the first 32 patients, and continuation of enrollment if ≥4/32 patients responded. Results Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well-tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and 8 patients with stable disease lasting at least through week 12, with one of these continuing for 31 months. The 6-month PFS was 9% (95% CI: 2–22%), and 1-year OS was 50% (95% CI: 32–66%). Peripheral blood T cell assays showed no significant inhibition of IL-2 production, a surrogate pharmacodynamic marker of Notch inhibition, suggesting that the drug levels were insufficient to achieve Notch target inhibition. Conclusions RO4929097 showed minimal clinical activity against metastatic melanoma in this phase II trial, possibly due to inadequate exposure to therapeutic drug levels. While Notch inhibition remains a compelling target in melanoma, our results do not support further investigation of RO4929097 at this dose and schedule. PMID:25250858

  2. Pirfenidone gel in patients with localized scleroderma: a phase II study.

    PubMed

    Rodríguez-Castellanos, Marco; Tlacuilo-Parra, Alberto; Sánchez-Enríquez, Sergio; Vélez-Gómez, Ezequiel; Guevara-Gutiérrez, Elizabeth

    2015-01-28

    Localized scleroderma is an inflammatory disease in its first stages and a fibrotic process in later stages, principally mediated by the transforming growth factor β. To date, there is no standard treatment. The objective of this study was to determine the effectiveness and safety of 8% pirfenidone gel in patients with localized scleroderma. This was an open phase II clinical trial that included 12 patients. Treatment with pirfenidone was indicated, three times daily for 6 months. Patients were evaluated clinically with the modified Localized Scleroderma Skin Severity Index (mLoSSI), as well with a durometer and histologically using hematoxylin and eosin stain and Masson's trichrome stain. The baseline mLoSSI average scores were 5.83 ± 4.80 vs. 0.83 ± 1.75 (P = 0.002) at 6 months. The initial durometer induration of the scleroderma plaques was 35.79 ± 9.10 vs. 32.47 ± 8.97 at 6 months (P = 0.05). We observed histopathological improvement with respect to epidermal atrophy, inflammation, dermal or adipose tissue fibrosis and annex atrophy from 12.25 ± 3.25 to 9.75 ± 4.35 (P = 0.032). The 8% pirfenidone gel application was well tolerated, and no side effects were detected. This is the first study on the therapeutic use of pirfenidone gel in localized scleroderma. It acts on both the inflammatory and the fibrotic phases. Considering its effectiveness, good safety profile and the advantage of topical application, pirfenidone is a treatment option in this condition.

  3. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  4. Phase II study of DTIC, ACNU, and vincristine combination chemotherapy for supratentorial malignant astrocytomas.

    PubMed

    Ikeda, J; Aida, T; Sawamura, Y; Abe, H; Kaneko, S; Kashiwaba, T; Kawamoto, T; Mitsumori, K; Saitoh, H

    1996-08-01

    This phase II clinical study evaluated the use of 5-(3-3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) pretreatment to reduce cellular resistance and enhance the antitumor effects of chloroethyl nitrosoureas in 32 patients with supratentorial malignant gliomas, including 13 anaplastic astrocytoma and 19 glioblastoma multiforme. All patients received a total dose of 50-65 Gy radiation therapy after surgery. Chemotherapy consisted of DTIC (1 mg/kg) on days 1-5, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (2 mg/kg) on day 5, and vincristine (0.02 mg/kg) on days 1 and 15 every 5 weeks. One patient achieved complete response and 12 patients showed partial response. Median survival time was 18 months and median time-to-progression was 11 months. No significant toxicity was encountered. There was no significant benefit of this pretreatment to combination chemotherapy when compared with previous results. This study does not support a further role for DTIC as a depleter of O6-alkylguanine deoxyribonucleic acid alkyltransferase activity preceding chloroethyl nitrosourea-based chemotherapy.

  5. Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin's lymphoma.

    PubMed

    Ribrag, Vincent; Caballero, Dolores; Fermé, Christophe; Zucca, Emanuele; Arranz, Reyes; Briones, Javier; Gisselbrecht, Christian; Salles, Gilles; Gianni, Alessandro M; Gomez, Henry; Kahatt, Carmen; Corrado, Claudia; Szyldergemajn, Sergio; Extremera, Sonia; de Miguel, Bernardo; Cullell-Young, Martin; Cavalli, Franco

    2013-03-01

    This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin's lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%-39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: NCT00884286).

  6. Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study

    PubMed Central

    LEONARDI, VITA; PALMISANO, VALENTINA; PEPE, ALESSIO; USSET, ANTONELLA; MANUGUERRA, GIOVANNA; SAVIO, GIUSEPPINA; DE BELLA, MANUELA TAMBURO; LAUDANI, AGATA; ALÙ, MASSIMO; CUSIMANO, MARIA PIA; SCIANNA, CATERINA; GIRESI, ARMANDO; AGOSTARA, BIAGIO

    2010-01-01

    Pegylated liposomal doxorubicin (PLD) has the advantage of delivering active anthracycline directly to the tumor site, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. Recently, a regimen in which paclitaxel is infused weekly over 1 h produced substantial antitumor activity with little myelosuppression. We designed a phase II trial to study the efficacy and toxicity of 10 mg/m2 PLD on Days 1, 8 and 15, plus 70 mg/m2 paclitaxel weekly in patients with untreated metastatic breast cancer and a high risk of cardiotoxicity. The study included 35 patients, with 31 (88.5%) evaluable for efficacy and 35 (100%) for toxicity. A total of 28 patients (80%) had two or more sites of disease. Overall, 4 complete and 16 partial responses were noted with an overall response rate of 64.5%, with 6 cases of stable and 5 cases of progressive disease. Toxicity was found to be manageable in that the only grade 3–4 side effects recorded were palmar-plantar erythrodysesthesia, 8.5%; mucositis, 2.8%; leucopenia, 12.5%; anemia, 2.8% and AST/ALT, 2.8%. No cardiotoxicity was observed. In conclusion, weekly PLD plus paclitaxel appears to be a well-tolerated and effective approach for metastatic breast cancer patients with a high risk of cardiotoxicity. PMID:22966374

  7. A phase II study of bryostatin 1 in metastatic malignant melanoma.

    PubMed Central

    Propper, D. J.; Macaulay, V.; O'Byrne, K. J.; Braybrooke, J. P.; Wilner, S. M.; Ganesan, T. S.; Talbot, D. C.; Harris, A. L.

    1998-01-01

    Bryostatin 1 is a protein kinase C partial agonist which has both antineoplastic and immune-stimulatory properties, including the induction of cytokine release and expansion of tumour-specific lymphocyte populations. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma and ovarian carcinoma. The dose-limiting toxicity is myalgia. Sixteen patients (age 35-76 years, median 57 years) with malignant melanoma were treated. All had received prior chemotherapy. In each cycle of treatment, patients received bryostatin 25 degrees g m(-2) weekly for three courses followed by a rest week. The drug was given in PET diluent (10 microg bryostatin ml(-1) of 60% polyethylene glycol, 30% ethanol, 10% Tween 80) and infused in normal saline over 1 h. The principal toxicities were myalgia (grade 2, eight patients and grade 3, six patients) and grade 2 phlebitis (four patients), fatigue (three patients) and vomiting (one patient). Of 15 patients evaluable for tumour response, 14 developed progressive disease. One patient developed stable disease for 9 months after bryostatin treatment. In conclusion, single-agent bryostatin appears ineffective in the treatment of metastatic melanoma in patients previously treated with chemotherapy. It should, however, be investigated further in previously untreated patients. PMID:9823975

  8. Phase II study of recombinant interleukin 1alpha and etoposide in patients with relapsed osteosarcoma.

    PubMed

    Worth, L L; Jaffe, N; Benjamin, R S; Papadopoulos, N E; Patel, S; Raymond, A K; Jia, S F; Rodriguez, C; Gano, J; Gianan, M A; Kleinerman, E S

    1997-10-01

    A Phase II trial using interleukin 1alpha (IL-1alpha) and etoposide for patients with relapsed osteosarcoma (OS) was undertaken to assess the feasibility and tolerability of combination therapy with biotherapy and chemotherapy. Nine patients with histologically proven relapsed OS were treated with IL-1alpha immediately followed by etoposide daily for 5 days every 3 weeks. Surgical resection of lung metastasis or peripheral tumor was performed after two or three cycles. We observed three partial responses; disease was stable in another case. One case could not be evaluated. The side effects associated with combination therapy were as predicted from known side effects of the individual agents; however, more profound neutropenia was observed. Four patients exhibited clinical signs of capillary leak syndrome, i.e., hypotension, edema, and weight gain. The etiology of the capillary leak was unclear, because serum IL-1alpha, IL-2, tumor necrosis factor, and nitric oxide levels could not be used to predict which patients would develop capillary leak. Histological analysis of tumor specimens obtained after two or more courses of therapy showed changes consistent with a response to a biological response modifier: peripheral fibrosis surrounded the metastasis with infiltration of chronic and acute inflammatory cells. Because the response of relapsed OS to any type of salvage regimen has been poor, we interpret the clinical response of this therapy as good. However, the significant side effects associated with this therapy must also be taken into consideration before deciding to use this combination therapy. It is unfortunate that the study was stopped early due to halted production of IL-1alpha. If this agent is again manufactured for clinical use, we conclude that additional evaluation in patients with relapsed OS is warranted.

  9. Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

    PubMed

    Eisen, Tim; Thatcher, Nick; Leyvraz, Serge; Miller, Wilson H; Couture, Felix; Lorigan, Paul; Lüthi, François; Small, David; Tanovic, Adnan; O'Brien, Mary

    2009-04-01

    To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

  10. Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma

    PubMed Central

    Slomovitz, Brian M.; Jiang, Yunyun; Yates, Melinda S.; Soliman, Pamela T.; Johnston, Taren; Nowakowski, Maureen; Levenback, Charles; Zhang, Qian; Ring, Kari; Munsell, Mark F.; Gershenson, David M.; Lu, Karen H.; Coleman, Robert L.

    2015-01-01

    Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way

  11. Phase II Study of Temozolomide (TMZ) and Everolimus (RAD001) Therapy for Metastatic Melanoma

    PubMed Central

    Dronca, Roxana S.; Allred, Jacob B.; Perez, Domingo G.; Nevala, Wendy K.; Lieser, Elizabeth A.T.; Thompson, Michael; Maples, William J.; Creagan, Edward T.; Pockaj, Barbara A.; Kaur, Judith S.; Moore, Timothy D.; Marchello, Benjamin T.; Markovic, Svetomir N.

    2014-01-01

    Objective Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents [temozolomide (TMZ)] and inhibition of tumor angiogenesis. Methods We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/ wk) and 200 mg/m2/d of TMZ for 5 days each cycle. Results Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%–59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). Conclusions The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma. PMID:23357973

  12. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.

    PubMed

    Stockley, Robert; De Soyza, Anthony; Gunawardena, Kulasiri; Perrett, John; Forsman-Semb, Kristina; Entwistle, Neil; Snell, Noel

    2013-04-01

    Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis. NCT00769119. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer.

    PubMed

    Jones, Robert J; Hussain, Syed A; Protheroe, Andrew S; Birtle, Alison; Chakraborti, Prabir; Huddart, Robert A; Jagdev, Satinder; Bahl, Amit; Stockdale, Andrew; Sundar, Santhanam; Crabb, Simon J; Dixon-Hughes, Judith; Alexander, Laura; Morris, Anna; Kelly, Caroline; Stobo, Jon; Paul, James; Powles, Thomas

    2017-06-01

    Purpose Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel.

  14. Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer.

    PubMed

    García, Margarita; Martinez-Villacampa, Mercedes; Santos, Cristina; Navarro, Valentin; Teule, Alex; Losa, Ferran; Pisa, Aleydis; Cambray, Maria; Soler, Gemma; Lema, Laura; Kreisler, Esther; Figueras, Agnes; Juan, Xavier San; Viñals, Francesc; Biondo, Sebastiano; Salazar, Ramon

    2015-02-26

    To evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. A phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m(2)/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. Forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC. ClinicalTrials.gov Identifier NCT00847119 . Trial registration date: February 18, 2009.

  15. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma

    PubMed Central

    Norden, Andrew D.; Ligon, Keith L.; Hammond, Samantha N.; Muzikansky, Alona; Reardon, David A.; Kaley, Thomas J.; Batchelor, Tracy T.; Plotkin, Scott R.; Raizer, Jeffrey J.; Wong, Eric T.; Drappatz, Jan; Lesser, Glenn J.; Haidar, Sam; Beroukhim, Rameen; Lee, Eudocia Q.; Doherty, Lisa; Lafrankie, Debra; Gaffey, Sarah C.; Gerard, Mary; Smith, Katrina H.; McCluskey, Christine; Phuphanich, Surasak

    2015-01-01

    Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months. PMID:25527270

  16. Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.

    PubMed

    Leichman, Lawrence; Groshen, Susan; O'Neil, Bert H; Messersmith, Wells; Berlin, Jordan; Chan, Emily; Leichman, Cynthia G; Cohen, Steven J; Cohen, Deirdre; Lenz, Heinz-Josef; Gold, Philip; Boman, Bruce; Fielding, Anitra; Locker, Gershon; Cason, Ronald C; Hamilton, Stan R; Hochster, Howard S

    2016-02-01

    Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors

  17. Phase II Study of Modified FOLFOX6 With Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma.

    PubMed

    Li, Jia; Yao, Xiaopan; Kortmansky, Jeremy S; Fischbach, Neal A; Stein, Stacey; Deng, Yanhong; Zhang, Yue; Doddamane, Indukala; Karimeddini, David; Hochster, Howard S; Lacy, Jill

    2017-04-01

    The median survival for patients with metastatic gastroesophageal adenocarcinoma is <12 months. Bevacizumab has demonstrated promising activity in metastatic gastroesophageal adenocarcinoma when used in combination with cisplatin-based regimens for patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of bevacizumab in combination with the oxaliplatin-based regimen, modified FOLFOX6, in patients with metastatic gastroesophageal adenocarcinoma. Patients with untreated metastatic adenocarcinoma of the stomach, gastroesophageal junction, or distal esophagus received mFOLFOX6 (leucovorin 400 mg/m, fluorouracil 400 mg/m bolus and 2400 mg/m continuous infusion over 46 h, oxaliplatin 85 mg/m) and bevacizumab (10 mg/kg) every 2 weeks until disease progression or intolerance. Response by RECIST was evaluated by CT scan every 8 weeks. The primary objective was progression-free survival (PFS); secondary objectives were safety, response rate, and overall survival (OS). A total of 39 patients with untreated metastastic gastroesophageal adenocarcinoma were enrolled between September 2008 and June 2012. Median number of cycles administered was 12 (range, 4 to 86). The confirmed response rate was 56.4% (3 complete response and 19 partial response). The median PFS was 7.8 months and median OS was 14.7 months. Three patients remain on treatment, and 11 patients are alive, of whom 6 have survived >24 months. Treatment-related grade 3/4 toxicities included neutropenia (33.3%), neuropathy (20.5%), thromboembolism (VTE) (7.7%), thrombocytopenia (7.7%), anemia (2.6%), hypertension (2.6%), and proteinuria (2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. First-line mFOLFOX6 with bevacizumab for metastatic gastroesophageal adenocarcinoma was well tolerated and associated with longer PFS and OS compared with historical data from similar populations treated without bevacizumab. Our results suggest that the addition of

  18. Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer

    PubMed Central

    Groshen, Susan; O’Neil, Bert H.; Messersmith, Wells; Berlin, Jordan; Chan, Emily; Leichman, Cynthia G.; Cohen, Steven J.; Cohen, Deirdre; Lenz, Heinz-Josef; Gold, Philip; Boman, Bruce; Fielding, Anitra; Locker, Gershon; Cason, Ronald C.; Hamilton, Stan R.; Hochster, Howard S.

    2016-01-01

    Background. Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. Methods. This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). Results. Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. Conclusion. Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. Implications for Practice: Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome

  19. A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma.

    PubMed

    Ornstein, Moshe C; Wood, Laura S; Elson, Paul; Allman, Kimberly D; Beach, Jennifer; Martin, Allison; Zanick, Beth R; Grivas, Petros; Gilligan, Tim; Garcia, Jorge A; Rini, Brian I

    2017-01-23

    Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, -2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not

  20. Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas.

    PubMed

    Losa, R; Fra, J; López-Pousa, A; Sierra, M; Goitia, A; Uña, E; Nadal, R; Del Muro, J García; Gión, M; Maurel, J; Escudero, P; Esteban, E; Buesa, José M

    2007-02-01

    Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.

  1. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

    PubMed

    Stathopoulos, George P; Boulikas, Teni; Vougiouka, Maria; Rigatos, Sotirios K; Stathopoulos, John G

    2006-05-01

    The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

  2. Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck.

    PubMed

    Tang, Patricia A; Siu, Lillian L; Chen, Eric X; Hotte, Sebastien J; Chia, Stephen; Schwarz, James K; Pond, Gregory R; Johnson, Caitlin; Colevas, A Dimitrios; Synold, Timothy W; Vasist, Lakshmi S; Winquist, Eric

    2008-06-01

    Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m2 IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3-2.3) months, median survival was 3.5 (95% CI 2.8-7.8) months, and 1 year overall survival was 20% (95% CI 8.3-48.1%). The most frequent attributable grades III-V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule.

  3. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma

    SciTech Connect

    Safran, Howard . E-mail: hsafran@lifespan.org; Di Petrillo, Thomas; Akerman, Paul; Ng, Thomas; Evans, Devon; Steinhoff, Margaret; Benton, David; Purviance, John; Goldstein, Lisa; Tantravahi, Umadevi; Kennedy, Teresa R.N.

    2007-02-01

    Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

  4. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study.

    PubMed

    van Dorp, Suzanne; Resemann, Henrike; te Boome, Liane; Pietersma, Floor; van Baarle, Debbie; Gmelig-Meyling, Frits; de Weger, Roel; Petersen, Eefke; Minnema, Monique; Lokhorst, Henk; Ebeling, Saskia; Beijn, Scott J P; Knol, Edward F; van Dijk, Marijke; Meijer, Ellen; Kuball, Jürgen

    2011-09-01

    Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8(+) T cells, suggesting that host B cells play a role in maintaining pathological CD8(+) T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42).

  5. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

    PubMed Central

    van Dorp, Suzanne; Resemann, Henrike; te Boome, Liane; Pietersma, Floor; van Baarle, Debbie; Gmelig-Meyling, Frits; de Weger, Roel; Petersen, Eefke; Minnema, Monique; Lokhorst, Henk; Ebeling, Saskia; Beijn, Scott J.P.; Knol, Edward F.; van Dijk, Marijke; Meijer, Ellen; Kuball, Jürgen

    2011-01-01

    Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8+ T cells, suggesting that host B cells play a role in maintaining pathological CD8+ T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42). PMID:21546493

  6. Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

    PubMed Central

    Rimassa, Lorenza; Abbadessa, Giovanni; Personeni, Nicola; Porta, Camillo; Borbath, Ivan; Daniele, Bruno; Salvagni, Stefania; Van Laethem, Jean-Luc; Van Vlierberghe, Hans; Trojan, Jörg; De Toni, Enrico N.; Weiss, Alan; Miles, Steven; Gasbarrini, Antonio; Lencioni, Monica; Lamar, Maria E.; Wang, Yunxia; Shuster, Dale; Schwartz, Brian E.; Santoro, Armando

    2016-01-01

    ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC. Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials. PMID:27579536

  7. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas.

    PubMed

    Medina, José Antonio; Rueda, Antonio; de Pasos, Antonio Sacchetti; Contreras, Jorge; Cobo, Manuel; Moreno, Paloma; Benavides, Manuel; Villanueva, Asunción; Alba, Emilio

    2006-04-01

    This phase II study evaluated the efficacy and toxicity of weekly cisplatin along with concomitant boost accelerated radiation regimen in patients with locally advanced unresectable head and neck carcinoma. A total of 94 patients (median age, 58 years) with UICC stage III (n = 19) and IV (n = 75) cancer of the oropharynx, larynx, hypopharynx and oral cavity were included. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. Most patients (95%) received both radiation and chemotherapy according to protocol. Toxicity was manageable with grade III mucositis and pharyngeal-oesophageal toxicity in 85 and 50% of patients, respectively. Haematological toxicity was mild. Four patients (4%) died due to complications. With a median follow of 41 months, median overall survival and time to progression were 27 and 25 months, respectively. The estimated overall survival at 4 years was 41%. Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with locally advanced unresectable head and neck carcinoma, with acceptable toxicity and survival data.

  8. VAC chemotherapy with valproic acid for refractory/relapsing small cell lung cancer: a phase II study.

    PubMed

    Berghmans, Thierry; Lafitte, Jean-Jacques; Scherpereel, Arnaud; Ameye, Lieveke; Paesmans, Marianne; Meert, Anne-Pascale; Colinet, Benoit; Tulippe, Christian; Willems, Luc; Leclercq, Nathalie; Sculier, Jean-Paul

    2015-10-01

    Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study was to determine whether epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine and cyclophosphamide (VAC) regimen improves 6-month progression-free survival (PFS). Patients with pathologically proven SCLC refractory to prior platinum derivatives and etoposide were eligible. After central registration, patients received VAC plus daily oral valproic acid. 64 patients were registered, of whom six were ineligible. Seven patients did not receive any CT, leaving 51 patients assessable for the primary end-point. The objective response rate was 19.6%. Median PFS was 2.8 months (95% CI 2.5-3.6 months) and 6-month PFS was 6%. Median survival time was 5.9 months (95% CI 4.7-7.5 months). Toxicity was mainly haematological, with 88% and 26% grade 3-4 neutropenia and thrombopenia, respectively. Despite an interesting response rate, the addition of valproic acid to VAC did not translate into adequate PFS in relapsing SCLC or SCLC refractory to platinum-etoposide.

  9. Irinotecan (CPT-11) in metastatic colorectal cancer patients resistant to 5-fluorouracil (5-FU): a phase II study.

    PubMed

    Antón, A; Aranda, E; Carrato, A; Marcuello, E; Massutti, B; Cervantes, A; Abad, A; Sastre, J; Fenández-Martos, C; Gallén, M; Díaz-Rubio, E; Huarte, L; Balcells, M

    2003-10-01

    The efficacy and toxicity of irinotecan (CPT-11) 350 mg/m(2) i.v. once every 3 weeks was assessed in 60 patients with advanced colorectal cancer (CRC) showing failure to 5-fluorouracil (5-FU) treatment. The overall objective response rate was 13.6% (1 complete response and 4 partial responses) and 25 patients (42.4%) showed stable disease; the median time to disease progression was 4.4 months and the median survival was 10.5 months. The main non-hematological toxicities were alopecia (80.3% of patients), diarrhea (75.0%), and nausea/vomiting (71.7%); neutropenia was the main hematological toxicity. Grade 3 or 4 diarrhea appeared in 21 of 131 cycles (16.1%), whereas grade 3 or 4 neutropenia appeared in 78 cycles (25.0%). In conclusion, the present phase II study confirms that CPT-11 350 mg/m(2) every 3 weeks is active and well tolerated as second-line chemotherapy for CRC in 5-FU resistant patients. (c) 2003 Prous Science. All rights reserved.

  10. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Sargent, Rachel; Burger, Jan A.; Ferrajoli, Alessandra

    2013-01-01

    Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. PMID:23270003

  11. 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.

  12. 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

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

    SciTech Connect

    Wang Xin; Liu Xiaoxia; Mei Guanghai; Dai Jiazhong; Pan Li; Wang Enmin

    2012-06-01

    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 radiotherapy 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.

  14. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas

    PubMed Central

    Karajannis, Matthias A.; Legault, Geneviève; Hagiwara, Mari; Giancotti, Filippo G.; Filatov, Alexander; Derman, Anna; Hochman, Tsivia; Goldberg, Judith D.; Vega, Emilio; Wisoff, Jeffrey H.; Golfinos, John G.; Merkelson, Amanda; Roland, J. Thomas; Allen, Jeffrey C.

    2014-01-01

    Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m2/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic (“phase 0”) study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors. PMID:24311643

  15. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients

    PubMed Central

    Sawada, Yu; Yoshikawa, Toshiaki; Ofuji, Kazuya; Yoshimura, Mayuko; Tsuchiya, Nobuhiro; Takahashi, Mari; Nobuoka, Daisuke; Gotohda, Naoto; Takahashi, Shinichiro; Kato, Yuichiro; Konishi, Masaru; Kinoshita, Taira; Ikeda, Masafumi; Nakachi, Kohei; Yamazaki, Naoya; Mizuno, Shoichi; Takayama, Tadatoshi; Yamao, Kenji; Uesaka, Katsuhiko; Furuse, Junji; Endo, Itaru; Nakatsura, Tetsuya

    2016-01-01

    ABSTRACT The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine. PMID:27467945

  16. A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201).

    PubMed

    Bando, Hideaki; Doi, Toshihiko; Muro, Kei; Yasui, Hirofumi; Nishina, Tomohiro; Yamaguchi, Kensei; Takahashi, Shunji; Nomura, Shogo; Kuno, Hirofumi; Shitara, Kohei; Sato, Akihiro; Ohtsu, Atsushi

    2016-07-01

    American phase I studies have reported that the recommended dose of TAS-102 (trifluridine/tipiracil) was 25 mg/m(2) twice a day (b.i.d.), although this schedule did not provide clinically relevant improvements in a phase II study of advanced gastric cancer (AGC). However, a pivotal phase III study revealed that TAS-102 at 35 mg/m(2) b.i.d. provided a clinically relevant improvement in overall survival (OS) among patients with metastatic colorectal cancer. Therefore, we re-evaluated the efficacy, safety, and pharmacokinetic parameters of TAS-102 at 35 mg/m(2) b.i.d among Japanese patients with AGC. All patients had undergone one or two previous chemotherapy regimens that contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. The primary end-point target was a disease control rate (DCR) of ≥50% after 8 weeks of the 35 mg/m(2) b.i.d. schedule. Twenty-nine patients were assessable after completing the 35 mg/m(2) b.i.d. schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI], 45.7-82.1%) and the independent central review's DCR was 51.9% (95% CI, 31.9-71.3%); both results exceeded the primary end-point target. The median progression-free survival and OS were 2.9 months (95% CI, 1.1-5.3 months) and 8.7 months (95% CI, 5.7-14.9 months), respectively. The grade III/IV adverse events included neutropenia (69.0%), leucopaenia (41.4%), anaemia (20.7%), and anorexia (10.3%). No AGC-specific toxicities were detected. The 35 mg/m(2) b.i.d. dose of TAS-102 provided positive efficacy and an acceptable toxicity profile in patients with AGC. A randomised, double-blind, placebo-controlled, phase III study is ongoing to validate these findings. UMIN000007421. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study.

    PubMed

    Hyams, David M; Chan, Arlene; de Oliveira, Celia; Snyder, Raymond; Vinholes, Jeferson; Audeh, M William; Alencar, Victor M; Lombard, Janine; Mookerjee, Bijoyesh; Xu, John; Brown, Kathryn; Klein, Paula

    2013-10-01

    Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.

  18. Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab

    PubMed Central

    Weber, Jeffrey; Gibney, Geoffrey; Kudchadkar, Ragini; Yu, Bin; Cheng, PingYan; Martinez, Alberto J.; Kroeger, Jodie; Richards, Allison; McCormick, Lori; Moberg, Valerie; Cronin, Heather; Zhao, Xiuhua; Schell, Michael; Chen, Yian Ann

    2016-01-01

    The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30% (95%CI: 21% - 41%). Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62% (95%CI: 38% - 82%) having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab. PMID:26873574

  19. 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

    2017-03-25

    Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation via 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 demonstrated promising anti-cancer activity in various cancers. We conducted 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 intravenous 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 [CI]: 20.8, 51.9), and the overall survival rate at 18 months was 56.5% (90% CI: 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 demonstrated favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. This article is protected by copyright. All rights reserved.

  20. 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.

  1. Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings.

    PubMed

    Czuczman, Myron S; Goy, A; Lamonica, D; Graf, D A; Munteanu, M C; van der Jagt, R H

    2015-12-01

    In most cases of relapsed/refractory mantle cell lymphoma (MCL), patients respond to salvage therapy, though typically responses are partial and/or transient followed by disease progression, even with newer agents (e.g., ibrutinib). In this multicenter, open-label, single-arm, phase II study, patients with relapsed/refractory non-blastoid MCL received bendamustine 90 mg/m(2) (days 1 and 2) and rituximab 375 mg/m(2) (day 1) for 6 planned 28-day cycles. Functional imaging with 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) was conducted at baseline and after cycle 6. Forty-five patients were enrolled (median age, 70 years; 82 % stage IV disease; median number of prior chemotherapies, 2 [range, 1-4]), showing an overall response rate (ORR; primary efficacy measure) of 82 % (complete response [CR], 40 %; partial response, 42 %). In the 32 patients with complete 18F-FDG PET/CT data, 75 % achieved a complete metabolic response. Median duration of response was 1.6 years, 1-year progression-free survival was 67 %, and 3-year overall survival was 55 %. Main non-hematologic adverse events were nausea (69 %), fatigue (56 %), decreased appetite (42 %), constipation (38 %), diarrhea (36 %), vomiting (36 %), and decreased weight (31 %). Grade 3/4 neutropenia and lymphopenia occurred in 44 and 89 % of patients, respectively. ORR and CR rate compared favorably with single-agent ibrutinib (ORR, 67 %; CR, 23 %); bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL.

  2. Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin's lymphoma.

    PubMed

    Czuczman, Myron S; Kahanic, Stephen; Forero, Andres; Davis, Glen; Munteanu, Mihaela; Van Den Neste, Eric; Offner, Fritz; Bron, Dominique; Quick, Donald; Fowler, Nathan

    2015-04-01

    The efficacy/tolerability of bendamustine, a unique alkylator, plus ofatumumab, a human anti-CD20 monoclonal antibody, was evaluated for previously untreated indolent B cell non-Hodgkin's lymphoma (NHL). The study investigated whether the overall response rate (ORR) for bendamustine-ofatumumab was similar to historical bendamustine-rituximab ORRs (≥90 %). In this multicenter, open-label, single-arm, phase II study, patients received six planned 28-day cycles of bendamustine (90 mg/m(2) on days 1 and 2 of each cycle) and ofatumumab (300 mg on day 1, 1000 mg on day 8 of cycle 1, and on day 1 of subsequent cycles). The primary outcome was ORR. Secondary objectives included safety and tolerability. Exploratory evaluations included percentage of patients with positive baseline [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans who converted to negative postbaseline and quality of life (QOL) scores. The treated/safety analysis population received ≥1 dose of either therapy. The bendamustine-ofatumumab ORR was 90 % (95 % confidence interval, 77.8-96.6) in 49 treated patients (67 % complete response, 22 % partial response). No patients had progressive disease. Bendamustine-ofatumumab was acceptably tolerated. All 49 patients had ≥1 adverse event, the most common being nausea (61 %), fatigue (55 %), and infusion-related reactions (45 %, all but 1 occurring during cycle 1). The proportion of patients whose FDG-PET scans converted to negative postbaseline was 88 %. Changes in QOL scores were minor. In patients with treatment-naive, indolent B cell NHL, bendamustine-ofatumumab exhibited a high degree of activity (90 % ORR), comparable with historical bendamustine-rituximab ORRs (≥90 %), and was adequately tolerated ( ClinicalTrials.gov identifier: NCT01108341).

  3. A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

    PubMed

    Vujaskovic, Zeljko; Kim, Dong W; Jones, Ellen; Lan, Lan; McCall, Linda; Dewhirst, Mark W; Craciunescu, Oana; Stauffer, Paul; Liotcheva, Vlayka; Betof, Allison; Blackwell, Kimberly

    2010-01-01

    The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%). Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.

  4. A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer

    PubMed Central

    Vujaskovic, Zeljko; Kim, Dong W.; Jones, Ellen; Lan, Lan; McCall, Linda; Dewhirst, Mark W.; Craciunescu, Oana; Stauffer, Paul; Liotcheva, Vlayka; Betof, Allison; Blackwell, Kimberly

    2010-01-01

    Purpose The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50–60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. Materials and methods Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30–75 mg/m2), paclitaxel (100–175 mg/m2), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. Results Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%–76%) and the four-year overall survival was 75% (95% CI, 58–86%). Conclusions Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response. PMID:20377362

  5. Phase II study of glucosamine with chondroitin on aromatase inhibitor-associated joint symptoms in women with breast cancer

    PubMed Central

    Greenlee, Heather; Crew, Katherine D.; Shao, Theresa; Kranwinkel, Grace; Kalinsky, Kevin; Maurer, Matthew; Brafman, Lois; Insel, Beverly; Tsai, Wei Yann

    2013-01-01

    Purpose Many women with hormone receptor-positive breast cancer discontinue effective aromatase inhibitor (AI) treatment due to joint symptoms. Methods We conducted a single-arm, open-label, phase II study evaluating glucosamine-sulfate (1,500 mg/day)+ chondroitin-sulfate (1,200 mg/day) for 24 weeks to treat joint pain/stiffness in postmenopausal women with early stage breast cancer who developed moderate-to-severe joint pain after initiating AIs. The primary endpoint was improvement in pain/stiffness at week 24 assessed by the Outcome Measure in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Secondary endpoints assessed changes in pain, stiffness, and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) for hands/wrists. The Brief Pain Inventory (BPI) assessed pain interference, severity, and worst pain. Results Of 53 patients enrolled, 39 were evaluable at week 24. From baseline to week 24, 46 % of patients improved according to OMERACT-OARSI criteria. At week 24, there were improvements (all P<0.05) in pain and function as assessed by WOMAC and M-SACRAH, and in pain interference, severity, and worst pain as assessed by BPI. Estradiol levels did not change from baseline. The most commonly reported side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %). Conclusions In this single-arm study, 24 weeks of glucosamine/chondroitin resulted in moderate improvements in AI-induced arthralgias, with minimal side effects, and no changes in estradiol levels. These results suggest a need to evaluate efficacy in a placebo-controlled trial. PMID:23111941

  6. A phase II study of GW786034 (pazopanib) with or without bicalutamide in patients with castration-resistant prostate cancer.

    PubMed

    Sridhar, Srikala S; Joshua, Anthony M; Gregg, Richard; Booth, Christopher M; Murray, Nevin; Golubovic, Jovana; Wang, Lisa; Harris, Pamela; Chi, Kim N

    2015-04-01

    Pazopanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. In this randomized, open label phase II study, pazopanib alone or in combination with bicalutamide was evaluated in patients with chemotherapy-naive castration-resistant prostate cancer (CRPC). Patients received either pazopanib 800 mg daily (arm A) or pazopanib 800 mg plus bicalutamide 50 mg daily (arm B). A 2-stage study design was used, and the primary endpoint was prostate-specific antigen (PSA) response rate (defined as a confirmed ≥ 50% decline from baseline). A total of 23 patients (arm A, 10; arm B, 13) were accrued. The main grade 3+ toxicities were hypertension, fatigue, decreased lymphocytes, and increased alanine transaminase. Owing to significant toxicity, the protocol was amended after the first 11 patients and the pazopanib starting dose was reduced to 600 mg daily. In arm A, of 9 evaluable patients, there was 1 patient (11%) with a PSA response, 3 (33%) with stable PSA, and 5 (56%) with PSA progression; in arm B, of 12 evaluable patients, there were 2 patients (17%) with PSA responses, 6 (50%) with stable PSA, and 4 (33%) with PSA progression. Median progression-free survival was similar in both arms at 7.3 months (95% CI, 2.5 months to not reached). Long-term stable disease was seen in 4 patients who remained on treatment for 18 months (arm A), 26 months (arm A), 35 months (arm B), and 52 months (arm B). In this unselected patient population, pazopanib either alone or in combination with bicalutamide failed to show sufficient activity to warrant further evaluation. However, 4 patients had long-term benefit, suggesting that targeting the VEGFR pathway may still be relevant in selected patients and emphasizing the need for improved predictive markers for patients with CRPC. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Phase I/II Study of Pre-operative Docetaxel and Mitoxantrone for High-risk Prostate Cancer

    PubMed Central

    Garzotto, Mark; Higano, Celestia S.; O’Brien, Catherine; Rademacher, Brooks L.S.; Janeba, Nicole; Fazli, Ladan; Lange, Paul H.; Lieberman, Stephen; Beer, Tomasz M.

    2009-01-01

    Background To determine the 5-year recurrence-free survival in patients with high-risk prostate cancer after neoadjuvant combination chemotherapy followed by surgery. Secondary endpoints included safety, pathologic effects of chemotherapy and predictors of disease recurrence. Patients and Methods Fifty seven patients were enrolled in a Phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 prior to prostatectomy. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. A tissue micro-array, constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum prostate-specific antigen (PSA) > 0.4 ng/ml. Results Of the 57 patients, 54 received 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months, 27 of 57 (47.4%) patients recurred. The Kaplan-Meier relapse-free survival at 2 years was 65.5% (95%CI 53.0% to 78.0%) and 49.8% at 5 years (95%CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions Preoperative chemotherapy with docetaxel and mitoxantrone is feasible. Approximately half of the high risk patients remain relapse free at 5 years and clinical and molecular predictors of early relapse were identified. PMID:20143429

  8. Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors

    PubMed Central

    Smith, David C.; Camacho, Luis H.; Thompson, John; Ramalingam, Suresh S.; Harvey, R. Donald; Campos, Luis; Ferry, David; Tang, Shande; Gao, Ling; Safran, Howard

    2016-01-01

    Lessons Learned Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs. The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer. Background. Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia’s formula (QTcF) in patients with advanced cancer. Methods. Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline. Results. Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline. Conclusion. Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF. PMID:26984445

  9. A phase II study of conventional radiation therapy and thalidomide for supratentorial, newly-diagnosed glioblastoma (RTOG 9806).

    PubMed

    Alexander, Brian M; Wang, Meihua; Yung, W K Alfred; Fine, Howard A; Donahue, Bernadine A; Tremont, Ivo W; Richards, Ray S; Kerlin, Kevin J; Hartford, Alan C; Curran, Walter J; Mehta, Minesh P

    2013-01-01

    The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.

  10. A multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma.

    PubMed

    Maruyama, Dai; Hatake, Kiyohiko; Kinoshita, Tomohiro; Fukuhara, Noriko; Choi, Ilseung; Taniwaki, Masafumi; Ando, Kiyoshi; Terui, Yasuhito; Higuchi, Yusuke; Onishi, Yasushi; Abe, Yasunobu; Kobayashi, Tsutomu; Shirasugi, Yukari; Tobinai, Kensei

    2017-03-07

    Overexpression of programmed death-1 (PD-1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD-1-blocking antibody that inhibits the PD-1 pathway and showed good efficacy in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was started in March 2015. We report data obtained at a cutoff of March 16, 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow-up were 7.0 (1.4-10.6) months and 9.8 (6.0-11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval [CI]: 54.4%-96.0%; 13/16 patients), with complete remission and partial remission in four and nine patients, respectively. The overall survival (OS) and progression-free survival (PFS) rates at 6 months were 100% and 60.0% (95% CI: 31.8%-79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AEs) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%), and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AEs, but most AEs were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin. This article is protected by copyright. All rights reserved.

  11. Treatment of nasopharyngeal carcinoma using simultaneous modulated accelerated radiation therapy via helical tomotherapy: a phase II study

    PubMed Central

    Du, Lei; Zhang, Xin Xin; Feng, Lin Chun; Chen, Jing; Yang, Jun; Liu, Hai Xia; Xu, Shou Ping; Xie, Chuan Bin

    2016-01-01

    Abstract Background The aim of the study was to evaluate short-term safety and efficacy of simultaneous modulated accelerated radiation therapy (SMART) delivered via helical tomotherapy in patients with nasopharyngeal carcinoma (NPC). Methods Between August 2011 and September 2013, 132 newly diagnosed NPC patients were enrolled for a prospective phase II study. The prescription doses delivered to the gross tumor volume (pGTVnx) and positive lymph nodes (pGTVnd), the high risk planning target volume (PTV1), and the low risk planning target volume (PTV2), were 67.5 Gy (2.25 Gy/F), 60 Gy (2.0 Gy/F), and 54 Gy (1.8 Gy/F), in 30 fractions, respectively. Acute toxicities were evaluated according to the established RTOG/EORTC criteria. This group of patients was compared with the 190 patients in the retrospective P70 study, who were treated between September 2004 and August 2009 with helical tomotherapy, with a dose of 70-74 Gy/33F/6.5W delivered to pGTVnx and pGTVnd. Results The median follow-up was 23.7 (12–38) months. Acute radiation related side-effects were mainly problems graded as 1 or 2. Only a small number of patients suffered from grade 4 leucopenia (4.5%) or thrombocytopenia (2.3%). The local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), local-nodal relapse-free survival (LNRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 96.7%, 95.5%, 92.2%, 92.7% and 93.2%, at 2 years, respectively, with no significant difference compared with the P70 study. Conclusions Smart delivered via the helical tomotherapy technique appears to be associated with an acceptable acute toxicity profile and favorable short-term outcomes for patients with NPC. Long-term toxicities and patient outcomes are under investigation. PMID:27247555

  12. Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

    PubMed Central

    Roy, A; Cunningham, D; Hawkins, R; Sörbye, H; Adenis, A; Barcelo, J-R; Lopez-Vivanco, G; Adler, G; Canon, J-L; Lofts, F; Castanon, C; Fonseca, E; Rixe, O; Aparicio, J; Cassinello, J; Nicolson, M; Mousseau, M; Schalhorn, A; D'Hondt, L; Kerger, J; Hossfeld, D K; Garcia Giron, C; Rodriguez, R; Schoffski, P; Misset, J-L

    2012-01-01

    Background: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. Methods: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m−2 plus irinotecan 250 mg m−2 (Day 1)) or 3-weekly DF (docetaxel 85 mg m−2 (Day 1) followed by 5-fluorouracil 750 mg m−2 per day as a continuous infusion (Days 1–5)). Results: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). Conclusion: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable. PMID:22767144

  13. Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.

    PubMed

    Weber, Jeffrey; Gibney, Geoffrey; Kudchadkar, Ragini; Yu, Bin; Cheng, Pingyan; Martinez, Alberto J; Kroeger, Jodie; Richards, Allison; McCormick, Lori; Moberg, Valerie; Cronin, Heather; Zhao, Xiuhua; Schell, Michael; Chen, Yian Ann

    2016-04-01

    The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

  14. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study.

    PubMed Central

    Punt, C. J.; van Herpen, C. M.; Jansen, R. L.; Vreugdenhil, G.; Muller, E. W.; de Mulder, P. H.

    1997-01-01

    High response rates in patients with metastatic melanoma have been achieved with combination chemoimmunotherapy. A response rate of 62% in 45 patients has been reported for treatment with dacarbazine, bleomycin, vincristine, lomustine (BOLD) plus interferon alpha (IFN-alpha). We conducted a multicentre phase II study to confirm these results. Melanoma patients with distant metastases were treated as outpatients with dacarbazine 200 mg m(-2) on days 1-5, vincristine 1 mg m(-2) on days 1 and 4, bleomycin 15 mg on days 2 and 5 i.v. and lomustine 80 mg orally on day 1, repeated every 4 weeks. IFN-alpha-2b was initiated s.c. on day 8 at 3 MU daily for 6 weeks, and 6 MU t.i.w. thereafter. Forty-three patients entered the study. The median number of metastatic sites was three (range 1-5), and 81% of patients had visceral metastases. Nine patients had brain metastases, and seven patients were systemically pretreated. Among the 41 patients that were evaluable for response, the response rate was 27% (95% CI 14-3%), with one complete and ten partial remissions. The response rate in 25 previously untreated patients without brain metastases was 40% (95% CI 21-61%). Median duration of response was 6 (range 2-14+) months; median overall survival was 5 (1-26) months. The main toxicity was malaise/fatigue. We confirm that BOLD plus IFN-alpha has activity in metastatic melanoma. The lower response rate in our study compared with the previous report is probably related to patient selection, as in the previous study 46% of patients had stage III disease, whereas all our patients had stage IV disease, which is associated with a worse prognosis. PMID:9231931

  15. Phase II study of capecitabine (Xeloda (registered) ) and concomitant boost radiotherapy in patients with locally advanced rectal cancer

    SciTech Connect

    Krishnan, Sunil; Janjan, Nora A.; Skibber, John M.; Rodriguez-Bigas, Miguel A.; Wolff, Robert A.; Das, Prajnan; Delclos, Marc E.; Chang, George J.; Hoff, Paulo M.; Eng, Cathy; Brown, Thomas D.; Crane, Christopher H.; Feig, Barry W.; Morris, Jeffrey; Vadhan-Raj, Saroj; Hamilton, Stanley R.; Lin, Edward H. . E-mail: elin@u.washington.edu

    2006-11-01

    Purpose: The aim of this study was to determine the efficacy of capecitabine (Xeloda (registered) ), an oral fluoropyrimidine, as a radiosensitizer in the neoadjuvant treatment of locally advanced rectal cancer (LARC). Methods and Materials: We conducted a phase II study of capecitabine (825 mg/m{sup 2} orally, twice daily continuous) with radiotherapy (52.5 Gy/30 fractions to the primary tumor and perirectal nodes) in 54 patients with LARC (node-negative {>=}T3 or any node-positive tumor) staged by endoscopic ultrasound (EUS). The primary endpoint was pathologic response rate; secondary endpoints included toxicity profiles and survival parameters. Results: Of the 54 patients (median age, 56.7 years; range, 21.3-78.7 years; male:female ratio, 1.7; Eastern Cooperative Oncology Group performance status 0-1: 100%), 51 patients (94%) had T3N0 or T3N1 disease by EUS. Surgery was not performed in 3 patients; 2 of these patients had metastatic disease, and the third patient refused after a complete clinical response. Of the 51 patients evaluable for pathologic response, 9 patients (18%) achieved complete response, and 12 patients (24%) had microscopic residual disease (<10% viable cells). In addition, 26 patients of all 54 patients (51%) achieved T-downstaging, and 15 patients of 29 patients (52%) achieved N-downstaging. Grade 3/4 toxicities were radiation dermatitis (9%) and diarrhea (2%). Sphincter preservation rate for tumor {<=}5 cm from the anal verge was 67% (18/27). Conclusion: This regimen of radiotherapy plus capecitabine is well tolerated and is more convenient than protracted venous infusion of 5-FU. The pathologic response rate is comparable to our previous experience using protracted venous infusion 5-FU for LARC.

  16. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis

    SciTech Connect

    Grigsby, P.W.; Pilepich, M.V.; Parsons, C.L. )

    1990-02-01

    This is a report of a phase I/II study of 13 patients treated with sodium pentosanpolysulfate (PPS) for chronic radiation-induced proctitis. A complete response was obtained in 82%, a partial response occurred in 9%, and 9% failed to respond to therapy. No significant toxicity was observed. It is concluded that PPS is an effective treatment for chronic radiation-induced proctitis and a phase III randomized, double-blind study of PPS versus placebo is planned.

  17. Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine.

    PubMed

    Luxembourg, Alain; Brown, Darron; Bouchard, Celine; Giuliano, Anna R; Iversen, Ole-Erik; Joura, Elmar A; Penny, Mary E; Restrepo, Jaime A; Romaguera, Josefina; Maansson, Roger; Moeller, Erin; Ritter, Michael; Chen, Joshua

    2015-01-01

    Our objective was to develop a multivalent prophylactic HPV vaccine that protects against infection and disease caused by HPV16/18 (oncogenic types in existing prophylactic vaccines) plus additional oncogenic types by conducting 3 Phase II studies comparing the immunogenicity (i.e., anti-HPV6/11/16/18 geometric mean titers [GMT]) and safety of 7 vaccine candidates with the licensed quadrivalent HPV6/11/16/18 vaccine (qHPV vaccine) in young women ages 16-26. In the first study (Study 1), subjects received one of 3 dose formulations of an 8-valent HPV6/11/16/18/31/45/52/58 vaccine or qHPV vaccine (control). In Study 2, subjects received one of 3 dose formulations (termed low-, mid-, and high-dose formulations, respectively) of a 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine (9vHPV vaccine) or qHPV vaccine (control). In Study 3, subjects concomitantly received qHPV vaccine plus 5-valent HPV31/33/45/52/58 or qHPV vaccine plus placebo (control). All vaccines were administered at day 1/month 2/month 6. In studies 1 and 3, anti-HPV6/11/16/18 GMTs at month 7 were non-inferior in the experimental arms compared with the control arm; however, there was a trend for lower antibody responses for all 4 HPV types. In Study 2, this immune interference was overcome with the mid- and high-dose formulations of the 9vHPV vaccine by increasing antigen and adjuvant doses. In all 3 studies, all vaccine candidates were strongly immunogenic with respect to HPV31/33/45/52/58 and were well tolerated. Based on the totality of the results, the middle dose formulation of the 9vHPV vaccine was selected for Phase III evaluation. Each 0.5mL dose contains 30μg/40μg/60μg/40μg/20μg/20μg/20μg/20μg/20μg of HPV6/11/16/18/31/33/45/52/58 virus-like particles, and 500μg of amorphous aluminum hydroxyphosphate sulfate adjuvant.ClinicalTrials.gov numbers NCT00260039, NCT00543543, and NCT00551187.

  18. A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer

    PubMed Central

    Otterson, Gregory A.; Dowlati, Afshin; Traynor, Anne M.; Horn, Leora; Owonikoko, Taofeek K.; Ross, Helen J.; Hann, Christine L.; Abu Hejleh, Taher; Nieva, Jorge; Zhao, Xiuhua; Schell, Michael; Sullivan, Daniel M.

    2016-01-01

    Lessons Learned Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. Background. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. Methods. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. Results. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71

  19. Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine

    PubMed Central

    Luxembourg, Alain; Brown, Darron; Bouchard, Celine; Giuliano, Anna R; Iversen, Ole-Erik; Joura, Elmar A; Penny, Mary E; Restrepo, Jaime A; Romaguera, Josefina; Maansson, Roger; Moeller, Erin; Ritter, Michael; Chen, Joshua

    2015-01-01

    Our objective was to develop a multivalent prophylactic HPV vaccine that protects against infection and disease caused by HPV16/18 (oncogenic types in existing prophylactic vaccines) plus additional oncogenic types by conducting 3 Phase II studies comparing the immunogenicity (i.e., anti-HPV6/11/16/18 geometric mean titers [GMT]) and safety of 7 vaccine candidates with the licensed quadrivalent HPV6/11/16/18 vaccine (qHPV vaccine) in young women ages 16–26. In the first study (Study 1), subjects received one of 3 dose formulations of an 8-valent HPV6/11/16/18/31/45/52/58 vaccine or qHPV vaccine (control). In Study 2, subjects received one of 3 dose formulations (termed low-, mid-, and high-dose formulations, respectively) of a 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine (9vHPV vaccine) or qHPV vaccine (control). In Study 3, subjects concomitantly received qHPV vaccine plus 5-valent HPV31/33/45/52/58 or qHPV vaccine plus placebo (control). All vaccines were administered at day 1/month 2/month 6. In studies 1 and 3, anti-HPV6/11/16/18 GMTs at month 7 were non-inferior in the experimental arms compared with the control arm; however, there was a trend for lower antibody responses for all 4 HPV types. In Study 2, this immune interference was overcome with the mid- and high-dose formulations of the 9vHPV vaccine by increasing antigen and adjuvant doses. In all 3 studies, all vaccine candidates were strongly immunogenic with respect to HPV31/33/45/52/58 and were well tolerated. Based on the totality of the results, the middle dose formulation of the 9vHPV vaccine was selected for Phase III evaluation. Each 0.5mL dose contains 30μg/40μg/60μg/40μg/20μg/20μg/20μg/20μg/20μg of HPV6/11/16/18/31/33/45/52/58 virus-like particles, and 500μg of amorphous aluminum hydroxyphosphate sulfate adjuvant.ClinicalTrials.gov numbers NCT00260039, NCT00543543, and NCT00551187. PMID:25912208

  20. Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study.

    PubMed

    Kuter, Irene; Gee, Julia M W; Hegg, Roberto; Singer, Christian F; Badwe, Rajendra A; Lowe, Elizabeth S; Emeribe, Ugochi A; Anderson, Elizabeth; Sapunar, Francisco; Finlay, Pauline; Nicholson, Robert I; Bines, José; Harbeck, Nadia

    2012-05-01

    NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

  1. Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer.

    PubMed

    Peschel, Christian; Hartmann, Joerg T; Schmittel, Alexander; Bokemeyer, Carsten; Schneller, Folker; Keilholz, Ulrich; Buchheidt, Dieter; Millan, Susana; Izquierdo, Miguel Angel; Hofheinz, Ralf-Dieter

    2008-06-01

    To evaluate the progression-free rate (PFR) at 3 months (13+/-1 weeks), antitumor response, time-to-event efficacy endpoints, and toxicity profile of plitidepsin administered as a 3-h continuous i.v. infusion at a dose of 5mg/m(2), every 2 weeks, to patients with chemotherapy pretreated advanced non-small cell lung cancer (NSCLC). This was a multicenter, non-randomized, exploratory, phase II study. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. PFR (primary efficacy endpoint) and objective response rate (secondary efficacy endpoint) were evaluated according to RECIST, while the toxic profile of plitidepsin was assessed using the NCI-CTC, version 2.0. A total of 21 patients with a median age of 61 years and with locally advanced or metastatic non-resectable NSCLC, who had previously received only one line of chemotherapy in an advanced setting, received a total of 54 cycles of treatment (median of two cycles per patient; range: 1-8). Antitumor activity was seen in 3 (1 PR, 2 SD) out of 17 evaluable patients according to RECIST. One patient was responder for the primary (PFR at 13+/-1 weeks) and secondary efficacy endpoint (stable disease according to RECIST). Other two patients were non-responders for the primary efficacy endpoint, but had stable disease (not confirmed at weeks 13+/-1 due to previous withdrawal due to adverse events). With a median follow-up of 12.3 months, the median time to progression (TTP) and the median overall survival (OS) were 1.2 months and 4.3 months, respectively. The incidence of plitidepsin-related toxicities was low and most of them were mild-to-moderate in severity. The most common side effects were anemia, and asymptomatic and non-cumulative increases of gamma-glutamyltransferase (GGT) and liver transaminase levels. This study shows that plitidepsin 3-h continuous i.v. infusion (5mg/m(2)) every 2 weeks, was feasible and well tolerated in patients with pretreated

  2. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma.

    PubMed

    Dreyling, M; Morschhauser, F; Bouabdallah, K; Bron, D; Cunningham, D; Assouline, S E; Verhoef, G; Linton, K; Thieblemont, C; Vitolo, U; Hiemeyer, F; Giurescu, M; Garcia-Vargas, J; Gorbatchevsky, I; Liu, L; Koechert, K; Peña, C; Neves, M; Childs, B H; Zinzani, P L

    2017-09-01

    Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

  3. ET-12PHASE II STUDY OF ONARTUZUMAB PLUS BEVACIZUMAB VERSUS PLACEBO PLUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

    PubMed Central

    Cloughesy, Tim; Finocchiaro, Gaetano; Belda-Iniesta, Cristobel; Recht, Lawrence; Brandes, Alba A; Pineda, Estela; Mikkelsen, Tom; Chinot, Olivier; Balana, Carmen; Macdonald, David; Westphal, Manfred; Hopkins, Kirsten; Weller, Michael; Bruey, Jean-Marie; Liu, Bo; Verret, Wendy

    2014-01-01

    BACKGROUND: Glioblastomas are highly vascularized with elevated VEGF expression and have been shown to respond to the anti-VEGF antibody bevacizumab. High MET expression has been associated with shorter progression-free survival (PFS) in glioblastomas (Pierscianek, et al. Brain Pathol 2013). This phase II study investigated the monovalent MET inhibitor, onartuzumab, plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pl + Bev) in recurrent glioblastoma. METHODS: Bevacizumab-naïve patients with glioblastoma at first recurrence following chemoradiation were randomized 1:1 to receive Ona (15mg/kg, q3w) + Bev (15mg/kg, q3w) or Pl + Bev until disease progression. Enrollment onto a third arm, Ona + Pl, was put on hold during assessment of safety data and was subsequently closed due to study conduct concerns (data not presented). Primary endpoint: PFS by RANO criteria (ITT and MET biomarker-positive subpopulations). Secondary endpoints: overall survival, objective response rate, duration of response, and safety. RESULTS: In the 129 patients enrolled (Ona + Bev n = 64, Pl + Bev n = 65) baseline characteristics were balanced; median age was 57 years; 43.4% had Karnofsky performance status 90-100%; 87.6% had measurable disease at baseline. Median number of bevacizumab cycles: 5 for Ona + Bev, 6 for Pl + Bev; median onartuzumab cycles, 4; median placebo cycles, 6. Grade ≥3 adverse events (AEs) were reported in 38.5% of Ona + Bev and 35.9% of Pl + Bev patients; serious AEs were reported in 30.8% and 29.7%, respectively. Grade 5 AEs: Ona + Bev n = 2 intestinal perforation; Pl + Bev n = 1 intracranial hemorrhage. AEs leading to study drug withdrawal were seen in 10.8% of Ona + Bev and 6.3% of Pl + Bev patients. AEs (all grades) with a difference in incidence of ≥10% between arms included peripheral edema (44.6% Ona + Bev, 14.1% Pl + Bev), hypertension (12.3% Ona + Bev, 32.8% Pl + Bev) and hypoalbuminemia (12.3% Ona + Bev, 1.6% Pl + Bev). Efficacy data are pending

  4. Immunochemotherapy with interleukin-2, interferon- α and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study

    PubMed Central

    Herpen, C M L van; Jansen, R L H; Kruit, W H J; Hoekman, K; Groenewegen, G; Osanto, S; Mulder, P H M De

    2000-01-01

    In patients with metastatic renal cell carcinoma response rates of 7–26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-α (IFN-α), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993 a) Eur J Cancer29A: S6–8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m−2was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m−2t.i.w. in weeks 2 and 3. Recombinant human IFN-α 2a 6 MU m−2was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m−2t.i.w. in weeks 5–8. 5-FU (750 mg m−2) was given as a bolus injection intravenous once a week in weeks 5–8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1–5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1–153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9–20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8–22.4+) months. Median survival was 16.5 (range 1.8–30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-α, IL-2 and 5-FU, as described

  5. Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme.

    PubMed

    Turner, Christopher D; Chi, Susan; Marcus, Karen J; MacDonald, Tobey; Packer, Roger J; Poussaint, Tina Young; Vajapeyam, Sridhar; Ullrich, Nicole; Goumnerova, Liliana C; Scott, R Michael; Briody, Caitlin; Chordas, Christine; Zimmerman, Mary Ann; Kieran, Mark W

    2007-03-01

    A phase II study was conducted to assess the efficacy of administering daily thalidomide concomitantly with radiation and continuing for up to 1 year following radiation in children with brain stem gliomas (BSG) or glioblastoma multiforme (GBM). Secondary objectives were to obtain preliminary evidence of biologic activity of thalidomide and to evaluate toxicities from chronic administration of thalidomide in this population. Thirteen patients (2-14 years old) with newly diagnosed BSG (12 patients) or GBM (one patient) were enrolled between July 1999 and June 2000. All patients received focal radiotherapy to a total dose of 5,580 cGy. Thalidomide was administered once daily beginning on the first day of radiation and continued for 12 months or until the patient came off study. The starting dose was 12 mg/kg (rounded down to the nearest 50 mg) and was increased by 20% weekly, if tolerated, to 24 mg/kg or 1,000 mg (whichever was lower). Advanced imaging techniques and urine and serum analysis for anti-angiogenic markers were performed in some patients in an attempt to correlate changes with clinical effect of therapy. No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression. The median duration of therapy was 5 months (range 2-11 months). Nine patients came off study for progressive disease (PD), three patients due to toxicity and one patient withdrew consent. Several patients on this study required more extended courses of high dose steroids than would have been otherwise expected for this population due to significant peritumoral edema and necrosis. No consistent pattern emerged from the biologic correlative studies from 11 patients. However, advanced imaging with techniques such as MR spectroscopy, MR perfusion and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were helpful in distinguishing growing tumor from treatment effect and necrosis in some patients. The median time to progression (TTP

  6. Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.

    PubMed

    Cowan, Andrew J; Stevenson, Phillip A; Gooley, Ted A; Frayo, Shani L; Oliveira, George R; Smith, Stephen D; Green, Damian J; Roden, Jennifer E; Pagel, John M; Wood, Brent L; Press, Oliver W; Gopal, Ajay K

    2017-02-01

    Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m(2) PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m(2) IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m(2) twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL. © 2017 John Wiley & Sons Ltd.

  7. Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: A multicentric phase II study

    SciTech Connect

    Valentini, Vincenzo . E-mail: vvalentini@rm.unicatt.it; Morganti, Alessio G.; Gambacorta, M. Antonietta; Mohiuddin, Mohammed; Doglietto, G. Battista; Coco, Claudio; De Paoli, Antonino; Rossi, Carlo; Di Russo, Annamaria; Valvo, Francesca; Bolzicco, Giampaolo; Dalla Palma, Maurizio

    2006-03-15

    Purpose: The combination of irradiation and total mesorectal excision for rectal carcinoma has significantly lowered the incidence of local recurrence. However, a new problem is represented by the patient with locally recurrent cancer who has received previous irradiation to the pelvis. In these patients, local recurrence is very often not easily resectable and reirradiation is expected to be associated with a high risk of late toxicity. The aim of this multicenter phase II study is to evaluate the response rate, resectability rate, local control, and treatment-related toxicity of preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis. Methods and Materials: Patients with histologically proven pelvic recurrence of rectal carcinoma, with the absence of extrapelvic disease or bony involvement and previous pelvic irradiation with doses {<=}55 Gy; age {>=}18 years; performance status (PS) (Karnofsky) {>=}60, and who gave institutional review board-approved written informed consent were treated by preoperative chemoradiation. Radiotherapy was delivered to a planning target volume (PTV2) including the gross tumor volume (GTV) plus a 4-cm margin, with a dose of 30 Gy (1.2 Gy twice daily with a minimum 6-h interval). A boost was delivered, with the same fractionation schedule, to a PTV1 including the GTV plus a 2-cm margin (10.8 Gy). During the radiation treatment, concurrent chemotherapy was delivered (5-fluorouracil, protracted intravenous infusion, 225 mg/m{sup 2}/day, 7 days per week). Four to 6 weeks after the end of chemoradiation, patients were evaluated for tumor resectability, and, when feasible, surgical resection of recurrence was performed between 6-8 weeks from the end of chemoradiation. Adjuvant chemotherapy was prescribed to all patients, using Raltitrexed, 3 mg/square meter (sm), every 3 weeks, for a total of 5 cycles. Patients were staged using the computed tomography (CT)-based F

  8. Phase II study of high-dose somatostatin analogue in patients either previously treated or untreated who have extensive-stage small cell lung cancer.

    PubMed

    Marschke, R F; Grill, J P; Sloan, J A; Wender, D B; Levitt, R; Mailliard, J A; Gerstner, J B; Ghosh, C; Morton, R F; Jett, J R

    1999-02-01

    The authors conducted a phase II study of somatostatin analogue in 18 patients with extensive stage small cell lung cancer (four with previous treatment, 14 without previous treatment). Patients received 2,000 mg subcutaneously thrice daily. They were required to have an Eastern Cooperative Oncology Group performance score of 0-2 and acceptable pretreatment biochemical parameters. No patient responded to treatment. The median time to progression was 44 days. The median survival was 106 days. Toxicity related to treatment consisted of mild diarrhea and anorexia. Somatostatin analogue is not active as a single agent in the treatment of extensive-stage small cell lung cancer.

  9. A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma.

    PubMed

    Goy, André; Hernandez-Ilzaliturri, Francisco J; Kahl, Brad; Ford, Peggy; Protomastro, Ewelina; Berger, Mark

    2014-12-01

    Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m(2), administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m(2) was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed.

  10. Methodological Aspects of the Phase II Study AFF006 Evaluating Amyloid-beta -Targeting Vaccine AFFITOPE® AD02 in Early Alzheimer's Disease - Prospective Use of Novel Composite Scales.

    PubMed

    Hendrix, S; Ellison, N; Stanworth, S; Tierney, L; Mattner, F; Schmidt, W; Dubois, B; Schneeberger, A

    2015-06-01

    Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aβ)-targeting vaccine to elicit anti-Aβ antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. Cognitive items that were selected for the adapted

  11. Phase I/II study of a combination of capecitabine, cisplatin, and intraperitoneal docetaxel (XP ID) in advanced gastric cancer patients with peritoneal metastasis.

    PubMed

    Cho, Hyungwoo; Ryu, Min-Hee; Kim, Kyu-Pyo; Ryoo, Baek-Yeol; Park, Sook Ryun; Kim, Bum Soo; Lee, In-Seob; Kim, Hee-Sung; Yoo, Moon-Won; Yook, Jeong Hwan; Oh, Seong Tae; Kim, Byung Sik; Kang, Yoon-Koo

    2017-03-16

    This study was conducted to determine the recommended dose (RD) of intraperitoneal docetaxel (ID) in combination with systemic capecitabine and cisplatin (XP) and to evaluate its efficacy and safety at the RD in advanced gastric cancer (AGC) patients with peritoneal metastasis. AGC patients with peritoneal metastasis received XP ID, which consists of 937.5 mg/m(2) of capecitabine twice daily on days 1-14, 60 mg/m(2) of intravenous cisplatin on day 1, and intraperitoneal docetaxel at 3 different dose levels (60, 80, or 100 mg/m(2)) on day 1, every 3 weeks. In the phase I study, the standard 3 + 3 method was used to determine the RD of XP ID. In the phase II study, patients received RD of XP ID. In the phase I study, ID 100 mg/m(2) was chosen as the RD, with one dose-limiting toxicity (ileus) out of six patients. The 39 AGC patients enrolled in the phase II study received the RD of XP ID. The median progression-free survival was 11.0 months (95% CI 6.9-15.1), and median overall survival was 15.1 months (95% CI 9.1-21.1). The most frequent grade 3/4 adverse events were neutropenia (38.6%) and abdominal pain (30.8%). The incidence of abdominal pain cumulatively increased in the later treatment cycles. Our study indicated that XP ID was effective, with manageable toxicities, in AGC patients with peritoneal metastasis. As the cumulative incidence of abdominal pain was probably related to bowel irritation by ID, it might be necessary to modify the dose.

  12. Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.

    PubMed

    Ishida, Takashi; Utsunomiya, Atae; Jo, Tatsuro; Yamamoto, Kazuhito; Kato, Koji; Yoshida, Shinichiro; Takemoto, Shigeki; Suzushima, Hitoshi; Kobayashi, Yukio; Imaizumi, Yoshitaka; Yoshimura, Kenichi; Kawamura, Kouichi; Takahashi, Takeshi; Tobinai, Kensei; Ueda, Ryuzo

    2017-08-04

    The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  13. A phase II study tests a new drug for patients with advanced thyroid cancer | Center for Cancer Research

    Cancer.gov

    A phase II trial of CUDC-907, a new drug that may be able to shrink thyroid tumors that have spread or gotten worse, is being tested in metastatic or advanced thyroid cancer.  Currently, there is no standard or effective treatment for the most aggressive types of thyroid cancer such as anaplastic and poorly differentiated thyroid cancer.  Learn more...

  14. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

    PubMed

    Wakelee, Heather A; Gettinger, Scott; Engelman, Jeffrey; Jänne, Pasi A; West, Howard; Subramaniam, Deepa S; Leach, Joseph; Wax, Michael; Yaron, Yifah; Miles, Dale R; Lara, Primo N

    2017-05-01

    Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

  15. A Phase II study of olaparib in breast cancer patients: biological evaluation from a 'window of opportunity' trial.

    PubMed

    Roviello, Giandomenico; Milani, Manuela; Gobbi, Angela; Dester, Martina; Cappelletti, Maria Rosa; Allevi, Giovanni; Aguggini, Sergio; Ravelli, Andrea; Gussago, Francesca; Cocconi, Alessandra; Zanotti, Laura; Senti, Chiara; Strina, Carla; Bottini, Alberto; Generali, Daniele

    2016-10-01

    The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.

  16. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma.

    PubMed

    Berdeja, Jesus G; Hart, Lowell L; Mace, Joseph R; Arrowsmith, Edward R; Essell, James H; Owera, Rami S; Hainsworth, John D; Flinn, Ian W

    2015-05-01

    The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m(2) carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118).

  17. Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Advanced Melanoma

    PubMed Central

    Ott, Patrick A.; Hamid, Omid; Pavlick, Anna C.; Kluger, Harriet; Kim, Kevin B.; Boasberg, Peter D.; Simantov, Ronit; Crowley, Elizabeth; Green, Jennifer A.; Hawthorne, Thomas; Davis, Thomas A.; Sznol, Mario; Hwu, Patrick

    2014-01-01

    Purpose The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. Patients and Methods Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. Results One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. Conclusion Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity. PMID:25267741

  18. Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia.

    PubMed

    Burns, C Patrick; Halabi, Susan; Clamon, Gerald; Kaplan, Ellen; Hohl, Raymond J; Atkins, James N; Schwartz, Michael A; Wagner, Brett A; Paskett, Electra

    2004-07-15

    The authors undertook a multiinstitutional Phase II cooperative group study to examine the potential of oral fish oil fatty acid supplements administered at high doses to slow weight loss and to improve quality of life in patients with malignancy-related cachexia. Patients with advanced malignancy and weight loss > or = 2% of body weight in the preceding month took concentrated, high-dose omega-3 fatty acid capsules (7.5 g eicosapentaenoic acid plus docosahexaenoic acid for a 70 kg individual) that were supplied by the National Institutes of Health. Forty-three patients with moderate or severe malnutrition were enrolled. The median time receiving treatment was 1.2 months. For the 36 patients who took at least 1 capsule and did not have edema, there was a weight change ranging from -6.2 kg to +3.5 kg and an overall median weight loss of 0.8 kg. Twenty-four patients had weight stabilization (a gain of < or = 5% or a loss of < 5%), 6 patients gained > 5% of their body weight, and 6 patients lost > or = 5% of their body weight. There was marked variability in the tolerability of the capsules, and many patients had gastrointestinal side effects. There was a correlation between time receiving treatment and weight gain for the 22 patients who were able to tolerate the capsules for at least 1 month. Quality-of-life scores were superior for patients who gained weight. A majority of patients did not gain weight, and in that sense, the results of the study were unfavorable. However, a small but definite subset of patients had weight stabilization or weight gain. This suggests that omega-3 fatty acids have potential utility at the study doses, which were more than twice the doses used in published Phase III studies. Copyright 2004 American Cancer Society.

  19. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer

    PubMed Central

    Paller, CJ; Ye, X; Wozniak, PJ; Gillespie, BK; Sieber, PR; Greengold, RH; Stockton, BR; Hertzman, BL; Efros, MD; Roper, RP; Liker, HR; Carducci, MA

    2012-01-01

    BACKGROUND Pomegranate juice has been associated with PSA doubling time (PSADT) elongation in a single-arm phase II trial. This study assesses biological activity of two doses of pomegranate extract (POMx) in men with recurrent prostate cancer, using changes in PSADT as the primary outcome. METHODS This randomized, multi-center, double-blind phase II, dose-exploring trial randomized men with a rising PSA and without metastases to receive 1 or 3 g of POMx, stratified by baseline PSADT and Gleason score. Patients (104) were enrolled and treated for up to 18 months. The intent-to-treat (ITT) population was 96% white, with median age 74.5 years and median Gleason score 7. This study was designed to detect a 6-month on-study increase in PSADT from baseline in each arm. RESULTS: Overall, median PSADT in the ITT population lengthened from 11.9 months at baseline to 18.5 months after treatment (P<0.001). PSADT lengthened in the low-dose group from 11.9 to 18.8 months and 12.2 to 17.5 months in the high-dose group, with no significant difference between dose groups (P =0.554). PSADT increases >100% of baseline were observed in 43% of patients. Declining PSA levels were observed in 13 patients (13%). In all, 42% of patients discontinued treatment before meeting the protocol-definition of PSA progression, or 18 months, primarily due to a rising PSA. No significant changes occurred in testosterone. Although no clinically significant toxicities were seen, diarrhea was seen in 1.9% and 13.5% of patients in the 1- and 3-g dose groups, respectively. CONCLUSIONS POMx treatment was associated with ≥6 month increases in PSADT in both treatment arms without adverse effects. The significance of this on-study slowing of PSADT remains unclear, reinforcing the need for placebo-controlled studies in this patient population. PMID:22689129

  20. 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

  1. 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.

  2. A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib.

    PubMed

    Lee, Ji Yun; Sun, Jong-Mu; Lim, Sung Hee; Kim, Hae Su; Yoo, Kwai Han; Jung, Ki Sun; Song, Haa-Na; Ku, Bo Mi; Koh, Jiae; Bae, Yeon-Hee; Lee, Se-Hoon; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung-Ju

    2016-05-01

    In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively. Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139-45. ©2015 AACR. ©2015 American Association for Cancer Research.

  3. A phase II study of AZD2171 (cediranib) in the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.

    PubMed

    Mattison, Ryan; Jumonville, Alcee; Flynn, Patrick James; Moreno-Aspitia, Alvaro; Erlichman, Charles; LaPlant, Betsy; Juckett, Mark B

    2015-07-01

    Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) not fit for intensive treatment need novel therapy options. Vascular endothelial growth factor (VEGF) receptor inhibition is one potential mechanism by which AML and MDS could be treated. The receptor tyrosine kinase inhibitor AZD2171 (cediranib) has activity against VEGF receptors KDR and FLT-1. This multicenter phase II study was designed to test cediranib's activity in patients with AML or high-risk MDS. The primary endpoint was confirmed disease response defined as a composite of complete remission, partial remission or hematologic improvement. The study enrolled 23 subjects in the AML cohort and 16 subjects in the MDS cohort. There were no confirmed responses in either group. Since the study met the stopping rule after the first stage of enrollment, the trial was closed to further accrual. Common adverse events in both cohorts included thrombocytopenia, neutropenia, anemia, fatigue, dyspnea, diarrhea, nausea and dehydration.

  4. A phase II study of sorafenib (BAY 43–9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404)

    PubMed Central

    2013-01-01

    Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43–9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1–12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 – 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 – 5 months). Median overall survival (OS) was 9 months (90% CI, 5 – 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL. PMID:23829878

  5. A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121).

    PubMed

    Mathew, Prasad; Gerbing, Robert; Alonzo, Todd A; Wallas, Tanya; Gong, Jerald Z; Jasty, Rama; Jorstad, Dean T; Raimondi, Susana C; Chavez, Cathy M; Eisenberg, Nancy L; Hirsch, Betsy; Gamis, Alan; Smith, Franklin O; Arceci, Robert J

    2011-12-15

    Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study. Copyright © 2011 Wiley Periodicals, Inc.

  6. RFS2000 (9-nitrocamptothecin) in advanced small cell lung cancer, a phase II study of the EORTC New Drug Development Group.

    PubMed

    Punt, C J A; de Jonge, M J A; Monfardini, S; Daugaard, G; Fiedler, W; Baron, B; Lacombe, D; Fumoleau, P

    2004-06-01

    Camptothecins have shown efficacy in terms of response rate in patients with small cell lung cancer (SCLC). RFS2000 is a new camptothecin derivative, which has shown objective responses in various tumour types. The aim of this phase II study was to determine the objective response rate of RFS2000 in patients with sensitive and refractory SCLC. RFS2000 was given orally at 1.5 mg/m(2) per day for five consecutive days (five days on - two days off) on a continuous basis. Patients were evaluated weekly for toxicity and every six weeks for response. Thirty seven patients were included, 36 patients (14 with sensitive and 22 with refractory SCLC) were evaluable for toxicity, and 35 patients were evaluable for response. No objective responses were observed. Toxicity was acceptable, with myelosuppression, nausea/vomiting, and diarrhoea as the main toxicities. RFS2000 therefore has an acceptable toxicity profile but is not active as a single agent in SCLC.

  7. Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer: Regimen of 1 week on, 1 week off.

    PubMed

    Li, Jin; Xu, Ruihua; Xu, Jianming; Denda, Tadamichi; Ikejiri, Koji; Shen, Lin; Toh, Yasushi; Shimada, Ken; Kato, Takeshi; Sakai, Kenji; Yamamoto, Manabu; Mishima, Hideyuki; Wang, Jinwan; Baba, Hideo

    2017-10-01

    A phase II study of S-1 plus leucovorin (LV) given in a 4-week schedule (2 weeks' administration followed by 2 weeks' rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2-week schedule of S-1 plus LV. Patients with mCRC received oral S-1 (40-60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S-1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy-three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression-free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment-related deaths. The pharmacokinetics profiles of S-1 plus LV in Chinese patients were similar to those in Japanese patients. This 2-week schedule of S-1 plus LV showed good efficacy and better tolerability than the 4-week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular-targeted drugs. The optimized treatment schedule for S-1 plus LV was 1 week on and 1 week off. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  8. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.

    PubMed

    Salloum, Ralph; Hummel, Trent R; Kumar, Shiva Senthil; Dorris, Kathleen; Li, Shaoyu; Lin, Tong; Daryani, Vinay M; Stewart, Clinton F; Miles, Lili; Poussaint, Tina Young; Stevenson, Charles; Goldman, Stewart; Dhall, Girish; Packer, Roger; Fisher, Paul; Pollack, Ian F; Fouladi, Maryam; Boyett, James; Drissi, Rachid

    2016-09-01

    Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

  9. Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma.

    PubMed

    Plummer, R; Lorigan, P; Brown, E; Zaucha, R; Moiseyenko, V; Demidov, L; Soriano, V; Chmielowska, E; Andrés, R; Kudryavtseva, G; Kahatt, C; Szyldergemajn, S; Extremera, S; de Miguel, B; Cullell-Young, M; Calvert, H

    2013-09-17

    This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38). The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found. This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.

  10. Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group Single-Arm Phase II study.

    PubMed

    Toulmonde, M; Le Cesne, A; Piperno-Neumann, S; Penel, N; Chevreau, C; Duffaud, F; Bellera, C; Italiano, A

    2015-07-01

    Preclinical data have suggested a therapeutic role of JUN pathway activation in dedifferentiated liposarcoma (DDLPS) tumorigenesis. Aplidin is a drug inducing apoptosis through a strong, sustained activation of c-Jun NH2-terminal kinase. This phase II trial included patients with progressive advanced DDLPS. They received Aplidin 5 mg/m(2) days 1-15, 28-day cycle until disease progression or unacceptable toxicity. The primary end point was the 3-month nonprogression rate (PFS3) defined as the proportion of patients with nonprogressive disease at 3 months. A PFS3 of 40% considered as a reasonable objective to claim drug efficacy. Between August 2012 and May 2013, 24 patients were included. Sixteen had received prior chemotherapy. Twenty-two were assessable for efficacy. The PFS3 was 9.1% [95% confidence interval (CI) 1.1-29.2]. Median progression-free and overall survivals were 1.6 months (95% CI 1.4-2.6) and 9.2 months (95% CI 6.6-). The most frequent adverse events of any grade were nausea, fatigue, anorexia, vomiting and diarrhea. Aplidin did not meet the primary end point of this trial and do not deserve further investigation in DDLPS. NCT01876043. © 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.

  11. Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group Single-Arm Phase II study

    PubMed Central

    Toulmonde, M.; Le Cesne, A.; Piperno-Neumann, S.; Penel, N.; Chevreau, C.; Duffaud, F.; Bellera, C.; Italiano, A.

    2015-01-01

    Background Preclinical data have suggested a therapeutic role of JUN pathway activation in dedifferentiated liposarcoma (DDLPS) tumorigenesis. Aplidin® is a drug inducing apoptosis through a strong, sustained activation of c-Jun NH2-terminal kinase. Methods This phase II trial included patients with progressive advanced DDLPS. They received Aplidin® 5 mg/m2 days 1–15, 28-day cycle until disease progression or unacceptable toxicity. The primary end point was the 3-month nonprogression rate (PFS3) defined as the proportion of patients with nonprogressive disease at 3 months. A PFS3 of 40% considered as a reasonable objective to claim drug efficacy. Results Between August 2012 and May 2013, 24 patients were included. Sixteen had received prior chemotherapy. Twenty-two were assessable for efficacy. The PFS3 was 9.1% [95% confidence interval (CI) 1.1–29.2]. Median progression-free and overall survivals were 1.6 months (95% CI 1.4–2.6) and 9.2 months (95% CI 6.6–). The most frequent adverse events of any grade were nausea, fatigue, anorexia, vomiting and diarrhea. Conclusion Aplidin® did not meet the primary end point of this trial and do not deserve further investigation in DDLPS. ClinicalTrials.gov Identifier NCT01876043. PMID:26041763

  12. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer.

    PubMed Central

    Adachi, I.; Watanabe, T.; Takashima, S.; Narabayashi, M.; Horikoshi, N.; Aoyama, H.; Taguchi, T.

    1996-01-01

    A late phase II clinical trial of RP56976 (docetaxel), derived from Taxus baccata was performed to evaluate anti-tumour activity, time to progression and clinical toxicity in patients with advanced or recurrent breast cancer. The patients, between 15 and 80 years old with performance status (PS) of 0-2, received at least two cycles of docetaxel 60 mg m-2 intravenously at 3-4 week intervals. Of the 81 patients enrolled, the 72 eligible for the study were given a total of 327 cycles, with a median of four cycles each. Five patients obtained a complete response (CR) and 27 a partial response (PR); the response rate (RR) was 44.4% (95% confidence interval 32.7-56.6%). A relatively high RR of 9/28 (32.1%) was observed in patients who had received prior chemotherapy involving anthracyclines. The dose-limiting toxicity was grade 3-4 leucocytopenia or neutropenia, found in 78.9% and 85.9% patients respectively. Other severe (grade > 3) toxicities included alopecia (38%), anorexia (18.3%), nausea/vomiting (11.3%), and fatigue (9.9%). Hypersensitivity reactions, oedema and skin toxicity were not severe and were reversible. One therapy-related death occurred 10 days after the initial dose was given. These findings indicate that docetaxel has potent activity against metastatic breast cancer, and that the dose of 60 mg m-2 is safe. PMID:8546908

  13. 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.

  14. Phase II Study of the Histone Deacetylase Inhibitor MGCD0103 in Patients with Previously Treated Chronic Lymphocytic Leukemia

    PubMed Central

    Blum, Kristie A.; Advani, Anjani; Fernandez, Louis; Van Der Jagt, Richard; Brandwein, Joseph; Kambhampati, Suman; Kassis, Jeannine; Davis, Melanie; Bonfils, Claire; Dubay, Marja; Dumouchel, Julie; Drouin, Michel; Lucas, David M.; Martell, Robert E.; Byrd, John C.

    2009-01-01

    MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/day, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after 2 or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0.23 μM and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of 2 cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and 4 patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consisted of infections, thrombocytopenia, anemia, diarrhea, and fatigue. HDAC inhibition was observed in 6 out of 9 patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs. PMID:19747365

  15. 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.

  16. A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer.

    PubMed

    Beardsley, Emma K; Hotte, Sebastien J; North, Scott; Ellard, Susan L; Winquist, Eric; Kollmannsberger, Christian; Mukherjee, Som D; Chi, Kim N

    2012-08-01

    The objective of this trial was to evaluate the clinical effects of sorafenib, a multi-targeted kinase inhibitor, in combination with androgen receptor blockade in patients with castration-resistant prostate cancer. This was a multicenter, two-stage, phase 2 trial. Eligible patients had rising PSA, minimal symptoms and were chemotherapy-naïve. Sorafenib 400 mg twice daily was administered with bicalutamide 50 mg once daily on a 28-day cycle. The primary endpoint was PSA response (≥ 50% decline) or stable disease ≥ 6 months. 39 patients were enrolled including eight without clinical evidence of metastases. Eighteen (47%) patients have had either a PSA response or stable disease ≥ 6 months. PSA declines of ≥ 50% occurred in 12 (32%) of 38 assessable patients, including seven of 27 patients (26%) with prior anti-androgen use. Median time to treatment failure was 5.5 months (95%CI = 4.8.1-8.3). Grade ≥ 3 adverse events included fatigue, skin rash, and hand-foot syndrome. PSA declines and stable disease were observed with a combination of sorafenib and bicalutamide including in patients previously progressing on bicalutamide. Strategies to combine multi-targeted kinase inhibitors with hormonal therapies warrant further study in patients with CRPC.

  17. Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study.

    PubMed

    Pels, Hendrik; Juergens, Annika; Glasmacher, Axel; Schulz, Holger; Engert, Andreas; Linnebank, Michael; Schackert, Gabriele; Reichmann, Heinz; Kroschinsky, Frank; Vogt-Schaden, Marlies; Egerer, Gerlinde; Bode, Udo; Schaller, Carlo; Lamprecht, Monika; Hau, Peter; Deckert, Martina; Fimmers, Rolf; Bangard, Christopher; Schmidt-Wolf, Ingo G H; Schlegel, Uwe

    2009-02-01

    A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.

  18. Immunosuppressive Therapy of LGL Leukemia: Prospective Multicenter Phase II Study by the Eastern Cooperative Oncology Group (E5998)

    PubMed Central

    Loughran, Thomas P.; Zickl, Lynette; Olson, Thomas L.; Wang, Victoria; Zhang, Dan; Rajala, Hanna L.M.; Hasanali, Zainul; Bennett, John M.; Lazarus, Hillard M.; Litzow, Mark R.; Evens, Andrew M.; Mustjoki, Satu; Tallman, Martin S.

    2015-01-01

    Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate at 10 mg/m2 orally weekly as initial therapy (Step 1). Patients failing methotrexate were eligible for treatment with cyclophosphamide at 100 mg orally daily (Step 2). The overall response in Step 1 was 38% with 95% confidence interval (CI): 26%, 53%. The overall response in Step 2 was 64% with 95% CI: 35%, 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether methotrexate is appropriate therapy. PMID:25306898

  19. Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin’s lymphoma

    PubMed Central

    Ribrag, Vincent; Caballero, Dolores; Fermé, Christophe; Zucca, Emanuele; Arranz, Reyes; Briones, Javier; Gisselbrecht, Christian; Salles, Gilles; Gianni, Alessandro M.; Gomez, Henry; Kahatt, Carmen; Corrado, Claudia; Szyldergemajn, Sergio; Extremera, Sonia; de Miguel, Bernardo; Cullell-Young, Martin; Cavalli, Franco

    2013-01-01

    This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m2 administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin’s lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%–39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: NCT00884286) PMID:23065525

  20. Molecular structure of phthalocyaninatotin(II) studied by gas-phase electron diffraction and high-level quantum chemical calculations.

    PubMed

    Strenalyuk, Tatyana; Samdal, Svein; Volden, Hans Vidar

    2008-10-09

    The molecular structure of phthalocyaninatotin(II), Sn(II)Pc, is determined by density functional theory (DFT/B3LYP) calculations using various basis sets and gas-phase electron diffraction (GED). The quantum chemical calculations show that Sn(II)Pc has C4V symmetry, and this symmetry is consistent with the structure obtained by GED at 427 degrees C. GED locates the Sn atom at h(Sn) ) 112.8(48) pm above the plane defined by the four isoindole N atoms, and a N-Sn bond length of 226.0(10) pm is obtained. Calculation at the B3LYP/ccpVTZ/cc-pVTZ-PP(Sn) level of theory gives h(Sn) ) 114.2 pm and a N-Sn bond length of 229.4 pm. The phthalocyanine (Pc) macrocycle has a slightly nonplanar structure. Generally, the GED results are in good agreement with the X-ray structures and with the computed structure; however, the comparability between these three methods has been questioned. The N-Sn bond lengths determined by GED and X-ray are significantly shorter than those from the B3LYP predictions. Similar trends have been found for C-Sn bonds for conjugated organometallic tin compounds. Computed vibrational frequencies give five low frequencies in the range of 18-54 cm-1, which indicates a flexible molecule.

  1. A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours

    PubMed Central

    FAZIO, NICOLA; BUZZONI, ROBERTO; BAUDIN, ERIC; ANTONUZZO, LORENZO; HUBNER, RICHARD A.; LAHNER, HARALD; DE HERDER, WOUTER W.; RADERER, MARKUS; TEULÉ, ALEXANDRE; CAPDEVILA, JAUME; LIBUTTI, STEVEN K.; KULKE, MATTHEW H.; SHAH, MANISHA; DEY, DEBARSHI; TURRI, SABINE; AIMONE, PAOLA; MASSACESI, CRISTIAN; VERSLYPE, CHRIS

    2016-01-01

    Background This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). Patients and Methods In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. Results As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7–67.3%). Conclusion BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2. PMID:26851029

  2. Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study.

    PubMed

    Suzuki, Kenshi; Shinagawa, Atsushi; Uchida, Toshiki; Taniwaki, Masafumi; Hirata, Hirokazu; Ishizawa, Kenichi; Matsue, Kosei; Ogawa, Yoshiaki; Shimizu, Takayuki; Otsuka, Maki; Matsumoto, Morio; Iida, Shinsuke; Terui, Yasuhito; Matsumura, Itaru; Ikeda, Takashi; Takezako, Naoki; Ogaki, Yumi; Midorikawa, Shuichi; Houck, Vanessa; Ervin-Haynes, Annette; Chou, Takaaki

    2016-05-01

    In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.

  3. Misteltoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases.

    PubMed

    Kjaer, M

    1989-01-01

    The public interest in alternative cancer therapy is considerable. Since the 1920s advocators of anthroposophical medicine have postulated a highly significant effect of misteltoe plant extracts on life quality and survival of patients with most solid tumours. Fourteen patients, 8 men and 6 women, median age 65, range 47-74 years, with earlier untreated histologically verified renal adenocarcinoma stage IV and clearly measurable lung metastases were treated with subcutaneous injections of Iscador every second day in escalating doses over 3 weeks followed by maintenance therapy, 20, 30, and 50 mg/ml on respective days. Patients were evaluated monthly and disease status classified according to WHO criteria. No response was demonstrated. 2/14 patients died without change of the disease (NC) after 30 and 60 days respectively. The median time to progressive disease (PD) was 108 days, range 33-348 days. First site of PD was lungs in 10/12, outside lungs in 2/12 patients. All patients have died. The median survival was 330 days, range 44-694, which in a retrospective comparison was quite similar to earlier phase 2 studies in the same type of patients. Apart from local reactions around the injection sites and moderate fever on the day of injection the treatment was well tolerated with no major toxicities. It is concluded that Iscador under the conditions chosen for the study had no objective or life prolonging effects postulated for most solid tumour types by advocators of anthrosophy.

  4. Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

    SciTech Connect

    DeLaney, Thomas F. Liebsch, Norbert J.; Pedlow, Francis X.; Adams, Judith; Dean, Susan; Yeap, Beow Y.; McManus, Patricia; Rosenberg, Andrew E.; Nielsen, G. Petur; Harmon, David C.; Spiro, Ira J.; Raskin, Kevin A.; Suit, Herman D.; Yoon, Sam S.; Hornicek, Francis J.

    2009-07-01

    Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of {>=}66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

  5. A Phase II study of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

    PubMed

    Estévez, Laura G; Batista, Norberto; Sánchez-Rovira, Pedro; Velasco, Amalia; Provencio, Mariano; León, Ana; Dómine, Manuel; Cruz, Josefina; Rodríguez, Milva

    2008-04-01

    The aim of this study was to evaluate the efficacy and safety of capecitabine in combination with vinorelbine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. In this prospective, multicenter, open-label phase II trial, patients received capecitabine (2000 mg/m2 daily, taken in 2 oral doses) on days 1-14 and vinorelbine (25 mg/m2 intravenous infusion) on days 1 and 8. Cycles were repeated every 3 weeks up to a maximum of 6 cycles, unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. Thirty-one patients were included and received 152 cycles of chemotherapy, with a median of 3 cycles per patient. All patients were evaluated for efficacy and toxicity in an intent-to-treat analysis. The overall response rate was 49% (95% CI, 30%-67%), including 4 complete (13%) and 11 partial (36%) responses. With a median follow-up time of 9 months, the median time to disease progression was 7.6 months (95% CI, 5.7-9.8 months), and the median survival time was 27.2 months. The most frequent severe hematologic toxicities were neutropenia (48% of patients) and leukopenia (10% of patients). Vomiting (16% of patients) was the most common nonhematologic toxicity, while asthenia, bone pain, dyspnea, plantar-palmar erythrodysesthesia, nausea, and transaminase elevation were observed in 6%-10% of patients. There was 1 death from septic shock. Capecitabine in combination with vinorelbine is an effective and safe schedule for patients with MBC pretreated with anthracycline- and taxane-containing regimens.

  6. Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology).

    PubMed

    Soffietti, Riccardo; Trevisan, Elisa; Bertero, Luca; Cassoni, Paola; Morra, Isabella; Fabrini, Maria Grazia; Pasqualetti, Francesco; Lolli, Ivan; Castiglione, Anna; Ciccone, Giovannino; Rudà, Roberta

    2014-02-01

    The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

  7. TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer

    PubMed Central

    Carey, Lisa A.; Rugo, Hope S.; Marcom, P. Kelly; Mayer, Erica L.; Esteva, Francisco J.; Ma, Cynthia X.; Liu, Minetta C.; Storniolo, Anna Maria; Rimawi, Mothaffar F.; Forero-Torres, Andres; Wolff, Antonio C.; Hobday, Timothy J.; Ivanova, Anastasia; Chiu, Wing-Keung; Ferraro, Madlyn; Burrows, Emily; Bernard, Philip S.; Hoadley, Katherine A.; Perou, Charles M.; Winer, Eric P.

    2012-01-01

    Purpose Epidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and Methods In this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m2 load then 250 mg/m2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. Results In 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. Conclusion Despite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms

  8. Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors.

    PubMed

    Ito, Tetsuhide; Honma, Yoshitaka; Hijioka, Susumu; Kudo, Atsushi; Fukutomi, Akira; Nozaki, Akira; Kimura, Yasutoshi; Motoi, Fuyuhiko; Isayama, Hiroyuki; Komoto, Izumi; Hisamatsu, Seiichi; Nakajima, Akihiro; Shimatsu, Akira

    2017-08-01

    Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. JapicCTI-132,375, JapicCTI-142,698.

  9. Tolerance and Acceptance Results of a Palladium-103 Permanent Breast Seed Implant Phase I/II Study

    SciTech Connect

    Pignol, Jean-Philippe Rakovitch, Eileen; Keller, Brian M.; Sankreacha, Raxa; Chartier, Carole

    2009-04-01

    Purpose: To test, in a prospective Phase I/II trial, a partial breast irradiation technique using a {sup 103}Pd permanent breast seed implant (PBSI) realized in a single 1-h procedure under sedation and local freezing. Methods and Materials: Eligible patients had infiltrating ductal carcinoma {<=}3 cm in diameter, surgical margin {>=}2 mm, no extensive intraductal component, no lymphovascular invasion, and negative lymph nodes. Patients received a permanent seed implant, and a minimal peripheral dose of 90 Gy was prescribed to the clinical target volume, with a margin of 1.5 cm. Results: From May 2004 to April 2007, 67 patients received the PBSI treatment. The procedure was well tolerated, with 17% of patients having significant pain after the procedure. Only 1 patient (1.5%) had an acute skin reaction (Grade 3 according to the National Cancer Institute Common Toxicity Criteria). The rates of acute moist desquamation, erythema, and indurations were 10.4%, 42%, and 27%, respectively. At 1 year the rate of Grade 1 telangiectasia was 14%. The rate of skin reaction decreased from 65% to 28% when skin received less than the 85% isodose. According to a Radiation Therapy Oncology Group questionnaire, 80-90% of patients were very satisfied with their treatment, and the remainder were satisfied. One patient (1.5%) developed an abscess, which resolved after the use of antibiotics. There was no recurrence after a median follow-up of 32 months (range, 11-49 months). Conclusions: The feasibility, safety, and tolerability of PBSI compares favorably with that of external beam and other partial breast irradiation techniques.

  10. Treatment of hepatic metastases of breast cancer with CT-guided interstitial brachytherapy - a phase II-study.

    PubMed

    Wieners, Gero; Mohnike, Konrad; Peters, Nils; Bischoff, Joachim; Kleine-Tebbe, Anke; Seidensticker, Ricarda; Seidensticker, Max; Gademann, Günther; Wust, Peter; Pech, Maciej; Ricke, Jens

    2011-08-01

    The aim of the study was the evaluation of feasibility, safety and effectiveness of interstitial brachytherapy for the treatment of hepatic metastases of breast cancer. Forty-one consecutive patients with 115 unresectable hepatic metastases of breast cancer were included in this phase-II-trial. They were treated in 69 interventions of CT-guided-interstitial-brachytherapy of the liver. Brachytherapy was applied as a single fraction high-dose-irradiation (15-25Gy (Gray)) using a (192)Ir-source of 10Ci. Nineteen patients presented systemically pretreated extrahepatic tumors. Primary endpoints were complications, local tumor control and progression-free survival. The median tumor diameter was 4.6 cm (1.5-11 cm). The median irradiation time per intervention was 26.5 min (range: 7-47 min). The applied median minimal dose at the CTV (clinical target volume) margin was 18.5 Gy (12-25 Gy). In 69 interventions and during the postinterventional period, one major complication (symptomatic post-interventional bleeding) (1.5%) and six minor complications occurred (8.7%). The median follow-up time was 18 months (range: 1-56). After 6, 12 and 18 months, local tumor control was 97%, 93.5% and 93.5%, intra- and extrahepatic progression free survival was 53%, 40% and 27%, and overall survival was 97%, 79% and 60%, respectively. CT-guided-brachytherapy is safe and effective for the treatment of liver metastases of breast cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

    PubMed

    Dalgleish, Angus G; Stebbing, Justin; Adamson, Douglas Ja; Arif, Seema Safia; Bidoli, Paolo; Chang, David; Cheeseman, Sue; Diaz-Beveridge, Robert; Fernandez-Martos, Carlos; Glynne-Jones, Rob; Granetto, Cristina; Massuti, Bartomeu; McAdam, Karen; McDermott, Raymond; Martín, Andrés J Muñoz; Papamichael, Demetris; Pazo-Cid, Roberto; Vieitez, Jose M; Zaniboni, Alberto; Carroll, Kevin J; Wagle, Shama; Gaya, Andrew; Mudan, Satvinder S

    2016-09-27

    Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01). IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

  12. A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response.

    PubMed

    Ferry, David R; Anderson, Mark; Beddard, Kate; Tomlinson, Simon; Atherfold, Paul; Obszynska, Jolanta; Harrison, Rebecca; Jankowski, Janusz

    2007-10-01

    At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor. This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after. Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment. Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.

  13. Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma

    PubMed Central

    Plummer, R; Lorigan, P; Brown, E; Zaucha, R; Moiseyenko, V; Demidov, L; Soriano, V; Chmielowska, E; Andrés, R; Kudryavtseva, G; Kahatt, C; Szyldergemajn, S; Extremera, S; de Miguel, B; Cullell-Young, M; Calvert, H

    2013-01-01

    Background: This phase I–II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. Methods: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m−2 (n=20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m−2 on days 1, 8 and 15 q4wk combined with DTIC 800 mg m−2 q4wk (n=38). Results: The overall response rate with plitidepsin/DTIC was 21.4% all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ⩽1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug–drug pharmacokinetic interactions were found. Conclusion: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m−2 fortnightly and DTIC 800 mg m−2 q4wk is recommended. PMID:23989947

  14. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study.

    PubMed

    Bauml, Joshua; Seiwert, Tanguy Y; Pfister, David G; Worden, Francis; Liu, Stephen V; Gilbert, Jill; Saba, Nabil F; Weiss, Jared; Wirth, Lori; Sukari, Ammar; Kang, Hyunseok; Gibson, Michael K; Massarelli, Erminia; Powell, Steven; Meister, Amy; Shu, Xinxin; Cheng, Jonathan D; Haddad, Robert

    2017-03-22

    Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

  15. Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease.

    PubMed

    Fleseriu, Maria; Pivonello, Rosario; Young, Jacques; Hamrahian, Amir H; Molitch, Mark E; Shimizu, Chikara; Tanaka, Tomoaki; Shimatsu, Akira; White, Tracy; Hilliard, Annie; Tian, Chuan; Sauter, Nicholas; Biller, Beverly M K; Bertagna, Xavier

    2016-04-01

    In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease. Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50% decrease from baseline) at weeks 10 and 22. Overall response rate was 89.5% (n/N = 17/19) at 10 weeks and 78.9% (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels. Osilodrostat treatment reduced UFC in all patients; 78.9% (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

  16. Phase II Study of Short-Course Radiotherapy Plus Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma

    SciTech Connect

    Minniti, Giuseppe; Lanzetta, Gaetano; Scaringi, Claudia; Caporello, Paola; Salvati, Maurizio; Arcella, Antonella; De Sanctis, Vitaliana; Giangaspero, Felice; Enrici, Riccardo Maurizi

    2012-05-01

    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{sup 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.

  17. [Early phase II study of FUT-187 (sepimostat mesilate) on reflux esophagitis--mainly on postgastrectomy reflux esophagitis].

    PubMed

    Abe, O; Yoshino, K; Kimura, K; Suzuki, H; Aoki, T; Hiki, Y; Mitomi, T; Makuuchi, H

    1994-05-01

    An early phase II clinical study with the proteolysis inhibitor FUT-187 was carried out on patients with reflux esophagitis. FUT-187 was administered orally at the dose of 300 mg/day or 400 mg/day four times daily, after meals and at bedtime, for 4 consecutive weeks. The total number of patients admitted to this study was 40, of whom 9 were assigned to 300 mg/day group and 31 to 400 mg/day group. The rate of effectiveness on postgastrectomy reflux esophagitis was 88% (7/8) in 300 mg/day group and 85%(22/26) in 400 mg/day group when "improved" or better final general improvement ratings were taken into consideration, and 75% (6/8) in 300 mg/day group and 69% (9/13) in 400 mg/day group when "improved" or better endoscopic general improvement ratings were used. The overall safety rating "no problem as to the drug safety" was 89% (8/9) in 300 mg/day group and 71% (22/31) in 400 mg/day group. The main side effect was diarrhea, which was experienced in 6 patients in 400 mg/day group. However, it was resolved by discontinuation of the drug treatment. Other symptoms of gastrointestinal upsets, such as nausea and anorexia, were also induced. Based on these results, it may be concluded that FUT-187 can be a drug with clinical utility that benefits postgastrectomy reflux esophagitis at the dose level of 300 mg/day or less.

  18. Phase II study of interim PET-CT-guided response-adapted therapy in advanced Hodgkin's lymphoma.

    PubMed

    Ganesan, P; Rajendranath, R; Kannan, K; Radhakrishnan, V; Ganesan, T S; Udupa, K; Lakshmipathy, K M; Mahajan, V; Sundersingh, S; Rajaraman, S; Krishnakumar, R; Sagar, T G

    2015-06-01

    Combination chemotherapy ABVD (doxorubicin, bleomycin, vinblastine and dacarabazine) cures ∼70% of patients with advanced Hodgkin's lymphoma (aHL, stages IIB, III and IV) while more toxic escalated BEACOPP (EB, combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) increases cure rates to 85%. Patients with a positive interim positron emission tomography-computerized tomography (PET-CT) scan after two cycles (PET-2) of ABVD have very poor outcomes with continued ABVD. Intensifying therapy with EB in PET-2-positive patients ('response-adapted therapy') may improve cure rates, whereas the negative patients can continue ABVD alone. Eligible patients with newly diagnosed aHL received two cycles of ABVD and underwent PET-2 (scored with semi-quantitative 5-point visual criteria, 'Deauville score'). PET-2-negative patients continued four additional cycles of ABVD, whereas PET-2-positive patients received four cycles of EB. A phase II sample size of 50 was estimated keeping the lower and higher proportion of rejection of the event-free survival (EFS) as 70% and 85%, respectively. Fifty patients [median age 28 (12-60) years; male : female: 39 : 11; stages: IIB-3 (6%), III-29 (58%) and IV-18 (36%); International Prognostic Score (IPS): 0-3: 34 (68%); 4-7: 16 (32%)] were enrolled; 49 underwent PET-2. Eight (16%) were PET-2-positive, whereas 41 (84%) were negative. Forty-seven were evaluable for EFS and all 50 for overall survival (OS). The 2-year EFS was 76% (95% CI: 68-83) and OS was 88% (95% CI: 82-94). PET-2 was strongly prognostic-2-year EFS, negative versus positive: 82% versus 50%; P = 0.013. PET-2 response-adapted strategy could not achieve EFS of 85% in aHL. However, escalated therapy improved outcomes in PET-2-positive patients compared with historical data. CTRI/2012/06/002741 (http://www.ctri.nic.in) and NCT01304849 (http://www.clinicaltrials.gov). © The Author 2015. Published by Oxford University Press on

  19. Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.

    PubMed

    Martinez, Jessica A; Chalasani, Pavani; Thomson, Cynthia A; Roe, Denise; Altbach, Maria; Galons, Jean-Philippe; Stopeck, Alison; Thompson, Patricia A; Villa-Guillen, Diana Evelyn; Chow, H-H Sherry

    2016-07-19

    Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin

  20. Phase II Study of Gemcitabine, Carboplatin, and Bevacizumab in Patients With Advanced Unresectable or Metastatic Urothelial Cancer

    PubMed Central

    Balar, Arjun V.; Apolo, Andrea B.; Ostrovnaya, Irina; Mironov, Svetlana; Iasonos, Alexia; Trout, Alisa; Regazzi, Ashley M.; Garcia-Grossman, Ilana R.; Gallagher, David J.; Milowsky, Matthew I.; Bajorin, Dean F.

    2013-01-01

    Purpose Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. Patients and Methods Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. Results Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. Conclusion The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC. PMID:23341513

  1. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer.

    PubMed

    Balar, Arjun V; Apolo, Andrea B; Ostrovnaya, Irina; Mironov, Svetlana; Iasonos, Alexia; Trout, Alisa; Regazzi, Ashley M; Garcia-Grossman, Ilana R; Gallagher, David J; Milowsky, Matthew I; Bajorin, Dean F

    2013-02-20

    Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.

  2. 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

  3. Arsenic trioxide as a radiation sensitizer for 131I-metaiodobenzylguanidine therapy: Results of a phase II study

    PubMed Central

    Modak, Shakeel; Zanzonico, Pat; Carrasquillo, Jorge A.; Kushner, Brian H.; Kramer, Kim; Cheung, Nai-Kong V.; Larson, Steven M.; Pandit-Taskar, Neeta

    2016-01-01

    Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that Arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG), and tested the combination in a phase II clinical trial. Methods Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated on an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289). Planned treatment was 131I-MIBG (444 or 666MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25mg/m2) intravenously on days 6–10 and 13–17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria version 3.0. Response was assessed by International NB response criteria or (for MP) by changes in 123I-MIBG or PET scans. Results Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received 131I-MIBG and AT both at maximal dosages, 2 patients received a 444MBq/kg dose of 131I-MIBG plus a 0.15mg/kg/dose dose of arsenic trioxide; and 3 patients received a 666MBq/kg dose of 131I-MIBG plus a 0.15mg/kg/dose dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently, thrombocytopenia (n=18), though none required autologous stem cell rescue. 12 of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 NB patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative 131I-MIBG scores were observed in 6 patients

  4. Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: A phase I-II study

    SciTech Connect

    Brade, Anthony . E-mail: anthony.brade@rmp.uhn.on.ca; Brierley, James; Oza, Amit; Gallinger, Steven; Cummings, Bernard; MacLean, Martha; Pond, Gregory R.; Hedley, David; Wong Shun; Townsley, Carol; Brezden-Masley, Christine; Moore, Malcolm

    2007-03-15

    Purpose: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. Methods and Materials: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m{sup 2} gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m{sup 2} within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m{sup 2}) and 52.5 Gy RT within 6 weeks. Results: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. Conclusion: Biweekly gemcitabine (40 mg/m{sup 2}) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.

  5. Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ohno, T; Kamiyama, Y; Aihara, R; Haga, N; Ojima, H; Nakamura, J; Ohsawa, H; Nakabayashi, T; Takeuchi, K; Asao, T; Kuwano, H

    2006-01-01

    Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m−2 day−1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m−2 day−1. The dose was increased in a stepwise manner to 70 mg m−2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m−2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m−2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1–17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. PMID:17133268

  6. 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)

    SciTech Connect

    Isobe, Koichi Kagami, Yoshikazu; Higuchi, Keiko; Kodaira, Takeshi; Hasegawa, Masatoshi; Shikama, Naoto; Nakazawa, Masanori; Fukuda, Ichiro; Nihei, Keiji; Ito, Kana; Teshima, Teruki; Matsuno, Yoshihiro; Oguchi, Masahiko

    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. The 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.

  7. A Phase II Study of 153Sm-EDTMP and High Dose Melphalan as a Peripheral Blood Stem Cell Conditioning Regimen in Patients with Multiple Myeloma

    PubMed Central

    Dispenzieri, A.; Wiseman, G.A.; Lacy, M.Q.; Hayman, S.R.; Kumar, S.K.; Buadi, F.; Dingli, D.; Laumann, K.M.; Allred, J.; Geyer, S.M.; Litzow, M.R.; Gastineau, D.A.; Inwards, D.J.; Micallef, I.N.; Ansell, S.M.; Porrata, L.; Elliott, M.A.; Johnston, P.B.; Hogan, W.J.; Gertz, M.A.

    2014-01-01

    Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a phase II study. Individualized doses of 153Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of 153Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 contemporaneously patients treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival from study registration was 6.2 years (95%CI 4.6–7.5 years) and 1.5 years (1.1–2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose 153Sm EDTMP to melphalan conditioning appears to be safe, well tolerated and worthy of further study in the context of novel agents and in the phase III setting. PMID:20513117

  8. Salvage brachytherapy in combination with interstitial hyperthermia for locally recurrent prostate carcinoma following external beam radiation therapy: a prospective phase II study.

    PubMed

    Kukiełka, Andrzej M; Strnad, Vratislav; Stauffer, Paul; Dąbrowski, Tomasz; Hetnał, Marcin; Nahajowski, Damian; Walasek, Tomasz; Brandys, Piotr; Matys, Robert

    2015-06-01

    Optimal treatment for patients with only local prostate cancer recurrence after external beam radiation therapy (EBRT) failure remains unclear. Possible curative treatments are radical prostatectomy, cryosurgery, and brachytherapy. Several single institution series proved that high-dose-rate brachytherapy (HDRBT) and pulsed-dose-rate brachytherapy (PDRBT) are reasonable options for this group of patients with acceptable levels of genitourinary and gastrointestinal toxicity. A standard dose prescription and scheme have not been established yet, and the literature presents a wide range of fractionation protocols. Furthermore, hyperthermia has shown the potential to enhance the efficacy of re-irradiation. Consequently, a prospective trial is urgently needed to attain clear structured prospective data regarding the efficacy of salvage brachytherapy with adjuvant hyperthermia for locally recurrent prostate cancer. The purpose of this report is to introduce a new prospective phase II trial that would meet this need. The primary aim of this prospective phase II study combining Iridium-192 brachytherapy with interstitial hyperthermia (IHT) is to analyze toxicity of the combined treatment; a secondary aim is to define the efficacy (bNED, DFS, OS) of salvage brachytherapy. The dose prescribed to PTV will be 30 Gy in 3 fractions for HDRBT, and 60 Gy in 2 fractions for PDRBT. During IHT, the prostate will be heated to the range of 40-47°C for 60 minutes prior to brachytherapy dose delivery. The protocol plans for treatment of 77 patients.

  9. Salvage brachytherapy in combination with interstitial hyperthermia for locally recurrent prostate carcinoma following external beam radiation therapy: a prospective phase II study

    PubMed Central

    Strnad, Vratislav; Stauffer, Paul; Dąbrowski, Tomasz; Hetnał, Marcin; Nahajowski, Damian; Walasek, Tomasz; Brandys, Piotr; Matys, Robert

    2015-01-01

    Optimal treatment for patients with only local prostate cancer recurrence after external beam radiation therapy (EBRT) failure remains unclear. Possible curative treatments are radical prostatectomy, cryosurgery, and brachytherapy. Several single institution series proved that high-dose-rate brachytherapy (HDRBT) and pulsed-dose-rate brachytherapy (PDRBT) are reasonable options for this group of patients with acceptable levels of genitourinary and gastrointestinal toxicity. A standard dose prescription and scheme have not been established yet, and the literature presents a wide range of fractionation protocols. Furthermore, hyperthermia has shown the potential to enhance the efficacy of re-irradiation. Consequently, a prospective trial is urgently needed to attain clear structured prospective data regarding the efficacy of salvage brachytherapy with adjuvant hyperthermia for locally recurrent prostate cancer. The purpose of this report is to introduce a new prospective phase II trial that would meet this need. The primary aim of this prospective phase II study combining Iridium-192 brachytherapy with interstitial hyperthermia (IHT) is to analyze toxicity of the combined treatment; a secondary aim is to define the efficacy (bNED, DFS, OS) of salvage brachytherapy. The dose prescribed to PTV will be 30 Gy in 3 fractions for HDRBT, and 60 Gy in 2 fractions for PDRBT. During IHT, the prostate will be heated to the range of 40–47°C for 60 minutes prior to brachytherapy dose delivery. The protocol plans for treatment of 77 patients. PMID:26207116

  10. Phase I/II study of biweekly vinorelbine and oxaliplatin as first-line treatment in patients with metastatic breast cancer.

    PubMed

    Guerrero, Antonio; Servitja, Sonia; Rodríguez-Lescure, Alvaro; Calvo, Lourdes; del Barco, Sonia; Quintanar, María Teresa; Juárez, José Ignacio; Gayo, Javier; Llombart, Antonio; Tusquets, Ignasi

    2011-03-01

    The objective of this phase I/II study was to establish the recommended dose of biweekly vinorelbine and oxaliplatin in patients with metastatic breast cancer and to evaluate the efficacy and safety profile of this schedule as first-line treatment. Four different dose levels of vinorelbine and oxaliplatin were selected for the phase I study: (i) 25 and 80 mg/m²; (ii) 25 and 90 mg/m²; (iii) 25 and 100 mg/m²; and (iv) 30 and 90 mg/m²; respectively. At least three patients were treated at each dose level. Overall, 12 patients were included in the phase I trial. No dose-limiting toxicities occurred at any dose level. Therefore, the fourth dose level (30 mg/m² of vinorelbine and 90 mg/m² of oxaliplatin) every 2 weeks was selected for the phase II trial. In this part, 44 patients were included and 61% completed the eight 2-week cycles of study treatment. On an intention-to-treat basis, overall response rate was 59%, and median progression-free survival and overall survival were 9.2 months (95% confidence interval: 7.6-10.9) and 18.6 months (95% confidence interval: 14.4-22.9), respectively. The main severe toxicities were neutropenia (46%) and fatigue (14%). We conclude that the biweekly combination of vinorelbine and oxaliplatin at doses of 30 mg/m² and 90 mg/m², respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer.

  11. Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small-cell lung cancer: a multicenter, randomized, open-label Phase II study.

    PubMed

    Babu, K Govind; Prabhash, Kumar; Vaid, Ashok K; Sirohi, Bhawna; Diwakar, Ravi B; Rao, Raghunadha; Kar, Madhuchanda; Malhotra, Hemant; Nag, Shona; Goswami, Chanchal; Raina, Vinod; Mohan, Ravi

    2014-01-01

    The purpose of this study was to evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV non-small-cell lung cancer. This multicenter, open-label, Phase II study randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m(2) and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan-Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data. The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (54% versus 34.5%; P=0.04). A complete response and partial response were achieved in 3.6% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. No significant differences in median progression-free survival and overall survival were observed. Safety profiles were comparable between the two groups. Nimotuzumab plus chemotherapy significantly improved the objective response rate as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV non-small-cell lung cancer.

  12. Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small-cell lung cancer: a multicenter, randomized, open-label Phase II study

    PubMed Central

    Babu, K Govind; Prabhash, Kumar; Vaid, Ashok K; Sirohi, Bhawna; Diwakar, Ravi B; Rao, Raghunadha; Kar, Madhuchanda; Malhotra, Hemant; Nag, Shona; Goswami, Chanchal; Raina, Vinod; Mohan, Ravi

    2014-01-01

    Background The purpose of this study was to evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV non-small-cell lung cancer. Methods This multicenter, open-label, Phase II study randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m2 and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan–Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data. Results The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (54% versus 34.5%; P=0.04). A complete response and partial response were achieved in 3.6% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. No significant differences in median progression-free survival and overall survival were observed. Safety profiles were comparable between the two groups. Conclusion Nimotuzumab plus chemotherapy significantly improved the objective response rate as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV non-small-cell lung cancer. PMID:24966687

  13. Quantitative Determination of ABT-925 in Human Plasma by On-Line SPE and LC-MS/MS: Validation and Sample Analysis in Phase II Studies.

    PubMed

    Wan, Katty; Rieser, Matthew; El-Shourbagy, Tawakol

    2010-05-04

    A fully automated 96-well On-Line Solid Phase Extraction (SPE) followed by High Performance Liquid Chromatography (HPLC)-Tandem Mass Spectrometric (MS/MS) method for the determination of ABT-925 (2-{3-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl)-propyl-sulfanyl}-3H-pyrimidin-4-one fumarate) in human plasma was developed, validated and utilized in Phase II clinical studies. 50 µL of plasma sample was fortified with internal standard (IS, d8-ABT-925) and extracted on-line with Cohesive Turbo Flow Cyclone P HTLC column. The chromatographic separation was performed on Aquasil C18 (3 μm 50 × 3 mm) HPLC column with a mobile phase consisting of 50/50/0.1 (v/v/v) ACN/H₂O/formic acid. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of m/z 457.4 → 329.4 for analyte and m/z 465.5 → 337.5 for IS.The peak area ratio (analyte/IS) was used to quantitate ABT-925. A dynamic range of 0.0102 μg/mL to 5.24 μg/mL was established after the validation. The validated method was then used for two Phase II studies. To demonstrate the method reproducibility, approximately 10% of the incurred samples from one study were repeated in singlet. The repeated values were compared to the initial values. All repeated values agreed within ±15% of the mean values.

  14. Quantitative Determination of ABT-925 in Human Plasma by On-Line SPE and LC-MS/MS: Validation and Sample Analysis in Phase II Studies

    PubMed Central

    Wan, Katty; Rieser, Matthew; El-Shourbagy, Tawakol

    2010-01-01

    A fully automated 96-well On-Line Solid Phase Extraction (SPE) followed by High Performance Liquid Chromatography (HPLC)-Tandem Mass Spectrometric (MS/MS) method for the determination of ABT-925 (2-{3-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl)-propyl-sulfanyl}-3H-pyrimidin-4-one fumarate) in human plasma was developed, validated and utilized in Phase II clinical studies. 50 µL of plasma sample was fortified with internal standard (IS, d8-ABT-925) and extracted on-line with Cohesive Turbo Flow Cyclone P HTLC column. The chromatographic separation was performed on Aquasil C18 (3 μm 50 × 3 mm) HPLC column with a mobile phase consisting of 50/50/0.1 (v/v/v) ACN/H2O/formic acid. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of m/z 457.4 → 329.4 for analyte and m/z 465.5 → 337.5 for IS. The peak area ratio (analyte/IS) was used to quantitate ABT-925. A dynamic range of 0.0102 μg/mL to 5.24 μg/mL was established after the validation. The validated method was then used for two Phase II studies. To demonstrate the method reproducibility, approximately 10% of the incurred samples from one study were repeated in singlet. The repeated values were compared to the initial values. All repeated values agreed within ±15% of the mean values. PMID:27721349

  15. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

    PubMed Central

    Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove; Dahl, Olav; Mella, Olav

    2015-01-01

    Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. Conclusion In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed

  16. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment.

    PubMed

    Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove; Dahl, Olav; Mella, Olav

    2015-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse

  17. Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group

    PubMed Central

    Ray-Coquard, I; Weber, B; Cretin, J; Haddad-Guichard, Z; Lévy, E; Hardy-Bessard, A C; Gouttebel, M C; Geay, J-F; Aleba, A; Orfeuvre, H; Agostini, C; Provencal, J; Ferrero, J M; Fric, D; Dohollou, N; Paraiso, D; Salvat, J; Pujade-Lauraine, É

    2009-01-01

    Advanced ovarian carcinoma in early progression (<6 months) (AOCEP) is considered resistant to most cytotoxic drugs. Gemcitabine (GE) and oxaliplatin (OXA) have shown single-agent activity in relapsed ovarian cancer. Their combination was tested in patients with AOCEP in phase II study. Fifty patients pre-treated with platinum–taxane received q3w administration of OXA (100 mg m–2, d1) and GE (1000 mg m–2, d1, d8, 100-min infusion). Patient characteristics were a : median age 64 years (range 46–79),and 1 (84%) or 2 (16%) earlier lines of treatment. Haematological toxicity included grade 3–4 neutropaenia (33%), anaemia (8%), and thrombocytopaenia (19%). Febrile neutropaenia occurred in 3%. Non-haematological toxicity included grade 2–3 nausea or vomiting (34%), grade 3 fatigue (25%),and grade 2 alopecia (24%). Eighteen (37%) patients experienced response. Median progression-free (PF) and overall survivals (OS) were 4.6 and 11.4 months, respectively. The OXA–GE combination has high activity and acceptable toxicity in AOCEP patients. A comparison of the doublet OXA–GE with single-agent treatment is warranted. PMID:19190632

  18. Phase I/II study of gemcitabine with pegylated liposomal doxorubicin as first-line therapy in Asian women with metastatic breast cancer.

    PubMed

    Wong, Zee-Wan; Ang, Peter Cher-Siang; Chowbay, Balram; Wong, Nan-Soon; See, Hui-Ti; Khoo, Kei-Siong

    2008-10-01

    This was a single institution phase I/II study to determine the maximum tolerated dose (MTD) and efficacy of pegylated liposomal doxorubicin (PLD) and gemcitabine in Asian women with metastatic breast cancer. PLD was administered on day 1 and gemcitabine on days 1 and 8 every 3 weeks at escalating doses from 25 mg/m(2) and 1000 mg/m(2) onwards respectively. The median age was 56 years with a median disease-free interval of 43 months. Majority of the patients had visceral involvement. At PLD 35 mg/m(2) and gemcitabine 1200 mg/m(2), the overall response rate for 23 evaluable patients was 83% (1 CR, 18 PR, 3 SD, 1 PD). Six had prior adjuvant anthracyclines (3 PR, 1 SD). The median follow-up was 81 weeks and progression free interval was 29 weeks. Overall survival was 23.9 months. The dose limiting toxicities were mucositis and myelosuppression. This regimen is active and reasonably tolerated as first-line therapy.

  19. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

    PubMed

    Ogura, Michinori; Ando, Kiyoshi; Suzuki, Tatsuya; Ishizawa, Kenichi; Oh, Sung Yong; Itoh, Kuniaki; Yamamoto, Kazuhito; Au, Wing Yan; Tien, Hwei-Fang; Matsuno, Yoshihiro; Terauchi, Takashi; Yamamoto, Keiko; Mori, Masahiko; Tanaka, Yoshinobu; Shimamoto, Takashi; Tobinai, Kensei; Kim, Won Seog

    2014-06-01

    Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

  20. Stage I of Phase II study assessing efficacy, safety and tolerability of barasertib (AZD1152) versus LDAC in elderly AML patients

    PubMed Central

    Kantarjian, Hagop M; Martinelli, Giovanni; Jabbour, Elias J; Quintás-Cardama, Alfonso; Ando, Kiyoshi; Bay, Jacques-Olivier; Wei, Andrew; Gröpper, Stefanie; Papayannidis, Cristina; Owen, Kate; Pike, Laura; Schmitt, Nicola; Stockman, Paul K; Giagounidis, Aristoteles

    2013-01-01

    Background This Phase II study evaluated the efficacy, safety and tolerability of the Aurora B kinase inhibitor barasertib, compared with low-dose cytosine arabinoside (LDAC), in patients aged ≥60 years with acute myeloid leukemia (AML). Methods Patients were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice-daily for 10 days) in 28-day cycles. The primary endpoint was objective complete response rate (OCRR: CR + CRi [Cheson criteria, additionally requiring CRi reconfirmation ≥21 days after first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety. Results 74 patients (barasertib, n=48; LDAC, n=26) completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9% [95% CI, 2.7–39.9]; P<0.05). Although not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC. (HR=0.88, 95% CI, 0.49-1.58; P=0.663;). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15%; 67% vs 19%, respectively). Conclusions Barasertib showed a significant improvement in OCRR versus LDAC, with a more toxic but manageable safety profile that was consistent with previous studies. Clinicaltrials.gov, NCT00952588. PMID:23605952

  1. Tetracaine oral gel in patients treated with radiotherapy for head-and-neck cancer: Final results of a phase II study

    SciTech Connect

    Alterio, Daniela . E-mail: daniela.alterio@ieo.it; Jereczek-Fossa, Barbara Alicja; Zuccotti, Gabriele Fulvio Phar; Leon, Maria Elena; Omodeo Sale, Emanuela Phar; Pasetti, Marcella; Modena, Tiziana Phar; Perugini, Paola; Mariani, Luigi; Orecchia, Roberto

    2006-02-01

    Purpose: We performed a phase II study to assess feasibility, pain relief, and toxicity of a tetracaine-based oral gel in the treatment of radiotherapy (RT)-induced mucositis. Methods and Materials: Fifty patients treated with RT for head-and-neck cancer with clinical evidence of acute oral mucositis of grade {>=}2 were scheduled to receive the tetracaine gel. A questionnaire evaluating the effect of the gel was given to all subjects. Results: In 38 patients (79.2%), a reduction in oral cavity pain was reported. Thirty-four patients (82.9%) reported no side effect. Seventy-one percent of patients had no difficulties in gel application. Unpleasant taste of the gel and interference with food taste were noticed in 5 (12%) and 16 patients (39%), respectively. Planned RT course was interrupted less frequently in patients who reported benefit from gel application than in patients who did not (p = 0.014). None of the patients who experienced pain relief needed a nasogastric tube, opposite to the patients who did not report any benefit from gel application (p = 0.001). Conclusion: Tetracaine oral gel administration seemed feasible and safe while reducing RT-induced mucositis-related oral pain in a sizeable proportion of treated head-and-neck cancer patients. A trial designed to compare efficacy of this gel vs. standard treatment is warranted.

  2. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy.

    PubMed

    Campone, M; Bondarenko, I; Brincat, S; Hotko, Y; Munster, P N; Chmielowska, E; Fumoleau, P; Ward, R; Bardy-Bouxin, N; Leip, E; Turnbull, K; Zacharchuk, C; Epstein, R J

    2012-03-01

    This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

  3. Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer).

    PubMed

    Del Mastro, L; Perrone, F; Repetto, L; Manzione, L; Zagonel, V; Fratino, L; Marenco, D; Venturini, M; Maggi, E; Bighin, C; Catzeddu, T; Venturino, A; Rosso, R

    2005-02-01

    First-line chemotherapy regimens suitable for elderly advanced breast cancer patients are still not defined. Women with stage III or IV breast cancer aged > or =70 years were enrolled in a phase II study aimed to evaluate both activity and toxicity of weekly paclitaxel. Among 46 planned patients, at least 18 responses and not more than seven unacceptable toxic events are required for a favourable conclusion. Paclitaxel 80 mg/m(2) was administered weekly for 3 weeks every 28 days. Unacceptable toxicity occurred in seven out of 46 patients evaluated for toxicity [15.2%; exact 95% confidence interval (CI) 7.6% to 28.2%] and was represented by one case of febrile neutropenia, one case of severe allergic reaction and five cases of cardiac toxicity. Among 41 patients evaluated for response, a complete response occurred in two (4.9%) patients and a partial response in 20 (48.8%), with an overall response rate of 53.7% (exact 95% CI 38.7% to 67.9%). The median progression-free survival was 9.7 months (95% CI 8.5-18.7) and median survival was 35.8 months (95% CI 19-not defined). Weekly paclitaxel is highly active in elderly advanced breast cancer patients. Data on cardiovascular complications, however, indicate the need for a careful monitoring of cardiac function before and during chemotherapy.

  4. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone.

    PubMed Central

    Lissoni, P.; Barni, S.; Meregalli, S.; Fossati, V.; Cazzaniga, M.; Esposti, D.; Tancini, G.

    1995-01-01

    Recent observations have shown that the pineal hormone melatonin (MLT) may modulate oestrogen receptor (ER) expression and inhibit breast cancer cell growth. On this basis, we have evaluated the biological and clinical effects of a concomitant MLT therapy in women with metastatic breast cancer who had progressed in response to tamoxifen (TMX) alone. The study included 14 patients with metastasis who did not respond (n = 3) to therapy with TMX alone or progressed after initial stable disease (SD) (n = 11). MLT was given orally at 20 mg day-1 in the evening, every day starting 7 days before TMX, which was given orally at 20 mg day-1 at noon. A partial response was achieved in 4/14 (28.5%) patients (median duration 8 months). The treatment was well tolerated in all cases, and no MLT-induced enhancement of TMX toxicity was seen; on the contrary, most patients experienced a relief of anxiety. Mean serum levels of insulin-like growth factor 1 (IGF-1), which is a growth factor for breast cancer, significantly decreased on therapy, and this decline was significantly higher in responders than in patients with SD or progression. This pilot phase II study would suggest that the concomitant administration of the pineal hormone MLT may induce objective tumour regressions in metastatic breast cancer patients refractory to TMX alone. PMID:7710954

  5. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

    PubMed Central

    Koeberle, D; Burkhard, R; von Moos, R; Winterhalder, R; Hess, V; Heitzmann, F; Ruhstaller, T; Terraciano, L; Neuweiler, J; Bieri, G; Rust, C; Toepfer, M

    2008-01-01

    This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m−2 bid on days 1–14 and oxaliplatin 130 mg m−2 on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m−2 bid on days 22–35 and 43–56, and oxaliplatin 50 mg m−2 on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13–36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer. PMID:18349837

  6. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer.

    PubMed

    Koeberle, D; Burkhard, R; von Moos, R; Winterhalder, R; Hess, V; Heitzmann, F; Ruhstaller, T; Terraciano, L; Neuweiler, J; Bieri, G; Rust, C; Toepfer, M

    2008-04-08

    This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13-36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer.

  7. A phase II study of intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer.

    PubMed

    Rao, Krishna; Kalapurakal, Sini; Chalasani, Pratima; Robinson, Kathy; Malone, James; Clausen, Cathy; Ronen, Ohad; Dhiwakar, Muthuswamy; Shevlin, Bruce; Robbins, K Thomas

    2013-09-01

    Based on the convenient oral dosing of erlotinib and the promising results of biologic therapy, we undertook a phase II study with 21 patients with locally advanced (T3-4) lesions combining radiation with intra-arterial (IA) cisplatin and oral daily erlotinib for a 7-week therapy. Treatment for the primary tumor and upper neck was given to a total dose of 70 Gy. Chemotherapy with IA cisplatin (150 mg/m(2)) was given on days 1, 8, 15, and 22 concurrently with radiotherapy. During the 7-week treatment period, patients were given erlotinib 150 mg/day. Overall survival is 63 %, and the relapse/persistent disease rate stands at 36.8 %. A total of 15.2 % of serious adverse event was considered related to erlotinib. Our study and several others now demonstrate the feasibility of combining anti-epidermal growth factor receptor (EGFR) therapy with chemoradiation, hint at improved survival outcomes with reduced distant metastatic rates, and suggest that maintenance therapy with anti-EGFR agent may be beneficial.

  8. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study.

    PubMed

    Bar-Sela, Gil; Wollner, Mira; Hammer, Liat; Agbarya, Abed; Dudnik, Elizabeth; Haim, Nissim

    2013-03-01

    Mistletoe preparations, such as iscador, are common complementary medications. This randomised phase II study of iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) patients to assess its influence on chemotherapy-related side-effects and QoL. Patients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed. Seventy-two patients (control: 39; iscador: 33) were enrolled in the study. Most (65%) were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11 months. Median TTP was 4.8 months for the controls and 6 months in the iscador arm (p=NS). Differences in grade 3-4 haematological toxicity were not significant but more control patients had chemotherapy dose reductions (44% versus 13%, p=0.005), grade 3-4 non-haematological toxicities (41% versus 16%, p=0.043) and hospitalisations (54% versus 24%, p=0.016). No effect of iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with iscador, warranting further investigation of iscador as a modifier of chemotherapy-related toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma.

    PubMed

    Baljevic, Muhamed; Zaman, Shadia; Baladandayuthapani, Veerabhadran; Lin, Yan Heather; de Partovi, Claudia Morales; Berkova, Zuzana; Amini, Behrang; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Fu, Min; Cleeland, Charles S; Wang, Xin Shelley; Stellrecht, Christine M; Davis, Richard E; Gandhi, Varsha; Orlowski, Robert Z

    2017-06-01

    The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.

  10. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study.

    PubMed

    Illerhaus, G; Marks, R; Müller, F; Ihorst, G; Feuerhake, F; Deckert, M; Ostertag, C; Finke, J

    2009-02-01

    To improve survival of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a phase II study with high-dose methotrexate (MTX) combined with procarbazine and CCNU. To reduce neurotoxicity, whole-brain irradiation was reserved for patients not responding to chemotherapy. High-dose MTX was applied on days 1, 15, and 30, procarbazine on days 1-10, and CCNU on day 1. Study treatment comprised up to three 45-day cycles. There was no lower limit of Karnofsky performance status (KPS). Thirty patients with PCNSL (n = 29) or primary ocular lymphoma (n = 1) were included (median age 70 years, range 57-79 years). The median initial KPS was 60% (range 30%-90%). Best documented response in 27 assessable patients were 12 of 27 (44.4%) complete remissions, 7 of 27 (25.9%) partial remissions, and 8 of 27 (29.6%) disease progressions. Two patients died of probable treatment-related causes. With a median follow-up of 78 months (range 34-105), the 5-year overall survival is 33%. Eight of 30 patients (26.7%) are currently alive and well, six without signs of leukoencephalopathy. The combination of high-dose MTX with procarbazine and CCNU is feasible and effective and results in a low rate of leukoencephalopathy. Comorbidity and toxicity remain of concern when treating PCNSL in elderly patients.

  11. Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group

    PubMed Central

    Ueoka, H; Tanimoto, M; Kiura, K; Tabata, M; Takigawa, N; Segawa, Y; Takata, I; Eguchi, K; Okimoto, N; Harita, S; Kamei, H; Shibayama, T; Watanabe, Y; Hiraki, S; Harada, M

    2001-01-01

    A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg m–2was given first and followed by CPT-11 at a dose of 50 mg m–2. Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32–63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11437395

  12. Beta-interferon, retinoids and tamoxifen in metastatic breast cancer: long-term follow-up of a phase II study.

    PubMed

    Recchia, Francesco; Sica, Gigliola; Candeloro, Giampiero; Necozione, Stefano; Bisegna, Roberta; Bratta, Massimo; Rea, Silvio

    2009-04-01

    Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of beta-interferon (beta-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, beta-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, beta-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

  13. A study from the EORTC new drug development group: open label phase II study of sabarubicin (MEN-10755) in patients with progressive hormone refractory prostate cancer.

    PubMed

    Fiedler, W; Tchen, N; Bloch, J; Fargeot, P; Sorio, R; Vermorken, J B; Collette, L; Lacombe, D; Twelves, C

    2006-01-01

    Sabarubicin (MEN-10755), a new synthetic anthracycline analogue, was evaluated for safety and efficacy in a multicentre phase II study in patients with advanced hormone refractory prostate cancer (HRPC). Thirty seven patients were included, of which 34 were evaluable for PSA response according to Bubley's criteria. Sabarubicin was administered as a short (30 min) intravenous infusion at a dose of 80 mg/m(2) every 3 weeks. The main toxicity consisted of grade 3/4 neutropenia in 24 patients (64.9%), with grade 3/4 febrile neutropenia occurring in one patient only. Grade 3/4 cardiotoxicity was observed in 4 patients including one ineligible. Other toxicities were mild. Nine patients achieved a PSA response (26.5%), 10 patients had stable disease (29.4%) and 14 patients disease progression (41.2%). One patient (2.9%) had a PSA response that was not confirmed by repeat PSA testing. The objective response rate according to RECIST criteria was 6.7% in 15 patients with measurable disease. The median duration of PSA responses was relatively long 7.1 months (95% CI 4.9-20.7) as was the median time to treatment progression in patients with stable disease. The median overall survival was 18.7 months (95% CI 9.1-N), comparable to results recently observed in taxotere-containing regimens. To confirm and extend these results, further testing of sabarubicin in larger trials is warranted.

  14. A Phase Ib/II Study Evaluating the Combination of Weekly Docetaxel and Cisplatin Together with Capecitabine and Bevacizumab in Patients with Advanced Esophago-Gastric Cancer

    PubMed Central

    Sarfaty, Michal; Purim, Ofer; Kundel, Yulia; Amit, Limor; Abramovich, Amir; Sadeh Gonik, Udi; Idelevich, Efraim; Gordon, Noa; Medalia, Gal; Sulkes, Aaron

    2016-01-01

    Introduction Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25–35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1–14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). Results The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5–52.2 months) and the median progression-free survival was 7.6 months (range, 1.3–26.6 months). The 2-year OS rate reached 23.7%. Conclusions AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further

  15. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver.

    PubMed

    Geevarghese, Sunil K; Geller, David A; de Haan, Hans A; Hörer, Markus; Knoll, Anette E; Mescheder, Axel; Nemunaitis, John; Reid, Tony R; Sze, Daniel Y; Tanabe, Kenneth K; Tawfik, Hoda

    2010-09-01

    This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3 × 10(6), 1 × 10(7), 3 × 10(7), and 1 × 10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1 × 10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.

  16. A theoretical and numerical approach to the plastic behaviour of steels during phase transformations—II. Study of classical plasticity for ideal-plastic phases

    NASA Astrophysics Data System (ADS)

    Leblond, J. B.; Mottet, G.; Devaux, J. C.

    THE RESPONSE of phase-transforming steels to variations of the applied stress (i.e. the ∑-term of the classical plastic strain rate Ė cp defined in Part I) is studied both theoretically and numerically for ideal-plastic individual phases. It is found theoretically that though the stress-strain curve contains no elastic portion, it is nevertheless initially tangent to the elastic line with slope equal to Young's modulus. Moreover an explicit formula for the beginning of the curve is derived for medium or high proportions of the harder phase, and a simple upper bound is given for the ultimate stress (maximum Von Mises stress). The finite element simulation confirms and completes these results, especially concerning the ultimate stress whose discrepancy with the theoretical upper bound is found to be maximum for low proportions of the harder phase. Based on these results, a complete model is proposed for the ∑-term of the classical plastic strain rate Ė cp in the case of ideal-plastic phases.

  17. Five-year Local Control in a Phase II Study of Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost for Early Stage Breast Cancer

    SciTech Connect

    Freedman, Gary M.; Anderson, Penny R.; Bleicher, Richard J.; Litwin, Samuel; Li Tianyu; Swaby, Ramona F.; Ma, Chang-Ming Charlie; Li Jinsheng; Sigurdson, Elin R.; Watkins-Bruner, Deborah; Morrow, Monica; Goldstein, Lori J.

    2012-11-15

    Purpose: Conventional radiation fractionation of 1.8-2 Gy per day for early stage breast cancer requires daily treatment for 6-7 weeks. We report the 5-year results of a phase II study of intensity modulated radiation therapy (IMRT), hypofractionation, and incorporated boost that shortened treatment time to 4 weeks. Methods and Materials: The study design was phase II with a planned accrual of 75 patients. Eligibility included patients aged {>=}18 years, Tis-T2, stage 0-II, and breast conservation. Photon IMRT and an incorporated boost was used, and the whole breast received 2.25 Gy per fraction for a total of 45 Gy, and the tumor bed received 2.8 Gy per fraction for a total of 56 Gy in 20 treatments over 4 weeks. Patients were followed every 6 months for 5 years. Results: Seventy-five patients were treated from December 2003 to November 2005. The median follow-up was 69 months. Median age was 52 years (range, 31-81). Median tumor size was 1.4 cm (range, 0.1-3.5). Eighty percent of tumors were node negative; 93% of patients had negative margins, and 7% of patients had close (>0 and <2 mm) margins; 76% of cancers were invasive ductal type: 15% were ductal carcinoma in situ, 5% were lobular, and 4% were other histology types. Twenty-nine percent of patients 29% had grade 3 carcinoma, and 20% of patients had extensive in situ carcinoma; 11% of patients received chemotherapy, 36% received endocrine therapy, 33% received both, and 20% received neither. There were 3 instances of local recurrence for a 5-year actuarial rate of 2.7%. Conclusions: This 4-week course of hypofractionated radiation with incorporated boost was associated with excellent local control, comparable to historical results of 6-7 weeks of conventional whole-breast fractionation with sequential boost.

  18. A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors

    PubMed Central

    2014-01-01

    Background Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. Methods A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. Results Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3–4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3–4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. Conclusions Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. Trial registration ClinicalTrials.gov identifier NCT00435916. PMID:24919462

  19. Five-year local control in a phase II study of hypofractionated intensity modulated radiation therapy with an incorporated boost for early stage breast cancer.

    PubMed

    Freedman, Gary M; Anderson, Penny R; Bleicher, Richard J; Litwin, Samuel; Li, Tianyu; Swaby, Ramona F; Ma, Chang-Ming Charlie; Li, Jinsheng; Sigurdson, Elin R; Watkins-Bruner, Deborah; Morrow, Monica; Goldstein, Lori J

    2012-11-15

    Conventional radiation fractionation of 1.8-2 Gy per day for early stage breast cancer requires daily treatment for 6-7 weeks. We report the 5-year results of a phase II study of intensity modulated radiation therapy (IMRT), hypofractionation, and incorporated boost that shortened treatment time to 4 weeks. The study design was phase II with a planned accrual of 75 patients. Eligibility included patients aged≥18 years, Tis-T2, stage 0-II, and breast conservation. Photon IMRT and an incorporated boost was used, and the whole breast received 2.25 Gy per fraction for a total of 45 Gy, and the tumor bed received 2.8 Gy per fraction for a total of 56 Gy in 20 treatments over 4 weeks. Patients were followed every 6 months for 5 years. Seventy-five patients were treated from December 2003 to November 2005. The median follow-up was 69 months. Median age was 52 years (range, 31-81). Median tumor size was 1.4 cm (range, 0.1-3.5). Eighty percent of tumors were node negative; 93% of patients had negative margins, and 7% of patients had close (>0 and <2 mm) margins; 76% of cancers were invasive ductal type: 15% were ductal carcinoma in situ, 5% were lobular, and 4% were other histology types. Twenty-nine percent of patients 29% had grade 3 carcinoma, and 20% of patients had extensive in situ carcinoma; 11% of patients received chemotherapy, 36% received endocrine therapy, 33% received both, and 20% received neither. There were 3 instances of local recurrence for a 5-year actuarial rate of 2.7%. This 4-week course of hypofractionated radiation with incorporated boost was associated with excellent local control, comparable to historical results of 6-7 weeks of conventional whole-breast fractionation with sequential boost. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study

    PubMed Central

    Kirzinger, Lukas; Boy, Sandra; Marienhagen, Jörg; Schuierer, Gerhard; Neu, Reiner; Ried, Michael; Hofmann, Hans-Stefan; Wiebe, Karsten; Ströbel, Philipp; May, Christoph; Kleylein-Sohn, Julia; Baierlein, Claudia; Bogdahn, Ulrich; Marx, Alexander; Schalke, Berthold

    2016-01-01

    Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%–86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents. PMID:27992479

  1. Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study.

    PubMed

    Kirzinger, Lukas; Boy, Sandra; Marienhagen, Jörg; Schuierer, Gerhard; Neu, Reiner; Ried, Michael; Hofmann, Hans-Stefan; Wiebe, Karsten; Ströbel, Philipp; May, Christoph; Kleylein-Sohn, Julia; Baierlein, Claudia; Bogdahn, Ulrich; Marx, Alexander; Schalke, Berthold

    2016-01-01

    Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%-86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents.

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

    SciTech Connect

    Vuong, Te; Waschke, Kevin; Niazi, Tamim; Richard, Carole; Parent, Josee; Liberman, Sender; Mayrand, Serge; Loungnarath, Rasmy; Stein, Barry; Devic, Slobodan

    2011-08-01

    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 receive 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.

  3. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study

    PubMed Central

    Slovin, S. F.; Higano, C. S.; Hamid, O.; Tejwani, S.; Harzstark, A.; Alumkal, J. J.; Scher, H. I.; Chin, K.; Gagnier, P.; McHenry, M. B.; Beer, T. M.

    2013-01-01

    Background This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. Patients and methods In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. Results Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3–13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8–6.1 months). Conclusions In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882. PMID:23535954

  4. An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: a collaborative ependymoma research network study (CERN).

    PubMed

    DeWire, Mariko; Fouladi, Maryam; Turner, David C; Wetmore, Cynthia; Hawkins, Cynthia; Jacobs, Carmen; Yuan, Ying; Liu, Diane; Goldman, Stewart; Fisher, Paul; Rytting, Michael; Bouffet, Eric; Khakoo, Yasmin; Hwang, Eugene I; Foreman, Nicholas; Stewart, Clinton F; Gilbert, Mark R; Gilbertson, Richard; Gajjar, Amar

    2015-05-01

    Co-expression of ERBB2 and ERBB4, reported in 75% of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤ 21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24-48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥ 4 courses (range 4-14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective.

  5. Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

    PubMed

    Vogelhuber, M; Feyerabend, S; Stenzl, A; Suedhoff, T; Schulze, M; Huebner, J; Oberneder, R; Wieland, W; Mueller, S; Eichhorn, F; Heinzer, H; Schmidt, K; Baier, M; Ruebel, A; Birkholz, K; Bakhshandeh-Bath, A; Andreesen, R; Herr, W; Reichle, A

    2015-04-01

    Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

  6. Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study

    PubMed Central

    Gattorno, Marco; Obici, Laura; Cattalini, Marco; Tormey, Vincent; Abrams, Ken; Davis, Nicole; Speziale, Antonio; Bhansali, Suraj G; Martini, Alberto; Lachmann, Helen J

    2017-01-01

    Objective To evaluate the efficacy of canakinumab, a high-affinity human monoclonal anti-interleukin-1β antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Methods Twenty patients (aged 7–78 years) with active recurrent or chronic TRAPS were treated with canakinumab 150 mg every 4 weeks for 4 months (2 mg/kg for those ≤40 kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5 months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8 weeks) for 24 months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physician's Global Assessment score ≤1) and full or partial serological remission. Results Nineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to canakinumab occurred rapidly; median time to clinical remission 4 days (95% CI 3 to 8 days). All patients relapsed after canakinumab was withdrawn; median time to relapse 91.5 days (95% CI 65 to 117 days). On reintroduction of canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of canakinumab, although limited, appeared to be consistent with historical canakinumab data. Conclusions Canakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment. Trial registration number NCT01242813; Results. PMID:27269295

  7. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma

    PubMed Central

    Chen, Robert; Frankel, Paul; Popplewell, Leslie; Siddiqi, Tanya; Ruel, Nora; Rotter, Arnold; Thomas, Sandra H.; Mott, Michelle; Nathwani, Nitya; Htut, Myo; Nademanee, Auayporn; Forman, Stephen J.; Kirschbaum, Mark

    2015-01-01

    This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1–14 along with 375 mg/m2 of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876. PMID:25596263

  8. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.

    PubMed

    Chen, Robert; Frankel, Paul; Popplewell, Leslie; Siddiqi, Tanya; Ruel, Nora; Rotter, Arnold; Thomas, Sandra H; Mott, Michelle; Nathwani, Nitya; Htut, Myo; Nademanee, Auayporn; Forman, Stephen J; Kirschbaum, Mark

    2015-03-01

    This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876. Copyright© Ferrata Storti Foundation.

  9. Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.

    PubMed

    Tagawa, Scott T; Milowsky, Matthew I; Morris, Michael; Vallabhajosula, Shankar; Christos, Paul; Akhtar, Naveed H; Osborne, Joseph; Goldsmith, Stanley J; Larson, Steve; Taskar, Neeta Pandit; Scher, Howard I; Bander, Neil H; Nanus, David M

    2013-09-15

    To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of (177)Lu-J591 (15 patients at 65 mCi/m(2), 17 at 70 mCi/m(2)) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m(2) to verify response rate and examine biomarkers. Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received (177)Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m(2)) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. A single dose of (177)Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising. ©2013 AACR.

  10. 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.

  11. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

    PubMed Central

    Catenacci, Daniel V.T.; Junttila, Melissa R.; Karrison, Theodore; Bahary, Nathan; Horiba, Margit N.; Nattam, Sreenivasa R.; Marsh, Robert; Wallace, James; Kozloff, Mark; Rajdev, Lakshmi; Cohen, Deirdre; Wade, James; Sleckman, Bethany; Lenz, Heinz-Josef; Stiff, Patrick; Kumar, Pankaj; Xu, Peng; Henderson, Les; Takebe, Naoko; Salgia, Ravi; Wang, Xi; Stadler, Walter M.; de Sauvage, Frederic J.; Kindler, Hedy L.

    2015-01-01

    Purpose Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. Patients and Methods Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied. Results No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. Conclusion The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant

  12. Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

    PubMed

    Ballester, O F; Agaliotis, D P; Hiemenz, J W; Janssen, W E; Fields, K K; Zorksy, P E; Goldstein, S C; Perkins, J B; Elfenbein, G J

    1996-07-01

    In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

  13. A randomized, placebo-controlled phase ii study evaluating the reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving pegfilgrastim with every-2-week chemotherapy.

    PubMed

    Hecht, J Randolph; Pillai, Madhavan; Gollard, Russell; Heim, William; Swan, Forrest; Patel, Ravi; Dreiling, Lyndah; Mo, May; Malik, Imtiaz

    2010-04-01

    Adding irinotecan and/or oxaliplatin to every-2-week 5-fluorouracil (5-FU)/leucovorin (LV) prolongs survival in patients with colorectal cancer (CRC) but increases neutropenia frequency. Pegfilgrastim is indicated to decrease infection as manifested by febrile neutropenia (FN) in patients receiving chemotherapy at > 14-day intervals. This randomized, placebo-controlled phase II study examined pegfilgrastim efficacy and safety in patients with CRC receiving every-2-week chemotherapy. Patients with CRC were randomized 1:1 to pegfilgrastim 6 mg or placebo administered per-cycle on day 4. Randomization was stratified by chemotherapy regimen (patients received every-2-week FOLFOX4 [5-FU/LV/oxaliplatin], FOLFIRI [5-FU/LV/irinotecan], or FOIL [5-FU/LV/oxaliplatin/irinotecan] at physician discretion). The primary endpoint was incidence of grade 3/4 neutropenia. Secondary endpoints included incidence of grade 3/4 FN and adverse events. After 4 cycles of study treatment, progression-free survival (PFS) and overall survival (OS) were followed for

  14. A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients.

    PubMed

    Cesaro, Simone; Zanazzo, Andrea Giulio; Frenos, Stefano; Luksch, Roberto; Pegoraro, Anna; Tridello, Gloria; Dallorso, Sandro

    2011-11-01

    Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy. This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 µg/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells ≥ 20 × 10(6) /L). The results were compared with a historical control group. Thirty of 36 recruited patients were classified as good mobilizers (83%). The median value of circulating CD34+ at leukapheresis was 143 × 10(6) /L (range, 20 × 10(6) -1988 × 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 × 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92%) and the median CD34+ count at leukapheresis was 158 × 10(6) /kg (range, 28 × 10(6) -4529 × 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival. A single dose of 100 µg/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients. © 2011 American Association of Blood Banks.

  15. A Phase II study of acute toxicity for Celebrex{sup TM} (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: Primary endpoint analysis of RTOG 0128

    SciTech Connect

    Gaffney, David K. . E-mail: david.gaffney@hci.utah.edu; Winter, Kathryn M.S.; Dicker, Adam P.; Miller, Brigitte; Eifel, Patricia J.; Ryu, Janice; Avizonis, Vilija; Fromm, Mitch; Greven, Kathryn

    2007-01-01

    Purpose: To determine treatment-related acute toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib, i.v. cisplatin and 5-FU, and concurrent pelvic radiation therapy. Methods and Materials: Eligible patients on this RTOG Phase I-II study for advanced cervix cancer included FIGO Stage IIB-IVA or patients with FIGO Stage IB through IIA with biopsy proven pelvic node metastases or tumor size {>=}5 cm. Patients were treated with pelvic radiotherapy and brachytherapy. Celecoxib was prescribed at 400 mg twice daily beginning on day 1 for 1 year. Cisplatin (75 mg/m2) and 5-FU (1g/m2 for 4 days) were administered every 3 weeks times 3. The primary end point of the study was treatment related toxicity. Results: Between August 2001 and March 2004, 84 patients were accrued to the study and 77 patients were evaluable for toxicity. Regarding the primary end point, toxicities were observed in the following areas: blood/bone marrow (16), gastrointestinal (14), pain (7), renal/genitourinary (6), cardiovascular (3), hemorrhage (1), and neurologic (1). For the first 75 evaluable patients, a toxicity failure was identified in 36 patients for a rate of 48%. Conclusions: Celecoxib at 400 mg twice daily together with concurrent cisplatin and 5-FU and pelvic radiotherapy has a high incidence of acute toxicities. The most frequent toxicities were hematologic. Albeit, the toxicity was deemed excessive in this trial, the rate of toxicities was not too different compared to other recent experiences with concurrent chemoradiation for advanced cervix cancer.

  16. Are three weeks hypofractionated radiation therapy (HFRT) comparable to six weeks for newly diagnosed glioblastoma patients? Results of a phase II study.

    PubMed

    Navarria, Pierina; Pessina, Federico; Tomatis, Stefano; Soffietti, Riccardo; Grimaldi, Marco; Lopci, Egesta; Chiti, Arturo; Leonetti, Antonella; Casarotti, Alessandra; Rossi, Marco; Cozzi, Luca; Ascolese, Anna Maria; Simonelli, Matteo; Marcheselli, Simona; Santoro, Armando; Clerici, Elena; Bello, Lorenzo; Scorsetti, Marta

    2017-09-15

    The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT). The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness. Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function. A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome. HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment.

  17. Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

    PubMed

    Adamo, V; Lorusso, V; Rossello, R; Adamo, B; Ferraro, G; Lorusso, D; Condemi, G; Priolo, D; Di Lullo, L; Paglia, A; Pisconti, S; Scambia, G; Ferrandina, G

    2008-06-17

    This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

  18. Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas

    PubMed Central

    Friedberg, Jonathan W.; Mahadevan, Daruka; Cebula, Erin; Persky, Daniel; Lossos, Izidore; Agarwal, Amit B.; Jung, JungAh; Burack, Richard; Zhou, Xiaofei; Leonard, E. Jane; Fingert, Howard; Danaee, Hadi; Bernstein, Steven H.

    2014-01-01

    Purpose Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event–related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated. PMID:24043741

  19. Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

    SciTech Connect

    Kato, Ken; Muro, Kei; Minashi, Keiko; Ohtsu, Atsushi; Ishikura, Satoshi; Boku, Narikazu; Takiuchi, Hiroya; Komatsu, Yoshito; Miyata, Yoshinori; Fukuda, Haruhiko

    2011-11-01

    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-week 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.

  20. Semicontinuous Low-Dose-Rate Teletherapy for the Treatment of Recurrent Glial Brain Tumors: Final Report of a Phase I/II Study

    SciTech Connect

    Siker, Malika L.; Firat, Selim Y.; Mueller, Wade; Krouwer, Hendrikus; Schultz, Christopher J.

    2012-02-01

    Purpose: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. Methods and Materials: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. Results: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed {>=}Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. Conclusion: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.

  1. Administration of alemtuzumab and G-CSF to adults with relapsed or refractory acute lymphoblastic leukemia: results of a phase II study.

    PubMed

    Gorin, Norbert-Claude; Isnard, Françoise; Garderet, Laurent; Ikhlef, Souhila; Corm, Selim; Quesnel, Bruno; Legrand, Ollivier; Cachanado, Marine; Rousseau, Alexandra; Laporte, Jean-Philippe

    2013-10-01

    The outlook for adults with refractory and relapsed acute lymphocytic leukemia (ALL) is poor. CD52 is expressed in most patients with ALL. Alemtuzumab is an anti-CD52 humanized monoclonal antibody. This phase II study assessed the efficacy of alemtuzumab combined with granulocyte-colony stimulating factor (G-CSF) to boost antibody-dependent cell cytotoxicity mediated by neutrophils. Twelve patients with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses postallogeneic stem cell transplantation, were treated and monitored between October 2006 and January 2011. Patients received 1 wk of alemtuzumab every other day at increasing doses of 3, 10, and 30 mg to test tolerance and 30 mg three times a week for 12-18 infusions. If in complete remission (CR), patients received maintenance therapy for 1 wk, every 2 months. G-CSF was administered at 5 μg/kg per day during alemtuzumab administration. The primary endpoint was disappearance of blast cells on a marrow aspirate. CD52 was expressed in all patients. Four patients reached CR. In one additional patient, clearance of blast cells was observed in peripheral blood but not in the marrow. The most frequent adverse events during course 1 of treatment were fever and chills (n = 3), skin rash (n = 3), and bronchospasm (n = 2). Tumor lysis syndrome was observed at treatment initiation in one patient who reached CR. All patients progressed within a few months and all but one died. The surviving patient is still alive after relapse and a second allogeneic stem cell transplantation. This study shows that in relapse/refractory ALL, alemtuzumab with G-CSF can produce good responses of short duration. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Concomitant chemoradiotherapy using carboplatin, tegafur-uracil and leucovorin for stage III and IV head-and-neck cancer: results of GORTEC Phase II study.

    PubMed

    Fesneau, Melanie; Pointreau, Yoann; Chapet, Sophie; Martin, Laurent; Pommier, Pascal; Alfonsi, Marc; Laguerre, Brigitte; Feham, Nasreddine; Berger, Christine; Garaud, Pascal; Calais, Gilles

    2010-01-01

    Concomitant chemoradiotherapy is the standard treatment of locally advanced, nonresectable, head-and-neck squamous cell carcinoma. However, the optimal chemotherapy regimen is still controversial. The objective of this Phase II study was to evaluate the feasibility and efficacy of a concomitant treatment using tegafur-uracil, leucovorin, carboplatin, and radiotherapy. A total of 77 patients with head-and-neck squamous cell carcinoma Stage III and IVA were enrolled between October 2003 and July 2005. Of the 77 patients, 72 were eligible. They were treated with tegafur-uracil (300 mg/m(2)/d) and leucovorin (75 mg/d) from Days 1 to 19 and from Days 29 to 47 and carboplatin (70 mg/m(2) intravenously for 4 consecutive days), in three cycles every 21 days. Conventional radiotherapy was delivered to a total dose of 70 Gy in 35 fractions. With a mean follow-up of 22.8 months, the 3-year locoregional control, overall survival and disease-free survival actuarial rate was 33.1%, 41.9%, and 27.2%, respectively. The compliance of the treatment was correct. The main acute toxicity was mucositis, with 62% Grade 3-4. Three patients (4.2%) died of acute toxicity. The incidence and severity of late toxicity was acceptable, with 32% Grade 3 and no Grade 4 toxicity. The protocol of concomitant chemoradiotherapy using tegafur-uracil, leucovorin, and carboplatin for locally advanced unresectable head-and-neck squamous cell carcinoma is feasible. The compliance was correct. The incidence and severity of the acute and late toxicities were acceptable, but not improved. The efficacy of this regimen seems equivalent to the main protocols of concurrent chemoradiotherapy. It represents a possible alternative for patients without an intravenous catheter.

  3. A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation.

    PubMed

    Dingemans, Anne-Marie C; Mellema, Wouter W; Groen, Harry J M; van Wijk, Atie; Burgers, Sjaak A; Kunst, Peter W A; Thunnissen, Erik; Heideman, Danielle A M; Smit, Egbert F

    2013-02-01

    Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.

  4. Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.

    PubMed

    Koinis, F; Agelaki, S; Karavassilis, V; Kentepozidis, N; Samantas, E; Peroukidis, S; Katsaounis, P; Hartabilas, E; Varthalitis, I I; Messaritakis, I; Fountzilas, G; Georgoulias, V; Kotsakis, A

    2017-06-27

    Pazopanib is a tyrosine kinase inhibitor with antiangiogenic activity. Vascular endothelial growth factor expression is increased in SCLC and is correlated with poor prognosis. The efficacy and tolerance of second-line pazopanib in SCLC was evaluated. Patients with platinum-sensitive (cohort A; n=39) and -resistant/refractory (cohort B; n=19) SCLC were enrolled in a multicentre phase II study. The primary end point was the progression-free survival rate (PFS-R) at week 8 in each cohort. Pazopanib (800 mg per day per os) was administered until progressive disease (PD). Circulating tumour cells (CTCs) were enumerated using the Cellsearch assay. All patients were evaluable for response and toxicity. In the intention-to-treat analysis, eight (13.8%) patients achieved partial response (PR) (95% confidence interval (CI): 5.0-22.7), 20 (34.5%) stable disease (SD) and 30 (51.7%) PD. Accrual in cohort B was halted because the hard-stop rule was met; in cohort A, the PFS-R was 59% (95% CI: 43.5-74.4; PR=7, SD=16). Nine (23.1%) patients received pazopanib for >6 months and 3 of them for >12 months. One pazopanib cycle resulted to a significant decrease to the number of patients with ⩾5 CTCs/7.5 ml of blood (20%) compared with baseline (50%). The median PFS and OS for all patients was 2.5 months (95% CI: 1.9-3.1 months) and 6.0 months (95% CI: 3.8-8.2 months), respectively (cohort A: PFS=3.7 months and OS=8.0 months). No unexpected toxicity was observed. Second-line treatment with pazopanib in platinum-sensitive SCLC is well tolerated and resulted in promising objective responses and disease control; CTC enumeration might serve as a reliable surrogate biomarker of response.

  5. A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: A report from the Pediatric Brain Tumor Consortium

    PubMed Central

    Pollack, Ian F.; Stewart, Clinton F.; Kocak, Mehmet; Poussaint, Tina Young; Broniscer, Alberto; Banerjee, Anu; Douglas, James G.; Kun, Larry E.; Boyett, James M.; Geyer, J. Russell

    2011-01-01

    This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m2/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents. PMID:21292687

  6. Maintenance treatment of Uracil and Tegafur (UFT) in responders following first-line fluorouracil-based chemotherapy in metastatic gastric cancer: a randomized phase II study.

    PubMed

    Li, Wenhua; Zhao, Xiaoying; Wang, Huijie; Liu, Xin; Zhao, Xinmin; Huang, Mingzhu; Qiu, Lixin; Zhang, Wen; Chen, Zhiyu; Guo, Weijian; Li, Jin; Zhu, Xiaodong

    2017-06-06

    Maintenance therapy proves to be effective in advanced lung and breast cancer after initial chemotherapy. The purpose of this phase II study was to evaluate the efficacy and safety of Uracil and Tegafur (UFT) maintenance in metastatic gastric cancer patients following the first-line fluorouracil-based chemotherapy. Metastatic gastric cancer patients with stable disease or a better response after the completion of first-line chemotherapy were randomized to oral UFT (360mg/m2 × 2 weeks) every 3 weeks until disease progression/intolerable toxicity or to observation (OBS). The primary endpoint was progression-free survival (PFS); the secondary endpoints were overall survival (OS) and safety. The trial was closed after the interim analysis of the 58 enrolled (120 planned) patients. Median PFS was not improved in the UFT group compared with the OBS group (3.2 months versus 3.6 months, P = 0.752), as well as the median OS (14.2 months for both, P = 0.983). However, subgroup analysis showed that low baseline hemoglobin (< 120 g/L) was associated with poorer PFS with maintenance therapy (P = 0.032), while the normal hemoglobin patients benefit from the UFT treatment (P = 0.008). Grade 3 to 4 toxicities in the UFT group were anemia (3.4%), thrombocytopenia (3.4%) and diarrhea (6.9%). This trial did not show superiority of UFT maintenance in non-selected patients responding to fluorouracil-based first-line chemotherapy. The normal hemoglobin level at baseline is a predictive biomarker for favorable patient subsets from the maintenance treatment.

  7. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer.

    PubMed

    Robert, Nicholas J; Conkling, Paul R; O'Rourke, Mark A; Kuefler, Paul R; McIntyre, Kristi J; Zhan, Feng; Asmar, Lina; Wang, Yanping; Shonukan, Oluwatoyin O; O'Shaughnessy, Joyce A

    2011-02-01

    Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

  8. 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.

  9. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study.

    PubMed

    Ribrag, Vincent; Kim, Won Seog; Bouabdallah, Reda; Lim, Soon Thye; Coiffier, Bertrand; Illes, Arpad; Lemieux, Bernard; Dyer, Martin J S; Offner, Fritz; Felloussi, Zakia; Kloos, Ioana; Luan, Ying; Vezan, Remus; Graef, Thorsten; Morschhauser, Franck

    2017-05-01

    Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. (Trial registered at: EudraCT-2009-013691-47). Copyright© Ferrata Storti Foundation.

  10. A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer.

    PubMed

    Trudel, Dominique; Labbé, David P; Araya-Farias, Monica; Doyen, Alain; Bazinet, Laurent; Duchesne, Thierry; Plante, Marie; Grégoire, Jean; Renaud, Marie-Claude; Bachvarov, Dimcho; Têtu, Bernard; Bairati, Isabelle

    2013-11-01

    A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890). Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Québec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients. During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7-100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported. DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment. © 2013.

  11. Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma.

    PubMed

    Wilgenhof, Sofie; Corthals, Jurgen; Heirman, Carlo; van Baren, Nicolas; Lucas, Sophie; Kvistborg, Pia; Thielemans, Kris; Neyns, Bart

    2016-04-20

    Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte-associated protein 4 receptor that counteracts physiologic suppression of T-cell function, improves the overall survival of patients with advanced melanoma. This phase II study investigated the combination of TriMixDC-MEL and ipilimumab in patients with pretreated advanced melanoma. Thirty-nine patients were treated with TriMixDC-MEL (4 × 10(6) cells administered intradermally and 20 × 10(6) cells administered intravenously) plus ipilimumab (10 mg/kg every 3 weeks for a total of four administrations, followed by maintenance therapy every 12 weeks in patients who remained progression free). Six-month disease control rate according to the immune-related response criteria served as the primary end point. The 6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor response rate was 38% (including eight complete and seven partial responses). Seven complete responses and one partial tumor response are ongoing after a median follow-up time of 36 months (range, 22 to 43 months). The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event. The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma. © 2016 by American Society of Clinical Oncology.

  12. Phase II study of concurrent selective lymph node late course accelerated hyper-fractionated radiotherapy and pemetrexed and cisplatin for locally advanced oesophageal squamous cell carcinoma

    PubMed Central

    Fu, C; Guo, L; Li, H; Huang, W; Gong, H; Sun, M; Wang, Z; Zhou, T; Liu, C

    2014-01-01

    Objective: To determine the clinical efficacy and toxicity of pemetrexed combined with low-dose cisplatin (CDDP) concurrent with late-course accelerated hyperfractionated (LCAF) intensity-modulated radiation therapy (IMRT) in patients with inoperable locally advanced oesophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC (less than or equal to 75 years of age, clinical stages IIB–IVA and Karnofsky performance status ≥70) were enrolled into the study. A target group size of 22 was projected based on the estimation that 2-year overall survival (OS) would increase from 20% to 40%. Patients were treated with pemetrexed, low-dose CDDP and LCAF IMRT concurrently. The main objective of the study was for a 2-year OS, and the secondary objectives were progression-free survival (PFS), objective response, locoregional failure rate, and acute and late toxicities. Results: 25 patients were recruited from October 2008 to July 2011. The median OS was 21 months, with 2- and 5-year OS rates of 44% and 44%, respectively. The median PFS was 18.2 months. The objective response rate was 96% (24/25), with 11 complete responses and 13 partial responses. The locoregional failure rate was 16%. Grades 4 and 5 acute toxicity rates were 8% and 4%, respectively, while no Grade 3 or greater late toxicity was observed. Conclusion: The findings of this Phase II study indicated that the therapeutic regimen appears to achieve an excellent response rate and favourable survival for locally advanced ESCC. However, the severe acute side effects should be considered cautiously in further studies. Advances in knowledge: To our knowledge, this is the first study that introduced pemetrexed and low-dose CDDP combined with LCAF IMRT to treat locally advanced ESCC. The 5-year OS rate was as high as 44%, which was more favourable than other studies. PMID:24666012

  13. Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study

    PubMed Central

    2014-01-01

    Background This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC). Methods Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg). Prior trastuzumab and/or lapatinib treatment were permitted. The primary endpoint was objective response rate (ORR). Results Sixty patients were enrolled and evaluable for safety; 57 were evaluable for efficacy. The majority of patients (58%) had received no prior chemotherapy in the metastatic setting. The ORR was 37%; the clinical benefit rate (CBR; percent objective response plus stable disease ≥ 24 weeks) was 56%. Among patients who were treatment-naïve or had received only adjuvant therapy, the ORR was 44% and the CBR was 59%. Overall, median overall survival had not been reached and the 1-year survival rate was 91%. The majority of adverse events (AEs) were mild to moderate in severity. Forty percent of patients experienced AEs related to measured left ventricular ejection fraction (LVEF) declines, which occurred more frequently in patients who had received prior anthracycline treatment. Ten percent of patients exhibited symptoms related to LVEF declines. One patient died on study from cardiogenic shock. Antitumor response and several safety parameters appeared to correlate with sunitinib exposure. Conclusions Sunitinib plus trastuzumab demonstrated antitumor activity in patients with HER2-positive ABC, particularly those who were treatment-naïve or had only received prior adjuvant treatment. Sunitinib plus trastuzumab had acceptable safety and tolerability in patients with HER2-positive ABC who had not received prior anthracycline therapy. Trial registration NCT00243503 PMID:24606768

  14. Lack of pharmacokinetic drug-drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors.

    PubMed

    Chow, Laura Q M; Smith, David C; Tan, Antoinette R; Denlinger, Crystal S; Wang, Ding; Shepard, Dale R; Chaudhary, Archana; Lin, Yong; Gao, Ling

    2016-08-01

    The objective of this phase II study was to evaluate pharmacokinetic interaction potential between ramucirumab and paclitaxel in patients with advanced cancer. This study was designed to assess 2-way pharmacokinetic drug-drug interactions between ramucirumab and paclitaxel. Twenty-four patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m(2) was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15). Patients could continue to receive combination therapy with ramucirumab and paclitaxel. In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle. Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel. Concomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0-∞) and 0.97 (90 % CI 0.83, 1.13) for C max. In addition, similar ramucirumab pharmacokinetic characteristics were observed with or without paclitaxel administration. The ratios of geometric LS means of AUC(0-∞) and C max of ramucirumab (with paclitaxel vs. alone) were 1.00 (90 % CI 0.84, 1.19) for AUC(0-∞) and 1.07 (90 % CI 0.93, 1.24) for C max, respectively. Concomitant paclitaxel administration is unlikely to affect the pharmacokinetics of ramucirumab, and vice versa. The incidence and severity of adverse events were consistent with the known safety profiles of paclitaxel and ramucirumab.

  15. A Phase I/II Study of Chemotherapy Followed by Donor Lymphocyte Infusion plus Interleukin-2 for Relapsed Acute Leukemia after Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Inamoto, Yoshihiro; Fefer, Alexander; Sandmaier, Brenda M.; Gooley, Theodore A.; Warren, Edus H.; Petersdorf, Stephen H.; Sanders, Jean E.; Storb, Rainer F.; Appelbaum, Frederick R.; Martin, Paul J.; Flowers, Mary E.D.

    2011-01-01

    Efficacy of donor lymphocyte infusion (DLI) for relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1×108 CD3/kg for patients with related donors, and 0.1×108 CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0×106 IU/m2/day representing levels I (n=7), Ia (n=9), and II (n=1)) for 5 days followed by maintenance (1.0×106 IU/m2/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2-related toxicities developed in 1 patient at level I, 2 at level Ia and 1 at level II. Grades III–IV acute GVHD developed in 5 patients, and extensive chronic GVHD developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0×106 IU/m2/day. IL-2 administration after DLI might increase the incidence of chronic GVHD. PMID:21232624

  16. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia.

    PubMed

    Brandes, Alba A; Basso, Umberto; Reni, Michele; Vastola, Francesca; Tosoni, Alicia; Cavallo, Giovanna; Scopece, Luciano; Ferreri, Andres J; Panucci, Maria G; Monfardini, Silvio; Ermani, Mario

    2004-05-01

    Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

  17. A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer

    PubMed Central

    Pandit-Taskar, Neeta; O'Donoghue, Joseph A.; Durack, Jeremy C.; Lyashchenko, Serge K.; Cheal, Sarah M.; Beylergil, Volkan; Lefkowitz, Robert A.; Carrasquillo, Jorge A.; Martinez, Danny F.; Fung, Alex Mak; Solomon, Stephen B.; Gonen, Mithat; Heller, Glenn; Loda, Massimo; Nanus, David M.; Tagawa, Scott T.; Feldman, Jarett L.; Osborne, Joseph R.; Lewis, Jason S.; Reuter, Victor E.; Weber, Wolfgang A.; Bander, Neil H.; Scher, Howard I.; Larson, Steven M.; Morris, Michael J.

    2015-01-01

    Purpose Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of 89Zr-DFO-huJ591 (89Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared to conventional imaging modalities (CIMs) and pathology. Experimental Design Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of 89Zr-J591. Whole body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis, and with biopsies of metastatic sites. Results Median standardized uptake value for 89Zr-J591-positive bone lesions (n = 491) was 8.9; soft tissue lesions (n = 90): 4.8 (p < .00003). 89Zr-J591 detected 491 osseous sites compared to 339 by MDP, and 90 soft tissue lesions compared to 124 by CT. Compared to all CIMs combined, 89Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone, 25 soft tissue) were biopsied in 34 patients; 18/19 89Zr-J591-positive osseous sites and 14/16 89Zr-J591-positive soft tissue sites were positive for prostate cancer. The overall accuracy of 89Zr-J591 was 95.2% (20/21) for osseous lesions and 60% (15/25) for soft tissue lesions. Conclusions 89Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft tissue lesions was less optimal, although 89Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed PSMA targeting agents for prostate cancer. PMID:26175541

  18. Continuous 7-Days-A-Week External Beam Irradiation in Locally Advanced Cervical Cancer: Final Results of the Phase I/II Study

    SciTech Connect

    Serkies, Krystyna; Dziadziuszko, Rafal; Jassem, Jacek

    2012-03-01

    Purpose: To evaluate the feasibility and efficacy of definitive continuous 7-days-a-week pelvic irradiation without breaks between external beam radiotherapy and brachytherapy in locally advanced cervical cancer. Methods and Materials: Between November 1998 and December 1999, 30 patients with International Federation of Obstetrics and Gynecology Stage IIB or IIIB cervical cancer were included in a prospective Phase I/II study of continuous 7-days-a-week pelvic irradiation, to the total Manchester point B dose of 40.0-57.6 Gy. The first 13 patients (Group A) were given a daily tumor dose of 1.6 Gy, and the remaining 17 patients (Group B) were given 1.8 Gy. One or two immediate brachytherapy applications (point A dose 10-20 Gy, each) were performed in 28 cases. Results: Two patients did not complete the irradiation because of apparent early progression of disease during the irradiation. Eleven of the 28 evaluable patients (39%; 45% and 35% in Groups A and B, respectively) completed their treatment within the prescribed overall treatment time. Acute toxicity (including severe European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 and 4 effects in 40%) was experienced by 83% of patients and resulted in unplanned treatment interruptions in 40% of all patients (31% and 47% of patients in Groups A and B, respectively). Severe intestinal side effects occurred in 31% and 41% of Patients in Groups A and B, respectively (p = 0.71). The 5-year overall survival probability was 33%. Cancer recurrence occurred in 63% of patients: 20% inside and 57% outside the pelvis. Cumulative incidence of late severe bowel and urinary bladder toxicity at 24 months was 15%. Conclusion: Continuous irradiation in locally advanced cervical cancer is associated with a high incidence of severe acute toxicity, resulting in unplanned treatment interruptions. Late severe effects and survival after continuous radiotherapy do not substantially differ from

  19. Are three weeks hypofractionated radiation therapy (HFRT) comparable to six weeks for newly diagnosed glioblastoma patients? Results of a phase II study

    PubMed Central

    Tomatis, Stefano; Soffietti, Riccardo; Grimaldi, Marco; Lopci, Egesta; Chiti, Arturo; Leonetti, Antonella; Casarotti, Alessandra; Rossi, Marco; Cozzi, Luca; Ascolese, Anna Maria; Simonelli, Matteo; Marcheselli, Simona; Santoro, Armando; Clerici, Elena; Bello, Lorenzo; Scorsetti, Marta

    2017-01-01

    Background The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT). The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness. Methods Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function. Results A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome. Conclusion HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment. PMID:28978064

  20. A phase II study of dose-dense and dose-intense ABVD (ABVDDD-DI ) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma.

    PubMed

    Russo, Filippo; Corazzelli, Gaetano; Frigeri, Ferdinando; Capobianco, Gaetana; Aloj, Luigi; Volzone, Francesco; De Chiara, Annarosaria; Bonelli, Annamaria; Gatani, Tindaro; Marcacci, Gianpaolo; Donnarumma, Daniela; Becchimanzi, Cristina; de Lutio, Elisabetta; Ionna, Franco; De Filippi, Rosaria; Lastoria, Secondo; Pinto, Antonello

    2014-07-01

    We explored activity and safety of a dose-dense/dose-intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI ) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two-stage Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without consolidation radiotherapy. Cycles were supported with granulocyte colony-stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m2; first four cycles only). Co-primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event-free (EFS) and disease-free survival (DFS). All patients received the four doxorubicin-intensified courses and 96% concluded all six cycles (82.3% within the intended 18 weeks). This translated into a 66.9% increase of received dose-intensity for doxorubicin and 31.8% for the other agents over standard ABVD. The CR rate was 95.1% (78/82) and 87.8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14.6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-year EFS and DFS was 88.3% and 93.7%, respectively. ABVDDD-DI regimen was well-tolerated and ensured substantial CR and EFS rates without radiotherapy.

  1. AT-33A PHASE II STUDY OF CONCURRENT RADIATION THERAPY, TEMOZOLOMIDE AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME

    PubMed Central

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Peter; Fine, Howard; Camphausen, Kevin A.

    2014-01-01

    BACKGROUND: Glioblastoma (GBM) remains an aggressive brain tumor with poor prognosis. Valproic acid (VPA) is an antiepileptic agent that has been shown to have HDACi activity and to radiosensitize GBM cells in preclinical models. This phase II study aimed to determine if the addition of VPA to standard radiation therapy and temozolomide would improve OS and PFS. METHODS: We prospectively assessed survival, radiological and clinical progression in 37 newly diagnosed glioblastoma patients with the administration of VPA at 25 mg/kg orally BID concurrent with radiation therapy (RT) and temozolomide (TMZ). The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently tapered up to 25 mg/kg/day over the week prior to radiation. RESULTS: 81% of patients took VPA according to protocol. Median OS was 29.6 months (21- 63.8), median PFS was 10.5 (6.8 - 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3 or 4 toxicities of VPA in conjunction with TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). At the end of the study 26 (70%) patients were dead, 7 were live without disease, 4 alive with disease. Younger age (<= 50 years) compared to older age and class V RPA were significant for both OS and PFS. Using a landmark analysis, an early progression was related to a shorter interval between progression and death, whereas, a later progression was related to a longer interval between progression and death (p = 0.0002) HR 4.7. CONCLUSION: The addition of VPA to concurrent RT and TMZ in the treatment of newly diagnosed GBM may result in superior outcomes as compared to contemporary and historical data and merits further study.

  2. Preoperative Chemoradiation With Irinotecan and Capecitabine in Patients With Locally Advanced Resectable Rectal Cancer: Long-Term Results of a Phase II Study

    SciTech Connect

    Hong, Yong Sang; Kim, Dae Yong; Lim, Seok-Byung; Choi, Hyo Seong; Jeong, Seung-Yong; Jeong, Jun Yong; Sohn, Dae Kyung; Kim, Dae-Hyun; Chang, Hee Jin; Park, Jae-Gahb; Jung, Kyung Hae

    2011-03-15

    Purpose: Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer has shown benefit over postoperative CRT; however, a standard CRT regimen has yet to be defined. We performed a prospective concurrent CRT Phase II study with irinotecan and capecitabine in patients with locally advanced rectal cancer to investigate the efficacy and safety of this regimen. Methods and Materials: Patients with locally advanced, nonmetastatic, and mid-to-lower rectal cancer were enrolled. Radiotherapy was delivered in 1.8-Gy daily fractions for a total of 45 Gy in 25 fractions, followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of 40 mg/m{sup 2} of irinotecan per week for 5 consecutive weeks and 1,650 mg/m{sup 2} of capecitabine per day for 5 days per week (weekdays only) from the first day of radiotherapy. Total mesorectal excision was performed within 6 {+-} 2 weeks. The pathologic responses and survival outcomes were included for the study endpoints. Results: In total, 48 patients were enrolled; 33 (68.7%) were men and 15 (31.3%) were women, and the median age was 59 years (range, 32-72 years). The pathologic complete response rate was 25.0% (11 of 44; 95% confidence interval, 12.2-37.8) and 8 patients (18.2% [8 of 44]) showed near-total tumor regression. The 5-year disease-free and overall survival rates were 75.0% and 93.6%, respectively. Grade 3 toxicities included leukopenia (3 [6.3%]), neutropenia (1 [2.1%]), infection (1 [2.1%]), alanine aminotransferase elevation (1 [2.1%]), and diarrhea (1 [2.1%]). There was no Grade 4 toxicity or treatment-related death. Conclusions: Preoperative CRT with irinotecan and capecitabine with treatment-free weekends showed very mild toxicity profiles and promising results in terms of survival.

  3. Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

    PubMed Central

    Propper, D J; Levitt, N C; O'Byrne, K; Braybrooke, J P; Talbot, D C; Ganesan, T S; Thompson, C H; Rajagopalan, B; Littlewood, T J; Dixon, R M; Harris, A L

    2000-01-01

    BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg−1over 1 h, followed by a maintenance infusion of 4 mg kg−1h−1for 5 h. MMC 6 mg m−2was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1–4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities – nausea/vomiting and vein pain – were mild and did not exceed CTC grade 2. Liver31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity. © 2000 Cancer Research Campaign PMID:10839290

  4. Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer.

    PubMed

    Montgomery, Bruce; Eisenberger, Mario A; Rettig, Matthew B; Chu, Franklin; Pili, Roberto; Stephenson, Joseph J; Vogelzang, Nicholas J; Koletsky, Alan J; Nordquist, Luke T; Edenfield, William J; Mamlouk, Khalid; Ferrante, Karen J; Taplin, Mary-Ellen

    2016-03-15

    Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. ©2015 American Association for Cancer Research.

  5. Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study.

    PubMed

    Soffietti, Riccardo; Nobile, Mauro; Rudà, Roberta; Borgognone, Marzia; Costanza, Alessandra; Laguzzi, Elena; Mutani, Roberto

    2004-02-15

    The efficacy of second-line chemotherapy for patients with recurrent or progressive oligodendroglial tumors is limited. In the current study, the authors investigated the use of carboplatin as a second-line chemotherapeutic agent against these types of tumors. Twenty-three patients with recurrent or progressive oligodendrogliomas or oligoastrocytomas after first-line PCV (procarbazine, lomustine, and vincristine) chemotherapy were enrolled in a single-institution Phase II study of second-line carboplatin chemotherapy. All patients had undergone surgery, and most also had undergone conventional radiotherapy. Carboplatin was administered at a dose of 560 mg/m2 intravenously every 4 weeks. Responses were evaluated according to conventional criteria, based on magnetic resonance imaging (MRI) findings. Three of 23 patients (13%) had partial responses, with neurologic improvement. Twelve patients (52%) had stable disease; in 2 of these 12 patients, a minor response was seen on MRI. Eight patients (35%) had progressive disease. The median time to tumor progression was 3 months for all patients and 9 months for patients who experienced responses to treatment. Progression-free survival rates at 6 and 12 months were 34.8% and 8.7%, respectively. Among the salvage treatment plans followed after carboplatin chemotherapy were supportive care alone, radiotherapy, third-line chemotherapy, and reoperation. The median survival duration from the start of carboplatin administration was 16 months. Myelotoxicity was severe, with Grade 3 or 4 thrombocytopenia in 60% of patients and Grade 3 or 4 neutropenia in 48% of patients. When administered according to a monthly schedule, carboplatin exhibited modest activity in adult patients with recurrent or progressive oligodendroglioma or oligoastrocytoma who experienced treatment failure after PCV chemotherapy; the current treatment regimen also was associated with severe toxicity. Further improvement of second-line chemotherapy for the

  6. Concurrent radiation, mitomycin C and 5-fluorouracil in poor prognosis carcinoma of cervix: preliminary results of a Phase I-II study

    SciTech Connect

    Thomas, G.; Dembo, A.; Beale, F.; Bean, H.; Bush, R.; Herman, J.; Pringle, J.; Rawlings, G.; Sturgeon, J.; Fine, S.

    1984-09-01

    Between July 1981 and June 1983, 27 patients with advanced primary squamous cell carcinoma (SCC) of cervix and 8 with recurrent disease were treated using a pilot regimen of combination chemotherapy (CT): Mitomycin C (MIT), 5 Fluorouracil (5 FU), and radiation therapy (RT). CT and RT doses on this Phase I-II Study were escalated to the current regimen. A split course of RT was used, either pelvic RT alone or the same pelvic RT plus para-aortic RT. CT was given by continuous IV infusion days 1 through 4 of each half-course of RT. This was followed by one application of intrauterine /sup 137/Cs when possible. Three of the 8 patients with recurrence in the pelvis or para-aortic nodes had a complete response (CR) to CT-RT and are alive without disease at 19, 19 and 22 months after treatment, respectively. Twenty of the 27 (74%) primary patients had a CR. With a median duration of follow-up of 6 months 4/20 have relapsed, 1 in RT field, 2 at distant sites, and 1 in both. The acute toxicity of this regimen was tolerable: 2/35 developed transient leukopenia with one febrile episode, 9/35 developed transient thrombocytopenia without bleeding. Symptomatic sigmoid strictures developed in two patients, one requiring surgical intervention. Typically, near complete regression of tumor is noted on completion of the external RT, reproducing the dramatic responses that have been observed in SCC of the anal canal, esophagus and head and neck, with this CT-RT regimen.

  7. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences.

    PubMed

    Eve, Heather E; Carey, Sean; Richardson, Sarah J; Heise, Carla C; Mamidipudi, Vidya; Shi, Tao; Radford, John A; Auer, Rebecca L; Bullard, Sheila H; Rule, Simon A J

    2012-10-01

    We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty-six patients received lenalidomide 25 mg/d (days 1-21 of a 28-d cycle) for up to 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0-53·6] and median progression-free survival (PFS) of 3·9 months (95% CI 0·0-11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3-21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40-60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low-dose maintenance agent. © 2012 Blackwell Publishing Ltd.

  8. A Phase II Study of Submandibular Gland Transfer Prior to Radiation for Prevention of Radiation-induced Xerostomia in Head-and-Neck Cancer (RTOG 0244)

    SciTech Connect

    Jha, Naresh; Harris, Jonathan; Seikaly, Hadi; Jacobs, John R.; McEwan, A.J.B.; Robbins, K. Thomas; Grecula, John; Sharma, Anand K.; Ang, K. Kian

    2012-10-01

    Purpose: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia. Methods and Materials: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were 'not per protocol,' then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of {<=}51% was acceptable. Results: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was 'per protocol' or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively. Conclusions: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia.

  9. A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.

    PubMed

    Ciuleanu, T; Bazin, I; Lungulescu, D; Miron, L; Bondarenko, I; Deptala, A; Rodriguez-Torres, M; Giantonio, B; Fox, N L; Wissel, P; Egger, J; Ding, M; Kalyani, R N; Humphreys, R; Gribbin, M; Sun, W

    2016-04-01

    This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response. In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms. The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned. © The Author 2016. 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.

  10. Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer

    PubMed Central

    Elez, E; Hendlisz, A; Delaunoit, T; Sastre, J; Cervantes, A; Varea, R; Chao, G; Wallin, J; Tabernero, J

    2016-01-01

    Background: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC). Methods: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m−2, folinic acid 400 mg m−2, and 5-fluorouracil (400 mg m−2 bolus then 2400 mg m−2 over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate. Results: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8–77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0–16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0–30.0) and 10.0 months (7.0–12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0–NA); median PFS 12.0 (8.0–20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0–37.0); median PFS 7.0 (4.0–18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%). Conclusion: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted. PMID:26766738

  11. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia.

    PubMed

    Konopleva, Marina; Thall, Peter F; Yi, Cecilia Arana; Borthakur, Gautam; Coveler, Andrew; Bueso-Ramos, Carlos; Benito, Juliana; Konoplev, Sergej; Gu, Yongchuan; Ravandi, Farhad; Jabbour, Elias; Faderl, Stefan; Thomas, Deborah; Cortes, Jorge; Kadia, Tapan; Kornblau, Steven; Daver, Naval; Pemmaraju, Naveen; Nguyen, Hoang Q; Feliu, Jennie; Lu, Hongbo; Wei, Caimiao; Wilson, William R; Melink, Teresa J; Gutheil, John C; Andreeff, Michael; Estey, Elihu H; Kantarjian, Hagop

    2015-07-01

    We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m(2). The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m(2) or 4 g/m(2) had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556.

  12. 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.

  13. 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

  14. Consolidative Involved-Node Proton Therapy for Stage IA-IIIB Mediastinal Hodgkin Lymphoma: Preliminary Dosimetric Outcomes From a Phase II Study

    SciTech Connect

    Hoppe, Bradford S.; Flampouri, Stella; Su Zhong; Morris, Christopher G.; Latif, Naeem

    2012-05-01

    Purpose: To compare the dose reduction to organs at risk (OARs) with proton therapy (PT) versus three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in patients with mediastinal Hodgkin lymphoma (HL) enrolled on a Phase II study of involved-node radiotherapy (INRT). Methods and Materials: Between June 2009 and October 2010, 10 patients were enrolled on a University of Florida institutional review board-approved protocol for de novo 'classical' Stage IA-IIIB HL with mediastinal (bulky or nonbulky) involvement after chemotherapy. INRT was planned per European Organization for Research and Treatment of Cancer guidelines. Three separate optimized plans were developed for each patient: 3D-CRT, IMRT, and PT. The primary end point was a 50% reduction in the body V4 with PT compared with 3D-CRT or IMRT. Results: The median relative reduction with PT in the primary end point, body V4, was 51% compared with 3D-CRT (p = 0.0098) and 59% compared with IMRT (p = 0.0020), thus all patients were offered treatment with PT. PT provided the lowest mean dose to the heart, lungs, and breasts for all 10 patients compared with either 3D-CRT or IMRT. The median difference in the OAR mean dose reduction with PT compared with 3D-CRT were 10.4 Gy/CGE for heart; 5.5 Gy/CGE for lung; 0.9 Gy/CGE for breast; 8.3 Gy/CGE for esophagus; and 4.1 Gy/CGE for thyroid. The median differences for mean OAR dose reduction for PT compared with IMRT were 4.3 Gy/CGE for heart, 3.1 Gy/CGE for lung, 1.4 Gy/CGE for breast, 2.8 Gy/CGE for esophagus, and 2.7 Gy/CGE for thyroid. Conclusions: All 10 patients benefitted from dose reductions to OARs with PT compared with either 3D-CRT or IMRT. It is anticipated that these reductions in dose to OAR will translate into lower rates of late complications, but long-term follow-up on this Phase II INRT study is needed.

  15. A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification.

    PubMed

    Tarpgaard, Line S; Qvortrup, Camilla; Nygård, Sune B; Nielsen, Signe L; Andersen, Diana R; Jensen, Niels Frank; Stenvang, Jan; Detlefsen, Sönke; Brünner, Nils; Pfeiffer, Per

    2016-02-11

    The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells. Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6% of these tumors had TOP2A copy gain and 2.0% had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5% had a ratio ≥ 1.5 consistent with gene amplification and 2.6% had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin. The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival. Eudract no. 2013-001648-79.

  16. A Phase II Study of Gemcitabine, Vincristine, and Cisplatin (Gvp) As Second-Line Treatment for Patients with Advanced Soft Tissue Sarcoma

    PubMed Central

    Luo, Zhiguo; Zhang, Xiaowei; Peng, Wei; Wu, Xianghua; Wang, Huijie; Yu, Hui; Wang, Jialei; Chang, Jianhua; Hong, Xiaonan

    2015-01-01

    Abstract Patients with advanced soft tissue sarcoma (aSTS) typically have a poor prognosis. Patients progressing to doxorubicin-based regimen have limited therapeutic options. Monotherapy with cytotoxic drugs appears to have only modest activity in the second-line setting. The purpose of this phase II study was to prospectively evaluate the safety and efficacy of combination regimen with gemcitabine, vincristine, and cisplatin (GVP) as a salvage treatment for patients with aSTS. Eligible patients were female with 18∼75 years old, and had aSTS that had progressed after 1 prior anthracyclines-based chemotherapy regimen. Patients were treated with 1,000 mg/m2 gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m2 (max 2 mg) vincristine IV on day 1 and 25 mg/m2 cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), over response rate (ORR) and safety. This trial was registered with www.clinicaltrials.gov (no. NCT01192633). A total of 26 patients with a median age 47 years (21–72) were recruited. ORR was 23.1% [1 complete response and 5 partial responses]. The median PFS and OS were 4.8 (95% CI, 0.1–9.5) months and 15.0 (95% CI, 6.1–23.9) months, respectively. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No febrile neutropenia and grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%). We conclude that GVP regimen is effective with a favorable safety profile as the second-line chemotherapy in aSTS patients, which warrants further investigation in a phase III study. PMID:26512574

  17. A phase II study of capecitabine and oxaliplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract.

    PubMed

    Graham, J S; Boyd, K; Coxon, F Y; Wall, L R; Eatock, M M; Maughan, T S; Highley, M; Soulis, E; Harden, S; Bützberger-Zimmerli, P; Evans, T R J

    2016-03-12

    Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m(2) po, twice daily, days 1-14) and oxaliplatin (130 mg/m(2) i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8% (95% CI 12.05-39.5%). Stable disease was observed in a further 13 patients (31%) and progressive disease observed in 12 (28.6%) of patients. The median progression-free survival was 4.6 months (95% CI 2.8-6.4 months; Fig. 1) and the median overall survival 7.9 months (95% CI 5.3-10.4 months; Fig. 2). Fig. 1 Progression-free survival Fig. 2 Overall survival Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease

  18. A Phase II Study of Sorafenib in Advanced Uterine Carcinoma / Carcinosarcoma: A Trial of the Chicago, PMH, and California Phase II Consortia

    PubMed Central

    Nimeiri, Halla S.; Oza, Amit M.; Morgan, Robert J.; Huo, Dezheng; Elit, Laurie; Knost, James A.; Wade, James L.; Agamah, Edem; Vokes, Everett E.; Fleming, Gini F.

    2010-01-01

    Objectives To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. Methods This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0–1 prior chemotherapy regimens, and ECOG performance status ≤ 2. Sorafenib at a dose of 400 mg was administered orally twice daily. A cycle was defined as 28 days. Objective tumor response was the primary endpoint and was assessed following every two cycles. Results Fifty–six patients (40 with carcinoma, 16 with carcinosarcoma) were enrolled between March 2005 and August 2007. Two (5%) patients with uterine carcinoma had a partial response (PR) and 17 (42.5%) achieved stable disease (SD). Five had SD lasting at least 4 months. The 6-month progression free survival rate for patients with carcinoma was 29%, and the median overall survival was 11.4 months. No patients with carcinosarcoma had an objective response. Four (25%) had SD, and one had SD lasting 18 months. The 6-month progression free survival rate was 13%, and the median overall survival was 5.0 months. Grade 3/4 drug related toxicities included: hypertension (13%), hand-foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%). Conclusion Sorafenib had minimal activity in patients with uterine carcinoma. Predictive factors for potential benefit are needed. PMID:20117828

  19. Results of a phase I-II study on intraductal confocal microscopy (IDCM) in patients with common bile duct (CBD) stenosis.

    PubMed

    Giovannini, M; Bories, E; Monges, G; Pesenti, C; Caillol, F; Delpero, J R

    2011-07-01

    accuracy rate of 86%, sensitivity of 83%, and specificity of 75%. The respective numbers for standard histopathology were 53, 65, and 53%. This phase I-II study on IDCM showed that IDCM is feasible. This new technique will open a new door for optical biopsy of the CBD.

  20. A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma

    PubMed Central

    2011-01-01

    Abstract Background The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS. Method Patients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m2 iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m2 day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA. Result Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far. Conclusion The current protocol is feasible for achieving local control rates, as well as OS and

  1. Gemcitabine plus mitoxantrone and prednisone in the palliative treatment of hormone-resistant prostate cancer (HRPC): A phase II study (GOAM 01.01 study).

    PubMed

    Cricca, Antonia; Marino, Antonella; Valenti, Danila; Melotti, Barbara; Amaducci, Elena; Guardigli, Cristina; Lenzi, Manuela; Martorana, Giuseppe; Buli, Pierfrancesco; Martoni, Andrea Angelo

    2006-01-01

    The present exploratory phase II study was performed to evaluate the activity and tolerability of adding a second agent (gemcitabine) to the well-tolerated mitoxantrone/prednisone regimen in patients with locally advanced or metastatic prostate cancer no longer responsive to hormonal treatment. Forty-three patients with hormone-refractory prostate cancer (HRPC) were included in the study from May 2000 to April 2004. Their median age was 71 years (range, 56-81) and their median Karnofsky performance status (KPS) was 90 (range, 70-100). The treatment schedule consisted of intravenous (i.v.) mitoxantrone (8 mg/m2 on day 1), i.v. gemcitabine 800 mg/m2 on days 1 and 8, recycled every 21 days and oral prednisone administered at a dose of 10 mg per day. Hormonal treatment with LHRH was continued in all patients. Up to six cycles of treatment were planned in the absence of progressive disease. Sixteen patients had measurable disease (six patients only measurable disease, ten patients bone disease plus measurable disease) and 27 patients had only bone disease. Concerning the PSA levels, a partial response (PR) was observed in 15 patients (38%), stable disease (SD) in 16 patients (41%) and progressive disease (PD) in eight patients (21%). The objective response was evaluable in 16 patients; one patient was not evaluable because he had received only one cycle. Ten patients (63%) had SD and five patients (31%) PD. In the ten evaluable patients with objective SD, depending upon the PSA response, three PR, six SD and one PD were observed. Among the five patients who progressed, three PD and two SD were observed as a PSA response. Pain remission was recorded in 15/41 patients (36%) and the KPS remained stable in most patients. The median overall survival was 15 months (range, 1-41) (95% CI: 10-20 months). The 1-year survival rate was 61%. Hematological toxicity was mild: G 3-4 neutropenia was observed in five (12%) patients. There were no neutropenic, fevers. No significant non

  2. Rebamipide (OPC-12759) in the treatment of dry eye: a randomized, double-masked, multicenter, placebo-controlled phase II study.

    PubMed

    Kinoshita, Shigeru; Awamura, Saki; Oshiden, Kazuhide; Nakamichi, Norihiro; Suzuki, Hiroyuki; Yokoi, Norihiko

    2012-12-01

    To investigate the dose response for efficacy of 1% and 2% rebamipide ophthalmic suspension compared with placebo in patients with dry eye. A randomized, double-masked, multicenter, placebo-controlled, parallel-group, dose-response phase II study. A total of 308 patients with dry eye. After a 2-week screening period, patients were randomized to receive placebo or 1% rebamipide or 2% rebamipide administered as 1 drop in each eye 4 times daily for 4 weeks. The primary objective end point was change in fluorescein corneal staining (FCS) score from baseline to last observation carried forward (LOCF). Secondary objective end points were lissamine green conjunctival staining (LGCS) score, tear film break-up time (TBUT), and the Schirmer's test. Secondary subjective end points included dry eye-related ocular symptoms (foreign body sensation, dryness, photophobia, eye pain, and blurred vision) score and patients' overall treatment impression score. Rebamipide dose response was observed in FCS, LGCS, and TBUT scores. Both 1% and 2% rebamipide were significantly more effective than the placebo in terms of the change from baseline to LOCF for FCS, LGCS, and TBUT scores. There was no significant difference between the rebamipide and placebo groups from baseline to LOCF in Schirmer's test values, and dose response was not observed. In the predefined dry eye subpopulation with a baseline FCS score of 10 to 15, the mean change from baseline in the 2% rebamipide group was larger than that in the 1% rebamipide group. Change from baseline to LOCF for all 5 dry eye-related ocular symptom scores and patients' overall treatment impression showed significant improvements in the 1% and 2% rebamipide groups compared with the placebo group, except for photophobia in the 1% rebamipide group. No deaths or drug-related serious adverse events occurred in any treatment group. The incidence of ocular abnormalities was similar across the rebamipide and placebo groups. Rebamipide was effective in

  3. [Water-filtered infrared-A-hyperthermia combined with radiotherapy in advanced and recurrent tumors. Initial results of a multicenter phase I-II study].

    PubMed

    Seegenschmiedt, M H; Klautke, G; Walther, E; Feldmann, H J; Katalinic, A; Stuschke, M; von Lieven, H; Vaupel, P

    1996-09-01

    Water-filtered infrared-A-radiation (IR/A-HT) can be used to heat superficial malignant tumors. A prospective multicenter phase I-II study was conducted to evaluate toxicity and efficacy of IR/A-HT combined with external beam radiotherapy (RT). From December 1991 to June 1994, a total of 53 patients with 58 malignant lesions were entered in the study. There were 14 primary, 36 recurrent and 8 metastatic tumors which were located in the head and neck region (14), chest wall (31), abdominal wall (2) and the extremities (11). The mean tumor volume was 100 cm3. IR/A-HT was applied 1 to 2 times per week with up to 3 IR/A-HT-radiators directly before or after external RT for 1 hour at 40.5 to 44 degrees C. Temperatures were controlled at various locations at the skin surface and invasively at depth. IR/A-HT was well tolerated: in 31 (53%) lesions acute (pain, pulse or blood pressure changes, increased skin reaction etc.) and in 25 (43%) chronic side-effects (atrophy, telangiectasis, fibrosis etc.) were noted; usually the toxicity was minor and temporary. At 3 months FU, 32 (55%) lesions achieved a local CR and 19 (35%) a PR; at 12 months FU, 25 (43%) had persistent CR; 16 patients (18 lesions) were deceased and 3 (4 lesions) not yet in FU. In univariate analysis the following prognostic factors for CR at 3 or 12 months FU were found: Karnofsky, metastatic status, tumor size, total RT-dose, thermal parameters T min(av) and T mean. For acute toxicity maximum temperature Tmax(av) was prognostically decisive. Significant differences were also found when considering the "quality of the HT-application". The microwave technique was superior to the infrared-A-HT-technique with regard to the penetration depth of energy deposition. Water-filtered infrared-A-radiation can be safely and effectively applied to heat localized superficial tumors (up to 1 cm depth). To increase the area of HT application multiple infrared-A-radiators have to be combined. A multi-element-system is in

  4. A prospective phase II study of L-asparaginase- CHOP plus radiation in newly diagnosed extranodal NK/T-cell lymphoma, nasal type

    PubMed Central

    2013-01-01

    Purpose To explore the efficacy and safety of L-asparaginase in newly-diagnosed extranodal nature killer (NK)/T –cell lymphoma (ENKTL), we conducted a prospective phase II study of L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone (CHOP-L) regimen in combination with radiotherapy. Patients and methods Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. Treatment included 6–8 cycles of CHOP-L (cyclophosphamide, 750 mg/m2 day 1; vincristine, 1.4 mg/m2 day 1 (maximal dose 2 mg), doxorubicin 50 mg/m2 day 1; dexamethasone 10 mg days 1–8; L-asparaginase 6000 u/m2 days 2–8). Radiotherapy was scheduled after 4–6 cycles of CHOP-L regimen, depending on stage and primary anatomic site. The primary endpoint was complete response (CR) rate. Results A total of 38 eligible patients were enrolled. The median age was 40.5 years (range, 15 to 71 years). Their clinical characteristics were male to female ratio, 24:14; Ann Arbor stage I, 20; II, 11; III, 3; IV, 4. CR and overall response rates were 81.6% (95% CI, 69.3% to 93.9%) and 84.2%, respectively. With a median follow-up of 25 months, the 2-year overall survival, progression-free survival and disease-free survival rates were 80.1% (95%CI, 73.3% to 86.9%), 81% (95%CI, 74.5% to 87.5%) and 93.6% (95%CI, 89.3% to 97.9%), respectively. The major adverse events were myelosuppression, liver dysfunction, and digestive tract toxicities. Grade 3 to 4 leukopenia and neutropenia were 76.3% and 84.2%, respectively. No treatment-related death was observed. Conclusion CHOP-L chemotherapy in combination with radiotherapy is a safe and highly effective treatment for newly diagnosed ENKTL. PMID:23816178

  5. Patient Reported Outcomes from HIV Facial Lipoatrophy Treatment With a Volumizing Hyaluronic Acid Filler: A Prospective, Open-Label, Phase I and II Study.

    PubMed

    Ho, Derek; Jagdeo, Jared

    2016-09-01

    Human immunodeficiency virus (HIV) facial lipoatrophy (FLA) is associated with the use of highly active antiretroviral therapy (HAART) and HIV disease. HIV FLA is primarily characterized by midface (cheeks and temples) volume loss, resulting in a "sunken" and aged appearance. Filler agents for treatment of HIV FLA can provide midface volumization and improve quality-of-life (QOL). A 20 mg/ml hyaluronic acid (HA) filler (Juvéderm Voluma® XC, Allergan plc, Irvine, CA) may provide an immediate, natural appearing facial enhancement outcome in one treatment. We hypothesized that this HA filler for treatment of HIV FLA is safe and efficacious and may help improve patients' QOL.
    To provide patient reported outcomes from HA filler for treatment of HIV FLA and suggest recommendations on use of validated QOL outcome measures to assess patient concerns specific to HIV FLA.
    This was a prospective, open-label, phase I and II study to evaluate patient reported outcomes, in addition to safety and efficacy, of this HA filler for treatment of HIV FLA in 20 subjects at the Sacramento Veterans Affairs Medical Center, Mather, CA (ClinicalTrials.gov NCT02342223). Outcome measures include the Dermatology Life Quality Index (DLQI) and a subject satisfaction questionnaire (SSQ).
    Nineteen subjects completed the 12-month follow-up. There was no significant improvement of DLQI score. Subject comments revealed high degree of satisfaction and there were no negative comments on the SSQ.
    In this study, we report that all subjects that completed this study were satisfied and had subjective improvement of their QOL post-treatment. We recommend against use of DLQI in the future as it may not fully encompass the emotional and mental health aspects that may be affected from HIV FLA. We recommend use of the Facial Appearance Inventory (FAI) and FACE-Q in future studies for HA filler treatment of HIV FLA.

    J Drugs Dermatol. 2016;15(9):1064-1069.

  6. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

    PubMed

    Chiappori, A A; Kolevska, T; Spigel, D R; Hager, S; Rarick, M; Gadgeel, S; Blais, N; Von Pawel, J; Hart, L; Reck, M; Bassett, E; Burington, B; Schiller, J H

    2015-02-01

    Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat. © The Author 2014. Published by Oxford University Press on behalf

  7. Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group

    PubMed Central

    Oza, Amit M.; Elit, Laurie; Tsao, Ming-Sound; Kamel-Reid, Suzanne; Biagi, Jim; Provencher, Diane Michele; Gotlieb, Walter H.; Hoskins, Paul J.; Ghatage, Prafull; Tonkin, Katia S.; Mackay, Helen J.; Mazurka, John; Sederias, Joana; Ivy, Percy; Dancey, Janet E.; Eisenhauer, Elizabeth A.

    2011-01-01

    Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting. Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles. Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN

  8. Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer.

    PubMed

    Ogata, Yutaka; Matono, Keiko; Tsuda, Hideaki; Ushijima, Masataka; Uchida, Shinji; Akagi, Yoshito; Shirouzu, Kazuo

    2015-01-01

    Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No

  9. A phase II study of capecitabine and cisplatin (XP) as first-line chemotherapy in patients with advanced esophageal squamous cell carcinoma.

    PubMed

    Lee, Jeeyun; Im, Young-Hyuck; Cho, Eun Yoon; Hong, Yong Sang; Lee, Hyo Rak; Kim, Hyo Song; Kim, Mi-Jin; Kim, Kwhanmien; Kang, Won Ki; Park, Keunchil; Shim, Young Mog

    2008-06-01

    The combination of 5-fluorouracil (5-FU) and cisplatin (FP) remains the mostly used regimen for metastatic esophageal squamous carcinoma. This phase II study assessed the efficacy and safety of capecitabine/cisplatin (XP) as a first-line chemotherapy in a homogenous cohort of patients with metastatic or recurrent esophageal squamous cell carcinoma. Patients received 60 mg/m(2) of cisplatin intravenously (IV) on day 1 and capecitabine 1,250 mg/m(2)/dose orally twice a day on days 1-14. Treatment cycles were repeated every 3 weeks until the documented disease progression, unacceptable toxicity, or patient's refusal. Immunohistochemical studies against thymidylate synthase (TS) and thymidine phosphorylase (TP) were performed to seek predictive markers for treatment response. Between December 2003 and March 2006, 45 patients entered the study. All patients had histologically proven squamous cell carcinoma of the esophagus. The overall response rate (ORR) was 57.8% (95% CI, 43.3-72.2) with 0 CR and 26 PRs. The median duration of response in responders was 4.6 months (1.0-15.6 months). With a median follow-up duration of 25.7 months (10.8-42.6 months), the median time to progression was 4.7 months (95% CI, 2.5-7.0) and the median survival time was 11.2 months (95% CI, 8.5-13.9). Common grade 3 or 4 non-hematological adverse events were anorexia (18/191, 9.4%), fatigue (9/191, 4.7%), constipation (6/191, 3.1%), hand-foot syndrome (6/191, 3.1%) and diarrhea (4/191, 2.1%). The most common grade 3 or 4 hematological adverse events were neutropenia (33/191, 17.3%), followed by leucopenia (11/191, 5.8%), anemia (2/191, 1.0%) and thrombocytopenia (1/191, 0.5%). There was no treatment-related death. Neither TS nor TP showed predictive value for treatment response. The XP regimen demonstrated a promising antitumor activity in metastatic esophageal squamous cell carcinoma, which may potentially replace the FP regimen.

  10. Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma.

    PubMed

    Rimner, Andreas; Zauderer, Marjorie G; Gomez, Daniel R; Adusumilli, Prasad S; Parhar, Preeti K; Wu, Abraham J; Woo, Kaitlin M; Shen, Ronglai; Ginsberg, Michelle S; Yorke, Ellen D; Rice, David C; Tsao, Anne S; Rosenzweig, Kenneth E; Rusch, Valerie W; Krug, Lee M

    2016-08-10

    We conducted a two-center phase II study to determine the safety of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) after chemotherapy and pleurectomy-decortication (P/D) as part of a multimodality lung-sparing treatment. Patients received up to four cycles of pemetrexed plus platinum. If feasible, P/D was performed. Hemithoracic IMPRINT was administered to a planned dose of 50.4 Gy in 28 fractions. The primary end point was the incidence of grade 3 or greater radiation pneumonitis (RP). A total of 45 patients were enrolled; 18 were not evaluable (because of disease progression before radiation therapy [RT], n = 9; refusal of surgery or RT, n = 5; extrapleural pneumonectomy at time of surgery, n = 2; or chemotherapy complications, n = 2). A total of 26 patients received pemetrexed plus cisplatin, 18 received pemetrexed plus carboplatin, and four received a combination. Thirteen patients (28.9%) had a partial response, 15 patients (33.3%) experienced disease progression, one patient died during chemotherapy, and all others had stable disease. Eight patients underwent P/D or an extended P/D, and 13 underwent a partial P/D. A total of 27 patients started IMPRINT (median dose, 46.8 Gy; range, 28.8 to 50.4 Gy) and were evaluable for the primary end point (median follow-up, 21.6 months). Six patients experienced grade 2 RP, and two patients experienced grade 3 RP; all recovered after corticosteroid initiation. No grade 4 or 5 radiation-related toxicities were observed. The median progression-free survival and overall survival (OS) were 12.4 and 23.7 months, respectively; the 2-year OS was 59% in patients with resectable tumors and was 25% in patients with unresectable tumors. Hemithoracic IMPRINT for malignant pleural mesothelioma (MPM) is safe and has an acceptable rate of RP. Its incorporation with chemotherapy and P/D forms a new lung-sparing treatment paradigm for patients with locally advanced MPM. © 2016 by American Society of Clinical

  11. Phase II Study of Nonmyeloablative Allogeneic Bone Marrow Transplantation for B Cell Lymphoma with Post-Transplantation Rituximab and Donor Selection Based First on Non-HLA Factors.

    PubMed

    Kanakry, Jennifer A; Gocke, Christopher D; Bolaños-Meade, Javier; Gladstone, Douglas E; Swinnen, Lode J; Blackford, Amanda L; Fuchs, Ephraim J; Huff, Carol Ann; Borrello, Ivan; Matsui, William H; Brodsky, Robert A; Rosner, Gary L; Shanbhag, Satish; Luznik, Leo; Jones, Richard J; Ambinder, Richard F; Kasamon, Yvette L

    2015-12-01

    Outcomes of nonmyeloablative (NMA), HLA-haploidentical (haplo), related-donor allogeneic blood or marrow transplantation (allo-BMT) with high-dose post-transplantation cyclophosphamide (PTCy) appear to be similar to those using HLA-matched donors. Thus, it may be possible to prioritize donor factors other than HLA matching that could enhance antitumor activity. The Fc receptor polymorphism FCGR3A-158VV may confer greater sensitivity to rituximab than FCGR3A-158FF. In a prospective phase II study of NMA, related-donor allo-BMT with PTCy and post-transplantation rituximab for patients with B cell lymphomas, we hypothesized that donor selection that prioritized FCGR3A-158 polymorphism over HLA matching would be feasible, safe, and improve outcomes. The primary endpoint was 1-year progression-free survival (PFS). Of 83 patients transplanted (median age, 59 years), 69 (83%) received haplo grafts. Fifty-four (65%) received a graft that maintained or improved their Fc receptor polymorphism status. With 2.6-year median follow-up, the 1-year PFS and overall survival (OS) probabilities were 71% and 86%, respectively, with 1-year relapse and nonrelapse mortality (NRM) probabilities of 20% and 8%. At 1 year, the probability of acute grades II to IV graft-versus-host disease (GVHD) was 41%, with acute grades III to IV GVHD probability of 5% and chronic GVHD probability of 11%. Among haplo transplants, the 1-year probabilities of PFS, OS, relapse, and NRM were 70%, 83%, 20%, and 10%, respectively. No differences in outcomes were observed based on donor FCGR3A-158 polymorphism. Excess infection risk was not apparent with post-transplantation rituximab. Although donor selection based on FCGR3A-158 polymorphism was not shown to influence PFS, this study suggests that donor selection based on criteria other than best HLA match is feasible and safe. This study opens the way for the future investigation of donor prioritization based on promising non-HLA factors that may improve

  12. Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer.

    PubMed

    Tamura, Kenji; Inoue, Kenichi; Masuda, Norikazu; Takao, Shintaro; Kashiwaba, Masahiro; Tokuda, Yutaka; Iwata, Hiroji; Yamamoto, Naohito; Aogi, Kenjiro; Saeki, Toshiaki; Nakayama, Takahiro; Sato, Nobuaki; Toyama, Tatsuya; Ishida, Takanori; Arioka, Hitoshi; Saito, Mitsue; Ohno, Shinji; Yamauchi, Hideko; Yamada, Kimito; Watanabe, Junichiro; Ishiguro, Hiroshi; Fujiwara, Yasuhiro

    2017-05-01

    Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m(2) nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m(2) docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5-11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4-13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m(2) did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  13. Phase I-II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints.

    PubMed

    Winqvist, Maria; Mozaffari, Fariba; Palma, Marzia; Eketorp Sylvan, Sandra; Hansson, Lotta; Mellstedt, Håkan; Österborg, Anders; Lundin, Jeanette

    2017-01-01

    This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3-4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67(+)) CD8(+) T cells was increased at week 4, with further increase in both the CD4(+) and CD8(+) subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8(+) subset (p < 0.003), while effector cells decreased in both the CD8(+) and CD4(+) subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B(+) T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.

  14. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study

    PubMed Central

    Steinfeld, Serge D; Tant, Laure; Burmester, Gerd R; Teoh, Nick KW; Wegener, William A; Goldenberg, David M; Pradier, Olivier

    2006-01-01

    This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sjögren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33–72 years) were to receive 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a ≥20% improvement in at least two of the aforementioned parameters, with ≥20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at ≥20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%–50% responded at the ≥30% level, while 10%–45% responded at the ≥50% level for 10–32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted. PMID:16859536

  15. A Phase II Study of Bevacizumab in Combination With Definitive Radiotherapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma: Preliminary Results of RTOG 0417

    SciTech Connect

    Schefter, Tracey E.; Winter, Kathryn; Kwon, Janice S.; Stuhr, Kelly; Balaraj, Khalid; Yaremko, Brian P.; Small, William; Gaffney, David K.

    2012-07-15

    Purpose: Concurrent cisplatin-based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. RTOG 0417 was a Phase II study exploring the safety and efficacy of the addition of bevacizumab to standard CRT. Methods and Materials: Eligible patients with bulky tumors (Stage IB-IIIB) were treated with once-weekly cisplatin (40 mg/m{sup 2}) chemotherapy and standard pelvic radiotherapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles. Treatment-related serious adverse event (SAE) and other adverse event (AE) rates within the first 90 days from treatment start were determined. Treatment-related SAEs were defined as any Grade {>=}4 vaginal bleeding or thrombotic event or Grade {>=}3 arterial event, gastrointestinal (GI) bleeding, or bowel/bladder perforation, or any Grade 5 treatment-related death. Treatment-related AEs included all SAEs and Grade 3 or 4 GI toxicity persisting for >2 weeks despite medical intervention, Grade 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia, Grade 3 or 4 other hematologic toxicity, and Grade 3 or 4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. All AEs were scored using the National Cancer Institute Common Terminology Criteria (CTCAE) v 3.0 (MedDRA version 6.0). Results: A total of 60 patients from 28 institutions were enrolled between 2006 and 2009, and of these, 49 patients were evaluable. The median follow-up was 12.4 months (range, 4.6-31.4 months).The median age was 45 years (range, 22-80 years). Most patients had FIGO Stage IIB (63%) and were of Zubrod performance status of 0 (67%). 80% of cases were squamous. There were no treatment-related SAEs. There were 15 (31%) protocol-specified treatment-related AEs within 90 days of treatment start; the most common were hematologic (12/15; 80%). 18 (37%) occurred during treatment or follow-up at any time. 37 of the 49 patients (76%) had cisplatin and bevacizumab

  16. Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study

    PubMed Central

    Bajetta, E; Di Bartolomeo, M; Buzzoni, R; Mariani, L; Zilembo, N; Ferrario, E; Lo Vullo, S; Aitini, E; Isa, L; Barone, C; Jacobelli, S; Recaldin, E; Pinotti, G; Iop, A

    2007-01-01

    This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, irinotecan 240 mg m−2 day 1; q21) or TEGAFOX (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, oxaliplatin 120 mg m−2 day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3–4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1–55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6–51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12–23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies. PMID:17245343

  17. Linac based SBRT for prostate cancer in 5 fractions with VMAT and flattening filter free beams: preliminary report of a phase II study

    PubMed Central

    2013-01-01

    Background To evaluate the feasibility and early side effects of a short course hypo-fractionated SBRT programme with Volumetric Modulated Arc Therapy (VMAT) and Flattening Filter Free (FFF) beams. Methods A prospective phase I-II study, started on February 2012. Inclusion criteria were: age ≤ 80 years, WHO-PS ≤ 2, PSA ≤ 20 ng/ml, histologically proven prostate adenocarcinoma, T1-T2 stage, no distant metastases, no previous surgery other than TURP, no malignant tumours in the previous 5 years, IPSS 0–7. The schedule was 35 Gy in 5 alternative days. SBRT was delivered with RapidArc VMAT, with 10MV FFF photons. Toxicity assessment was performed according to CTCAE v4.0 scale. EPIC questionnaires assessed Quality-of-Life. Neo-adjuvant/concomitant hormonal-therapy was prescribed according to risk classification. SpaceOAR™ gel was optionally implanted to increase the separation space between the prostate and the rectal wall. Results Median follow-up was 11 months (range: 5–16); 40 patients were recruited in the protocol and treated. According to NCCN criteria, 26/40 patients were low-risk and 14/40 were intermediate risk. Median age was 70 years (56–80), median initial PSA was 6.25 ng/ml (0.50-13.43 ng/ml). Median Gleason score was 6 (6–7). All patients completed the treatment as programmed (median 11.8 days (9–22). Acute Toxicities were as follow: Rectum G0: 30/40 cases (75%); G1: 6/40 (15%); G2: 4/40 (10%). Genito-urinary: G0: 16/40 (40%); G1: 8/40 (20%); G2: 16/34 (40%). In two G2 urinary retention cases, intermittent catheter was needed. No acute G3 or greater toxicity was found. Median treatment time was 126 sec (120–136). SpaceOAR™ was implanted in 8 patients. PSA reduction from the pre-treatment value of the marker was documented in all patients. Conclusions Early findings suggest that SBRT with RapidArc and FFF beams for prostate cancer in 5 fractions is feasible and tolerated in acute setting. Longer follow-up is needed

  18. Linac based SBRT for prostate cancer in 5 fractions with VMAT and flattening filter free beams: preliminary report of a phase II study.

    PubMed

    Alongi, Filippo; Cozzi, Luca; Arcangeli, Stefano; Iftode, Cristina; Comito, Tiziana; Villa, Elisa; Lobefalo, Francesca; Navarria, Pierina; Reggiori, Giacomo; Mancosu, Pietro; Clerici, Elena; Fogliata, Antonella; Tomatis, Stefano; Taverna, Gianluigi; Graziotti, Pierpaolo; Scorsetti, Marta

    2013-07-08

    To evaluate the feasibility and early side effects of a short course hypo-fractionated SBRT programme with Volumetric Modulated Arc Therapy (VMAT) and Flattening Filter Free (FFF) beams. A prospective phase I-II study, started on February 2012. Inclusion criteria were: age ≤ 80 years, WHO-PS ≤ 2, PSA ≤ 20 ng/ml, histologically proven prostate adenocarcinoma, T1-T2 stage, no distant metastases, no previous surgery other than TURP, no malignant tumours in the previous 5 years, IPSS 0-7. The schedule was 35 Gy in 5 alternative days. SBRT was delivered with RapidArc VMAT, with 10MV FFF photons. Toxicity assessment was performed according to CTCAE v4.0 scale. EPIC questionnaires assessed Quality-of-Life. Neo-adjuvant/concomitant hormonal-therapy was prescribed according to risk classification. SpaceOAR™ gel was optionally implanted to increase the separation space between the prostate and the rectal wall. Median follow-up was 11 months (range: 5-16); 40 patients were recruited in the protocol and treated. According to NCCN criteria, 26/40 patients were low-risk and 14/40 were intermediate risk. Median age was 70 years (56-80), median initial PSA was 6.25 ng/ml (0.50-13.43 ng/ml). Median Gleason score was 6 (6-7). All patients completed the treatment as programmed (median 11.8 days (9-22). Acute Toxicities were as follow: Rectum G0: 30/40 cases (75%); G1: 6/40 (15%); G2: 4/40 (10%). Genito-urinary: G0: 16/40 (40%); G1: 8/40 (20%); G2: 16/34 (40%). In two G2 urinary retention cases, intermittent catheter was needed. No acute G3 or greater toxicity was found. Median treatment time was 126 sec (120-136). SpaceOAR™ was implanted in 8 patients. PSA reduction from the pre-treatment value of the marker was documented in all patients. Early findings suggest that SBRT with RapidArc and FFF beams for prostate cancer in 5 fractions is feasible and tolerated in acute setting. Longer follow-up is needed for assessment of late toxicity and outcome.

  19. Randomized Phase II Study of 5-Fluorouracil Hepatic Arterial Infusion with or without Antineoplastons as an Adjuvant Therapy after Hepatectomy for Liver Metastases from Colorectal Cancer

    PubMed Central

    Ogata, Yutaka; Matono, Keiko; Tsuda, Hideaki; Ushijima, Masataka; Uchida, Shinji; Akagi, Yoshito; Shirouzu, Kazuo

    2015-01-01

    Background Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. Methods Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. Findings Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the

  20. Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients.

    PubMed

    Castagneto, B; Zai, S; Mutti, L; Lazzaro, A; Ridolfi, R; Piccolini, E; Ardizzoni, A; Fumagalli, L; Valsuani, G; Botta, M

    2001-01-01

    Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and

  1. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study

    PubMed Central

    Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Matsusaka, Satoshi; Shinozaki, Eiji; Ozaka, Masato; Ogura, Mariko; Yamaguchi, Toshiharu

    2015-01-01

    Background The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths. Conclusion Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior

  2. Intermediate-dose cytarabine treatment delivered at moderate infusion rates for de novo acute myeloid leukemia-results of a phase I-II study.

    PubMed

    Mantovani, Luisa; Hasenclever, Dirk; Krahl, Rainer; Pönisch, Wolfram; Herold, Michael; Pasold, Rita; Fiedler, Friedrich; Dölken, Gottfried; Kämpfe, Dietrich; Schmoll, Hans Joachim; Súbert, Rita; Kubel, Martin; Niederwieser, Dietger; Helbig, Werner

    2002-02-01

    Published randomized trials on different cytarabine doses for the treatment of acute myeloid leukemia (AML) provide evidence of a dose-response effect. However, high-dose cytarabine (HIDAC) regimens correlate with increased morbidity and toxicity related mortality. Typical HIDAC regimens deliver 6 g/m2/d in infusion rates of 500-3000 mg/m2/h. However, pharmacokinetic measurements indicate that intracellular Ara-CTP formation is saturated at lower infusion rates than used in HIDAC schedules, probably causing cytarabine accumulation in the plasma and increased toxicity. It was our objective to investigate in a prospective non-randomized phase I-II study feasibility and efficacy of intermediate doses of cytarabine delivered at the presumptive saturating moderate infusion rate (mir-IDAC), as induction therapy in order to optimize intensified treatment for acute myeloid leukemia. Forty previously untreated patients younger than 60 years of age with de novo AML received intermediate doses of cytarabine (2-4 g/m2/d) at moderate infusion rates (250-667 mg/m2/h) over 6 or 8 h. Cytarabine was applied on alternate days (day 1, 3, 5, 7) in combination with an anthracycline as induction and consolidation therapy. Thirty-two of the 40 patients (80%, 95%CI:64-91%) achieved CR after induction treatment. Treatment-related mortality during induction chemotherapy was 2.5%. No cerebellar toxicity was observed. After two to four mir-IDAC courses stem cell harvesting was successful in 71% of the patients eligible for high-dose chemotherapy. After three years 56% (95%CI:40-72%) of all patients are alive and 59% (95%CI:42-76%) of the patients who entered CR are free of leukemia. In conclusion, favorable long-term outcomes and moderate acute toxicities were observed in patients with de novo AML treated with IDAC schedules delivered at moderate infusion rates (mir-IDAC) starting as induction treatment. The data suggest that a randomized trial should now be undertaken to examine whether mir

  3. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib

    PubMed Central

    Ganjoo, K. N.; Villalobos, V. M.; Kamaya, A.; Fisher, G. A.; Butrynski, J. E.; Morgan, J. A.; Wagner, A. J.; D'Adamo, D.; McMillan, A.; Demetri, G. D.; George, S.

    2014-01-01

    Background Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (−1, −2, and −3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Methods Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. Results Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2–7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5–37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6–5.2), and the median OS was 10.7 months (95% CI 3.9–NR). Conclusions Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in

  4. "Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

    PubMed Central

    2010-01-01

    Background This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC). Methods Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks. Results Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%. Conclusion Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered. Trial registration Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34 PMID:20958992

  5. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

    PubMed

    Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

    2015-10-01

    Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted

  6. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.

    PubMed

    Mitsuhashi, A; Sato, Y; Kiyokawa, T; Koshizaka, M; Hanaoka, H; Shozu, M

    2016-02-01

    Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. UMIN 000002210. © 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.

  7. Phase II Study of a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide-Based Vaccine Administered to Stage IIIB and IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab Monotherapy

    DTIC Science & Technology

    2008-05-01

    Intracellular Domain (ICD) Peptide - Based Vaccine Administered to Stage IIIB and IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab...To) 27 APR 2007 - 26 APR 2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Phase II Study of a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide ...intracellular domain (ICD) peptide -based vaccine while receiving maintenance trastuzumab. Patients enrolled will be HER2 overexpressing stage IIIB and IV

  8. A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia.

    PubMed

    Diaz-Padilla, Ivan; Wilson, Michelle K; Clarke, Blaise A; Hirte, Hal W; Welch, Stephen A; Mackay, Helen J; Biagi, Jim J; Reedijk, Michael; Weberpals, Johanne I; Fleming, Gini F; Wang, Lisa; Liu, Geoffrey; Zhou, Chen; Blattler, Chantale; Ivy, S Percy; Oza, Amit M

    2015-05-01

    A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer. Women with progressive platinum-resistant ovarian cancer treated with ≤2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week in a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumor tissue and serum. Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response, with a median duration of 3.1 months. The median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 1.3 months, p=0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels. RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression. Copyright © 2015. Published by Elsevier Inc.

  9. Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

    SciTech Connect

    Herchenhorn, Daniel; Dias, Fernando L.; Viegas, Celia M.P.; Federico, Miriam H.; Araujo, Carlos Manoel M.; Small, Isabelle; Bezerra, Marcos; Fontao, Karina M.D.; Knust, Renata E.; Ferreira, Carlos G.; Martins, Renato G.

    2010-11-01

    Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m{sup 2} of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.

  10. Two-Phase Calorimetry. II. Studies on the Thermodynamics of Cesium and Strontium Extraction by Mixtures of H+CCD- and PEG-400 in FS-13

    SciTech Connect

    Zalupski, Peter R.; Herbst, R. S.; Delmau, Laetitia Helene; Martin, L. R.; Peterman, D. R.; Nash, Ken L

    2010-01-01

    Thermochemical characterization of the partitioning of cesium and strontium from nitric acid solutions into mixtures of the acid form of chlorinated cobalt dicarbollide (H+CCD-) and polyethylene glycol (PEG-400) in FS-13 diluent has been completed using isothermal titration microcalorimetry and radiotracer distribution methods. The phase transfer reaction for Cs+ is a straightforward (H+ for Cs+) cation exchange reaction. In contrast, the extraction of Sr2+ does not proceed in the absence of the co-solvent molecule PEG-400. This molecule is believed to facilitate the dehydration of the Sr2+ aquo cation to overcome its resistance to partitioning. The phase transfer reactions for both Cs+ and Sr2+ are enthalpy driven (exothermic), but partially compensated by an unfavorable entropy. The results of the calorimetry studies suggest that the PEG-400 functions as a stoichiometric phase transfer reagent rather than acting simply as a phase transfer catalyst or phase modifier. The calorimetry results also demonstrate that the extraction of Sr2+ is complex, including evidence for both the partitioning of Sr(NO3)+ and endothermic ion pairing interactions in the organic phase that contribute to the net enthalpic effect. The thermodynamics of the liquid-liquid distribution equilibria are discussed mainly considering the basic features of the ion solvation thermochemistry.

  11. Concurrent Chemoradiotherapy Followed by Consolidation Chemotherapy With Bi-Weekly Docetaxel and Carboplatin for Stage III Unresectable, Non-Small-Cell Lung Cancer: Clinical Application of a Protocol Used in a Previous Phase II Study

    SciTech Connect

    Saitoh, Jun-Ichi; Saito, Yoshihiro; Kazumoto, Tomoko; Kudo, Shigehiro; Yoshida, Daisaku; Ichikawa, Akihiro; Sakai, Hiroshi; Kurimoto, Futoshi; Kato, Shingo; Shibuya, Kei

    2012-04-01

    Purpose: To assess the clinical applicability of a protocol evaluated in a previously reported phase II study of concurrent chemoradiotherapy followed by consolidation chemotherapy with bi-weekly docetaxel and carboplatin in patients with stage III, unresectable, non-small-cell lung cancer (NSCLC). Methods and Materials: Between January 2000 and March 2006, 116 previously untreated patients with histologically proven, stage III NSCLC were treated with concurrent chemoradiotherapy. Radiation therapy was administered in 2-Gy daily fractions to a total dose of 60 Gy in combination with docetaxel, 30 mg/m{sup 2}, and carboplatin at an area under the curve value of 3 every 2 weeks during and after radiation therapy. Results: The median survival time for the entire group was 25.5 months. The actuarial 2-year and 5-year overall survival rates were 53% and 31%, respectively. The 3-year cause-specific survival rate was 60% in patients with stage IIIA disease, whereas it was 35% in patients with stage IIIB disease (p = 0.007). The actuarial 2-year and 5-year local control rates were 62% and 55%, respectively. Acute hematologic toxicities of Grade {>=}3 severity were observed in 20.7% of patients, while radiation pneumonitis and esophagitis of Grade {>=}3 severity were observed in 2.6% and 1.7% of patients, respectively. Conclusions: The feasibility of the protocol used in the previous phase II study was reconfirmed in this series, and excellent treatment results were achieved.

  12. Efficacy and safety of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) as reported in phase I and II studies: a systematic review.

    PubMed

    Chow, Ronald; Chiu, Leonard; Navari, Rudolph; Passik, Steven; Chiu, Nicholas; Popovic, Marko; Lam, Henry; Pasetka, Mark; Chow, Edward; DeAngelis, Carlo

    2016-02-01

    Olanzapine is an atypical antipsychotic drug that inhibits serotonergic, dopaminergic, alpha-1 adrenergic, histaminic, and muscarinic receptors. Several phase I and II trials have been published documenting the use of olanzapine in controlling chemotherapy-induced nausea and vomiting (CINV). This review aims to summarize all phase I and II trials that reported on olanzapine for the prophylaxis of CINV. A literature search was conducted in Ovid MEDLINE from 1946 to July week 1 2015, Embase Classic and Embase from 1947 to 2015 week 28, and the Cochrane Central Register of Controlled Trials up until June 2015. Phase I and II trials reporting on olanzapine for the prophylaxis for CINV were included if they reported on at least one of four primary endpoints: complete response (CR), complete control (CC), no nausea, and no emesis. Other endpoints of interest included the safety of olanzapine as measured by the M.D. Anderson Symptom Inventory. Across the seven included studies, there were a total of 201 patients. The CR across four studies was 97.2, 83.1, and 82.8 % for the acute, delayed, and overall phases, respectively. The CC for acute, delayed, and overall phases was 92.5, 87.5, and 82.5 %, respectively. The overall no nausea rate was 92.7, 71.8, and 70.6 % for the acute, delayed, and overall phases, respectively. The overall no emesis rates for the acute, delayed, and overall phases were 100, 94.5, and 90.4 %, respectively. Fatigue, drowsiness, and disturbed sleep were common side effects. Olanzapine is efficacious and safe when used as a prophylaxis for CINV.

  13. The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer

    PubMed Central

    2011-01-01

    Background The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. Methods/design This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). Discussion The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic

  14. The PACOVAR-trial: a phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer.

    PubMed

    Eichbaum, Michael; Mayer, Christine; Eickhoff, Regina; Bischofs, Esther; Gebauer, Gerhard; Fehm, Tanja; Lenz, Florian; Fricke, Hans-Christian; Solomayer, Erich; Fersis, Nikos; Schmidt, Marcus; Wallwiener, Markus; Schneeweiss, Andreas; Sohn, Christof

    2011-10-20

    The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in

  15. A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF).

    PubMed

    Mascarenhas, John; Sandy, Lonette; Lu, Min; Yoon, James; Petersen, Bruce; Zhang, David; Ye, Fei; Newsom, Carrie; Najfeld, Vesna; Hochman, Tsivia; Goldberg, Judith D; Hoffman, Ronald

    2017-02-01

    Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

  16. A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

    PubMed

    Obara, W; Eto, M; Mimata, H; Kohri, K; Mitsuhata, N; Miura, I; Shuin, T; Miki, T; Koie, T; Fujimoto, H; Minami, K; Enomoto, Y; Nasu, T; Yoshida, T; Fuse, H; Hara, I; Kawaguchi, K; Arimura, A; Fujioka, T

    2017-04-01

    S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. JapicCTI-090980.

  17. Randomized phase II study of gemcitabine plus S-1 combination therapy vs. S-1 in advanced biliary tract cancer: Japan Clinical Oncology Group Study (JCOG0805).

    PubMed

    Takashima, Atsuo; Morizane, Chigusa; Ishii, Hiroshi; Nakamura, Kenichi; Fukuda, Haruhiko; Okusaka, Takuji; Furuse, Junji

    2010-12-01

    A randomized Phase II selection design trial comparing gemcitabine plus S-1 combination therapy with S-1 monotherapy for chemo-naïve unresectable or recurrent biliary tract cancer patients was started in Japan. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen to be compared with the current standard regimen, gemcitabine plus cisplatin, in a subsequent Phase III trial. Patients with unresectable or recurrent biliary tract cancer are randomized to either gemcitabine plus S-1 combination therapy arm or S-1 monotherapy arm. A total of 100 patients will be accrued for this study from 18 institutions over 1 year. The primary endpoint is the proportion of 1-year overall survival, and the secondary endpoints are progression-free survival, response rate and adverse events.

  18. A Phase I/II Study of Docetaxel, Oxaliplatin, and Fluorouracil (D-FOX) Chemotherapy in Patients With Untreated Locally Unresectable or Metastatic Adenocarcinoma of the Stomach and Gastroesophageal Junction.

    PubMed

    Blum Murphy, Mariela A; Qiao, Wei; Mewada, Nishith; Wadhwa, Roopma; Elimova, Elena; Takashi, Taketa; Ho, Linus; Phan, Alexandria; Baker, Jackie; Ajani, Jaffer

    2016-02-22

    A randomized phase III study established docetaxel, cisplatin, and 5-fluorouracil (DCF) as one of the standard treatments for patients with untreated advanced gastric cancer (AGC). However, DCF use is limited due toxicity. With the purpose to evaluate a less toxic regimen, we conducted a single arm, phase I/II trial of modified DCF (oxaliplatin, 5-fluorouracil, and docetaxel [D-FOX]) for untreated AGC patients. The primary objective of the phase I study was to determine the maximum tolerated dose of docetaxel and for the phase II study was to assess the progression-free survival (PFS) at 6 months and overall survival (OS). We enrolled a total of 98 patients with AGC. Docetaxel and oxaliplatin were administered intravenously on day 1 and 5-fluorouracil was infused starting on day 1 over 48 hours. Cycles were repeated every 2 weeks and patients were monitored for toxicities. Kaplan-Meir curve was used to estimate unadjusted OS and PFS. The maximum tolerated dose of docetaxel was 50 mg/m. In total, 24 (45%) patients experienced grade 2 adverse events, 22 (41%) experienced grade 3, and 1 (1.9%) experienced grade 4 toxicity. The median PFS in the phase II portion of the study was approximately 6.5 (95% confidence interval, 5.5-9.5) months and the median OS was 11.1 (95% confidence interval, 9.4-18.8) months. D-FOX administered every 2 weeks is a well-tolerated and active regimen in untreated AGC patients.

  19. TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.

    PubMed

    Mitri, Zahi; Nanda, Rita; Blackwell, Kimberly; Costelloe, Colleen M; Hood, Ilona; Wei, Caimiao; Brewster, Abenaa M; Ibrahim, Nuhad K; Koenig, Kimberly B; Hortobagyi, Gabriel N; Van Poznak, Catherine; Rimawi, Mothaffar F; Moulder-Thompson, Stacy

    2016-12-01

    Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases. A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured. A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84-5.72] in the general cohort, 3.65 months (95% CI, 1.97-7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30-NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels. Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR. ©2016 American Association for Cancer Research.

  20. A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study).

    PubMed

    Shoji, Tadahiro; Takatori, Eriko; Omi, Hideo; Kagabu, Masahiro; Honda, Tatsuya; Futagami, Masayuki; Yokoyama, Yoshihito; Kaiho, Michiko; Tokunaga, Hideki; Otsuki, Takeo; Takano, Tadao; Yaegashi, Nobuo; Kojimahara, Takanobu; Ohta, Tsuyoshi; Nagase, Satoru; Soeda, Shu; Watanebe, Takafumi; Nishiyama, Hiroshi; Sugiyama, Toru

    2017-08-01

    We report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial. PLD was administered intravenously at a dose of 30 mg/m(2) on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m(2) on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS). The response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months. The treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.

  1. Phase I/II study of docetaxel combined with resminostat, an oral hydroxamic acid HDAC inhibitor, for advanced non-small cell lung cancer in patients previously treated with platinum-based chemotherapy.

    PubMed

    Tambo, Yuichi; Hosomi, Yukio; Sakai, Hiroshi; Nogami, Naoyuki; Atagi, Shinji; Sasaki, Yasutsuna; Kato, Terufumi; Takahashi, Toshiaki; Seto, Takashi; Maemondo, Makoto; Nokihara, Hiroshi; Koyama, Ryo; Nakagawa, Kazuhiko; Kawaguchi, Tomoya; Okamura, Yuta; Nakamura, Osamu; Nishio, Makoto; Tamura, Tomohide

    2017-04-01

    Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m(2). In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m(2)) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1-5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m(2) of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8-5.7) months with docetaxel group and 4.1 (1.5-5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.

  2. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions

    PubMed Central

    Tyndall, A; Saccardi, R

    2005-01-01

    Around 700 patients have received an autologous haematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The majority of these have been within the context of phase I/II clinical trials and following international guidelines proposed 7 years ago. In general, a positive benefit/risk ratio has led to phase III prospective randomized controlled trials in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis (RA) in Europe. In the US, similar trials are being planned for SSc, MS and systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has fallen in all disease subgroups since the inception due to more appropriate patient selection, and so far a clear advantage of the more intense myeloablative regimens in terms of remission induction and relapse rate has not emerged. Although each AD has a different profile, over a third of patients have sustained a durable remission, often with no further need for immunosuppressive drugs. In those who relapsed, many responded to agents which pre transplant had been ineffective. The study of immune reconstitution and gene expression pre and post HSCT is being undertaken to further understand the mechanism of autoimmunity. PMID:15958063

  3. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study.

    PubMed

    Schey, Stephen A; Morgan, Gareth J; Ramasamy, Karthik; Hazel, Beth; Ladon, Dariusz; Corderoy, Sophie; Jenner, Matthew; Phekoo, Karen; Boyd, Kevin; Davies, Faith E

    2010-08-01

    We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.

  4. Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study.

    PubMed

    Eve, Heather E; Linch, David; Qian, Wendi; Ross, Moira; Seymour, John F; Smith, Paul; Stevens, Lindsey; Rule, Simon A J

    2009-02-01

    The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

  5. Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

    PubMed Central

    Rudin, Charles M.; Hann, Christine L.; Garon, Edward B.; Ribeiro de Oliveira, Moacyr; Bonomi, Philip D.; Camidge, D. Ross; Chu, Quincy; Giaccone, Giuseppe; Khaira, Divis; Ramalingam, Suresh S.; Ranson, Malcolm R.; Dive, Caroline; McKeegan, Evelyn M.; Chyla, Brenda J.; Dowell, Barry L.; Chakravartty, Arunava; Nolan, Cathy E.; Rudersdorf, Niki; Busman, Todd A.; Mabry, Mack H.; Krivoshik, Andrew P.; Humerickhouse, Rod A.; Shapiro, Geoffrey I.; Gandhi, Leena

    2013-01-01

    Purpose Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Experimental Design Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Conclusion Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. PMID:22496272

  6. Misonidazole and unconventional radiation in advanced squamous cell carcinoma of the esophagus: a phase II study of the Radiation Therapy Oncology Group

    SciTech Connect

    Ydrach, A.A.; Marcial, V.A.; Parsons, J.; Concannon, J.; Asbell, S.O.; George, F.

    1982-03-01

    This is a report on Radiation Therapy Oncology Group (RTOG) Protocol78-32, a Phase I/II prospective study aimed at determining tolerance, tumor response, and survival of squamous cell carcinoma of the esophagus treated with unorthodox fractionation radiotherapy combined with misonidazole. Misonidazole was administered by mouth 4 to 6 hr prior to radiation, at a dose of 1.0 to 1.25 Gm/.m/sup 2/; blood levels were measured at about 4 hr after intake of the drug and reported in micrograms/ml. Radiotherapy was administered at 4 to 6 hr post-misonidazole dose and given with 400 rad fractions, alternating 2 or 3 times/week, up to 4,800 rad. A total of 43 patients were entered; 26 are evaluated for survival at 1 year post accession. Thirty patients (88%) received the planned radiation course. Twenty-eight patients (78%) received the planned misonidazole dosage. Tumor response, evaluated in 18 patients, showed a complete regression (C.R.) in only 2 patients (11%); and partial response (P.R.) in 6 patients (33%). Eight patients (44%) showed no tumor response to planned therapy. Toxicity was acceptable and in 38 evaluated patients only 4 reported (11%) nausea and vomiting, 7 reported mild paresthesias (18%). The median survival was only five months. In 26 patients evaluated for 1 year survival determination, only 1 survived (3.8%) this period. In view of the poor tumor response and low survival observed, we do not recommend that this particular fractionation regimen with misonidazole be used in a Phase III randomized trial in squamous cell carcinoma of the esophagus.

  7. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study.

    PubMed

    Schwartzbach, Caryl J; Grove, Richard A; Brown, Robert; Tompson, Debra; Then Bergh, Florian; Arnold, Douglas L

    2017-02-01

    Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

  8. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer.

    PubMed

    Hochster, H S; Uboha, N; Messersmith, W; Gold, P J; ONeil, B H; Cohen, D; Denlinger, C; Cohen, S; Leichman, C G; Leichman, L; Lenz, H-J

    2015-01-01

    More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.

  9. 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

    2017-03-15

    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.

  10. A Phase II Study of a Paclitaxel-Based Chemoradiation Regimen With Selective Surgical Salvage for Resectable Locoregionally Advanced Esophageal Cancer: Initial Reporting of RTOG 0246

    SciTech Connect

    Swisher, Stephen G.; Winter, Kathryn A.; Komaki, Ritsuko U.; Ajani, Jaffer A.; Wu, Tsung T.; Hofstetter, Wayne L.; Konski, Andre A.; Willett, Christopher G.

    2012-04-01

    Purpose: The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. Methods and Materials: The study was designed to detect an improvement in 1-year survival from 60% to 77.5% ({alpha} = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg{sup 2}/day), cisplatin (15 mg/mg{sup 2}/day), and paclitaxel (200 mg/mg{sup 2}/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg{sup 2}/day) with cisplatin (15 mg/mg{sup 2}/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. Results: Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was {>=}T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. Conclusions: In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%-82%).

  11. 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

    SciTech Connect

    Glynne-Jones, Rob Meadows, Helen; Wan, Susan; Gollins, Simon; Leslie, Martin; Levine, Ed; McDonald, Alec C.; Myint, Sun; Samuel, Les; Sebag-Montefiore, David

    2008-09-01

    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 (825 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.

  12. A PHASE II STUDY OF A PACLITAXEL-BASED CHEMORADIATION REGIMEN WITH SELECTIVE SURGICAL SALVAGE FOR RESECTABLE LOCOREGIONALLY ADVANCED ESOPHAGEAL CANCER: INITIAL REPORTING OF RTOG 0246

    PubMed Central

    Swisher, Stephen G.; Winter, Kathryn A.; Komaki, Ritsuko U.; Ajani, Jaffer A.; Wu, Tsung T.; Hofstetter, Wayne L.; Konski, Andre A.; Willett, Christopher G.

    2013-01-01

    Purpose The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. Methods and Materials The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (α= 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg2/day), cisplatin (15 mg/mg2/day), and paclitaxel (200 mg/mg2/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg2/day) with cisplatin (15 mg/mg2/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. Results Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was ≥T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. Conclusions In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%–82%). PMID:21507583

  13. Phase II study of a novel taxane (Cabazitaxel-XRP 6258) in previously treated advanced non-small cell lung cancer (NSCLC) patients.

    PubMed

    Madan, Ankit; Jones, Benjamin S; Bordoni, Rodolfo; Saleh, Mansoor N; Jerome, Mary S; Miley, Deborah K; Jackson, Bradford E; Robert, Francisco

    2016-09-01

    Given the success of cabazitaxel in patients with prostate cancer who progressed after receiving prior chemotherapy, its preclinical efficacy in various cell lines and possible ability to cross blood-brain barrier, cabazitaxel was hypothesized to increase objective response rate (ORR) in second-line setting in non-small cell lung cancer (NSCLC). This was a phase II 2-stage trial in 28 patients using two different treatment schedules (A: 20 mg/m(2) every 3 weeks intravenously and B: 8.4 mg/m(2) intravenously weekly) to determine the ORR of cabazitaxel with secondary end points including progression-free survival (PFS), safety, and overall survival (OS). There was one objective response in schedule B. PFS and OS of schedule A was 3 and 6 months, respectively. PFS and OS of schedule B was 3 and 13 months, respectively. The stable disease rate was higher in schedule A (SD = 69.23 %; 95 % CL 38.57, 90.90) as compared to schedule B (SD = 38.46 %; 95 % CL 13.86, 68.42), but this difference was not statistically significant (P value = 0.1156). There were two grade 5 toxicities from sepsis. Hematuria of any grade developed in greater percentage of patients (35%) as compared to previous cabazitaxel phase 3 trial and led to change in our protocol. Response to cabazitaxel in NSCLC was not as robust as seen in prostate cancer and not superior to currently used agents such as docetaxel, pemetrexed, and erlotinib. In absence of significant objective responses, the second stage of the study was not undertaken.

  14. Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116).

    PubMed

    Oza, A M; Elit, L; Swenerton, K; Faught, W; Ghatage, P; Carey, M; McIntosh, L; Dorr, A; Holmlund, J T; Eisenhauer, E

    2003-04-01

    ISIS 5132 is a 20-base phosphorothioate DNA oligonucleotide against human c-raf kinase, a downstream effector of ras oncogene function. C-raf kinase is a molecule in the MAP kinase signaling cascade which is essential for cellular proliferation, the overexpression of which leads to malignant expression. Activity of this compound was documented in a woman with ovarian cancer in a Phase I study. We evaluated ISIS 5132 at a dose of 4 mg/kg/day by continuous venous infusion, administered for 21 days q 4 weeks in 22 patients with recurrent ovarian cancer in a standard two-stage Phase II design. Three patients were ineligible; 19 patients are evaluable for toxicity and 16 for response. All patients had previously received systemic therapy for ovarian cancer (6 had one and 13 had two prior regimens). Patients were treated with a median of two cycles and 79% of the patients received >90% planned dose intensity. ISIS 5132 was well tolerated with no episodes of Grade 3 or 4 hematologic or biochemical (creatinine, AST, bilirubin) toxicity. There were six episodes of grade 3 nonhematologic toxicity in 4 patients thought to be treatment related (lethargy 2; anorexia 1; abdominal pain 2; shortness of breath 1). No responses were seen in the 16 patients who are evaluable for response; 4 had stable disease for a median of 3.8 months and 12 patients had documented progressive disease. ISIS 5132 at 4 mg/kg/day as a single agent did not show activity in recurrent ovarian cancer.

  15. Long-term outcomes for newly-diagnosed multiple myeloma patients treated with pegylated liposomal doxorubicin and bortezomib: final results of CALGB (Alliance) 10301, a multicentre phase II study

    PubMed Central

    Voorhees, Peter M.; Orlowski, Robert Z.; Mulkey, Flora; Watson, Peter; Geyer, Susan; Sanford, Ben L.; Bennett, Elizabeth; Chanan-Khan, Asher A.; Bloomfield, Clara D.; Larson, Richard A.

    2017-01-01

    SUMMARY Long-term outcomes and updated clinical efficacy and safety data were evaluated for newly-diagnosed multiple myeloma patients treated on a phase II study of bortezomib and pegylated liposomal doxorubicin (PegLD). Out of 61 patients, the overall response rate was 57% and the near-complete/complete response rate was 7%. Patients aged ≥65 years old had a higher incidence of treatment-related ≥Grade 3 non-haematological toxicity (80% vs 51%, P = 0.020). Median overall survival was 5.6 years and negatively impacted by the presence of International Staging System stage III disease, underscoring the need for novel treatment strategies for this group of patients. PMID:26202857

  16. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

    PubMed Central

    Wo, Jennifer Y.; Yeap, Beow Y.; Ben-Josef, Edgar; McDonnell, Erin I.; Blaszkowsky, Lawrence S.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Goyal, Lipika; Murphy, Janet E.; Javle, Milind M.; Wolfgang, John A.; Drapek, Lorraine C.; Arellano, Ronald S.; Mamon, Harvey J.; Mullen, John T.; Yoon, Sam S.; Tanabe, Kenneth K.; Ferrone, Cristina R.; Ryan, David P.; DeLaney, Thomas F.; Crane, Christopher H.; Zhu, Andrew X.

    2016-01-01

    Purpose To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Materials and Methods In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Results Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. Conclusion High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC. PMID:26668346

  17. Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer

    PubMed Central

    2011-01-01

    Background The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer. Methods/Design This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrolment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrolment. Discussion This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also

  18. A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).

    PubMed

    Forette, F; Anand, R; Gharabawi, G

    1999-07-01

    Rivastigmine is a carbamate acetylcholinesterase (AChE) inhibitor with central selectivity. Early studies showed that daily doses up to 6 mg/day have some efficacy in patients with dementia of the Alzheimer type (DAT). The present study was designed to assess the safety, tolerability and efficacy of rivastigmine at doses up to 12 mg/day. A total of 114 patients with mild-moderate DAT were randomly assigned to either rivastigmine (b.i.d. (twice daily) or t.i.d. (three times daily)) or placebo in a double-blind fashion titrated to their maximum tolerated dose over 10 weeks followed by an eight-week maintenance phase. The mean maximum tolerated dose was approximately 10 mg/day (b.i.d. or t.i.d.). Gastrointestinal complaints, the majority of which were mild to moderate, were the most frequently reported adverse events. No clinically relevant changes in vital signs, haematology or organ function were detected. Significantly more patients taking rivastigmine b.i.d. were considered improved according to the Clinicians' Interview-Based Impression of Change-Plus (CIBIC-Plus) vs. placebo (57% vs. 16%, respectively; P = 0.027). The Nurses' Observation Scale for Geriatric Patients (NOSGER) (memory component) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) also improved in the rivastigmine b.i.d. group vs. placebo (mean change from baseline on NOSGER = -0.7 vs. +1.3, respectively; P = 0.037: mean change from baseline on ADAS-cog = -2.7 vs. +0.2, respectively; P = 0.054). Despite the relatively small size and limited duration of the study, the finding that rivastigmine induced changes in the same (positive) direction in all three dimensions measured suggests that rivastigmine at doses of up to 12 mg/day has useful efficacy in patients with mild-moderate DAT. Reports from larger phase III studies confirm this finding. The results of this study also suggest that b.i.d. is the more efficacious regimen and has comparable tolerability to the t.i.d. regimen

  19. Phase I/II Study of Inhaled Doxorubicin Combined with Platinum-Based Therapy for Advanced Non–Small Cell Lung Cancer

    PubMed Central

    Otterson, Gregory A.; Villalona-Calero, Miguel A.; Hicks, William; Pan, Xueliang; Ellerton, John A.; Gettinger, Scott N.; Murren, John R.

    2014-01-01

    Purpose We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non–small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. Experimental Design Patients who had chemo-naïve advanced non–small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity ≥50%, resting/exercise O2 saturation ≥90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m2) and level 2 (7.5 mg/m2). Escalation was permitted if ≤2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O2 saturation of <85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of ≥20% from baseline or ≤30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m2. Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. Results Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m2, however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m2. Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. Conclusion Although

  20. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck†

    PubMed Central

    Seiwert, T. Y.; Fayette, J.; Cupissol, D.; del Campo, J. M.; Clement, P. M.; Hitt, R.; Degardin, M.; Zhang, W.; Blackman, A.; Ehrnrooth, E.; Cohen, E. E. W.

    2014-01-01

    Background Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. Patients and methods An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). Results A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. Conclusion Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients

  1. Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology.

    PubMed

    Krishnan, Amrita Y; Palmer, Joycelynne; Nademanee, Auayporn P; Chen, Robert; Popplewell, Leslie L; Tsai, Ni-Chun; Sanchez, James F; Simpson, Jennifer; Spielberger, Ricardo; Yamauchi, Dave; Forman, Stephen J

    2017-03-04

    Standard-dose (90)yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20(+) non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.

  2. A phase II study of sirolimus, tacrolimus, and rabbit anti-thymocyte globulin as graft-versus-host prophylaxis after unrelated-donor peripheral blood stem cell transplant

    PubMed Central

    Khaled, Samer K.; Palmer, Joycelynne; StillerMS, Tracey; Senitzer, David; Maegawa, Rodrigo; Rodriguez, Roberto; Parker, Pablo M.; Nademanee, Auayporn; Cai, Ji-Lian; Snyder, David S.; Karanes, Chatchada; Osorio, Edna; Thomas, Sandra H.; Forman, Stephen J.; Nakamura, Ryotaro

    2012-01-01

    We report on a prospective phase II trial of 32 patients who underwent unrelated donor hematopoietic cell transplantation, with a tacrolimus, sirolimus and rabbit anti-thymoctye globulin GVHD prophylactic regimen. The primary study endpoint was incidence of grades II-IV acute GVHD, with 80% power to detect a 30% decrease compared to institutional historical controls. Median age at transplant was 60 (19-71). Twenty-three patients (72%) received reduced-intensity conditioning, while the remainder received full-intensity regimens. Median follow up for surviving patients was 35 months (range: 21 - 49). The cumulative incidence of acute GVHD was 37.3% and the 2-year cumulative incidence of cGVHD was 63%. We observed TMA in seven patients (21.8%), one of whom also developed sinusoidal obstructive syndrome (SOS). Four patients of 32 (12.5%) failed to engraft, and three of these four died. As a result, enrollment to this trial was closed before the targeted accrual of 60 patients. Two-year overall survival was 65.5% and event-free survival was 61.3%. Two-year cumulative incidence of relapse was 12.5% and non-relapse mortality (NRM) was 15.6%. NRM and aGVHD rates were lower than historical rates; however, the unexpectedly high incidence of graft failure requires caution in the design of future studies with this regimen. PMID:23000644

  3. Cyclosporine A, alpha-lnterferon and interleukin-2 following chemotherapy with BCNU, DTIC, cisplatin, and tamoxifen: a phase II study in advanced melanoma.

    PubMed

    Feun, Lynn; Marini, Angela; Moffat, Frederick; Savaraj, Niramol; Hurley, Judith; Mazumder, Amitabha

    2005-01-01

    Preclinical data suggest that one method of inducing autoimmunity to tumor is the administration and subsequent withdrawal of cyclosporine A following chemotherapy and that this effect may be enhanced with interferon and interleukin-2. Consequently, we performed a phase II trial in patients with advanced melanoma to explore this approach. Thirty-three patients were treated with BCNU (150 mg/m2 iv every 8 weeks), cisplatin (25 mg/m2 iv days 1-3) every 4 weeks, DTIC (220 mg/m2 iv days 1-3 every 4 weeks) along with tamoxifen (10 mg po BID days 1-4). Cyclosporine A at 3 mg/kg/day in two divided doses was given on days 4-21, alpha-interferon 1 million units/m2 subcutaneously every other day on days 4-21 and interleukin-2 1 million units/m2 BID subcutaneously days 21-28 were also given. Of the 33 patients, 3 patients (9%) had complete response and 8 patients (24%) had a partial response for a total response rate of 33% (95% confidence interval 18-52%). Median duration of response was 17 months (range 3+ to 24+ months). Six patients continue to show no signs of tumor progression for 3+, 5+, 10+, 24+, 60+, and 72+ months. Toxicity was generally well tolerated and included myelosuppression and fatigue. This regimen is feasible and generally tolerable and has produced an antitumor response rate comparable with inpatient biochemotherapy regimens.

  4. Phase II Study of Biweekly Plitidepsin as Second-Line Therapy for Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium

    PubMed Central

    Dumez, Herlinde; Gallardo, Enrique; Culine, Stephane; Galceran, Joan Carles; Schöffski, Patrick; Droz, Jean P.; Extremera, Sonia; Szyldergemajn, Sergio; Fléchon, Aude

    2009-01-01

    The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m2) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting ≥ 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting. PMID:19841725

  5. Phase II study of biweekly plitidepsin as second-line therapy for advanced or metastatic transitional cell carcinoma of the urothelium.

    PubMed

    Dumez, Herlinde; Gallardo, Enrique; Culine, Stephane; Galceran, Joan Carles; Schöffski, Patrick; Droz, Jean P; Extremera, Sonia; Szyldergemajn, Sergio; Fléchon, Aude

    2009-09-16

    The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m(2)) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting > or = 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting.

  6. Emtonjeni-A Structural Intervention to Integrate Sexual and Reproductive Health into Public Sector HIV Care in Cape Town, South Africa: Results of a Phase II Study.

    PubMed

    Mantell, J E; Cooper, D; Exner, T M; Moodley, J; Hoffman, S; Myer, L; Leu, C-S; Bai, D; Kelvin, E A; Jennings, K; Stein, Z A; Constant, D; Zweigenthal, V; Cishe, N; Nywagi, N

    2017-03-01

    Integration of sexual and reproductive health within HIV care services is a promising strategy for increasing access to family planning and STI services and reducing unwanted pregnancies, perinatal HIV transmission and maternal and infant mortality among people living with HIV and their partners. We conducted a Phase II randomized futility trial of a multi-level intervention to increase adherence to safer sex guidelines among those wishing to avoid pregnancy and adherence to safer conception guidelines among those seeking conception in newly-diagnosed HIV-positive persons in four public-sector HIV clinics in Cape Town. Clinics were pair-matched and the two clinics within each pair were randomized to either a three-session provider-delivered enhanced intervention (EI) (onsite contraceptive services and brief milieu intervention for staff) or standard-of-care (SOC) provider-delivered intervention. The futility analysis showed that we cannot rule out the possibility that the EI intervention has a 10 % point or greater success rate in improving adherence to safer sex/safer conception guidelines than does SOC (p = 0.573), indicating that the intervention holds merit, and a larger-scale confirmatory study showing whether the EI is superior to SOC has merit.

  7. Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.

    PubMed

    Dronca, Roxana S; Allred, Jacob B; Perez, Domingo G; Nevala, Wendy K; Lieser, Elizabeth A T; Thompson, Michael; Maples, William J; Creagan, Edward T; Pockaj, Barbara A; Kaur, Judith S; Moore, Timothy D; Marchello, Benjamin T; Markovic, Svetomir N

    2014-08-01

    Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.

  8. Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

    PubMed

    Weide, Benjamin; Martens, Alexander; Wistuba-Hamprecht, Kilian; Zelba, Henning; Maier, Ludwig; Lipp, Hans-Peter; Klumpp, Bernhard D; Soffel, Daniel; Eigentler, Thomas K; Garbe, Claus

    2017-04-01

    Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

  9. Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome

    SciTech Connect

    Malone, Shawn . E-mail: smalone@ottawahospital.on.ca; Perry, Gad; Eapen, Libni; Segal, Roanne; Gallant, Victor; Dahrouge, Simone; Crook, Juanita; Spaans, Johanna N.

    2007-07-01

    Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. Results: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.

  10. GEMCITABINE AND CISPLATIN IN UNRESECTABLE MALIGNANT MESOTHELIOMA OF THE PLEURA: A PHASE II STUDY OF THE SOUTHWEST ONCOLOGY GROUP (SWOG 9810)

    PubMed Central

    Kalmadi, Sujith R.; Rankin, Cathryn; Kraut, Michael J.; Jacobs, Andrew D.; Petrylak, Daniel P.; Adelstein, David J.; Keohan, Mary Louise; Taub, Robert N.; Borden, Ernest C.

    2009-01-01

    Purpose The purpose of this open- label phase II SWOG study was to evaluate the activity of gemcitabine (Gemzar ®; Eli Lilly, Indiana, USA) and cisplatin combination therapy, in patients with unresectable malignant mesothelioma of the pleura. Patients and methods Fifty eligible chemotherapy naïve patients with histologically proven malignant mesothelioma of the pleura, and a SWOG performance status 0–2 were enrolled between February 1999 to August 2000. Treatment consisted of gemcitabine 1000mg/m2 and cisplatin 30 mg/m2 on days 1,8 and 15 of a 28-day cycle, until progression of disease or two cycles beyond complete response. Results Using SWOG response criteria, one patient had a confirmed complete response and five patients had a confirmed partial response, for a total response rate of 12% (95% C.I. of 5% – 24%). All the responses were seen in patients with epithelioid or unspecified histology. Stable disease was seen in 25 patients (50%). The median overall survival was 10 months (95% C.I. 7 – 15 mo.), with a median progression free survival of 6 months. Sixteen patients experienced Grade 4 toxicity. Twelve of these grade 4 toxicities were hematologic. There were no treatment-related deaths. Conclusions Cisplatin-gemcitabine combination chemotherapy has modest activity with an acceptable toxicity profile, as first line treatment for patients with malignant mesothelioma. PMID:18006112

  11. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer

    PubMed Central

    Munster, P N; Thurn, K T; Thomas, S; Raha, P; Lacevic, M; Miller, A; Melisko, M; Ismail-Khan, R; Rugo, H; Moasser, M; Minton, S E

    2011-01-01

    Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. Methods: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. Results: In all, 43 patients (median age 56 years (31–71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1–12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. Conclusion: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination. PMID:21559012

  12. A phase II study of bendamustine in combination with rituximab as initial treatment for patients with indolent non-follicular non-Hodgkin lymphoma.

    PubMed

    Luminari, Stefano; Goldaniga, Maria; Cesaretti, Marina; Orsucci, Lorella; Tucci, Alessandra; Pulsoni, Alessandro; Salvi, Flavia; Arcaini, Luca; Carella, Angelo Michele; Tedeschi, Alessandra; Pinto, Antonello; Stelitano, Caterina; Baldini, Luca

    2016-01-01

    The purpose of this phase 2 study was to determine the activity and safety of six cycles of bendamustine and eight rituximab (RB) as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary end-point was the complete response rate (CRR) with expected CRR of 75%. Sixty-nine patients were enrolled; median age was 65 years (45-75), 65% were male, 93% of patients had stage IV disease. Complete and overall response rates were 48% (95% CI = 35.6-60.2) and 86% (CI = 75.0-92.8). The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (7%) and anemia (4%); whereas the rate of febrile neutropenia was very low (3%). At a median follow-up of 22 months (1-43 months), 2-year progression-free survival was 89% (CI = 79-95) and 2-year overall survival was 96% (CI = 87-99). RB combination is active and well tolerated in patients with advanced stage previously untreated INFL.

  13. Phase I/II study of GM-CSF DNA as an adjuvant for a multipeptide cancer vaccine in patients with advanced melanoma

    PubMed Central

    Perales, Miguel-Angel; Yuan, Jianda; Powel, Sarah; Gallardo, Humilidad F.; Rasalan, Teresa S.; Gonzalez, Christina; Manukian, Gregor; Wang, Jian; Zhang, Yan; Chapman, Paul B.; Krown, Susan E.; Livingston, Philip O.; Ejadi, Samuel; Panageas, Katherine S.; Engelhorn, Manuel E.; Terzulli, Stephanie L.; Houghton, Alan N.; Wolchok, Jedd D.

    2014-01-01

    Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances immune responses by inducing dendritic cell proliferation, maturation, and migration and B and T lymphocyte expansion and differentiation. The potency of DNA vaccines can be enhanced by the addition of DNA encoding cytokines, acting as molecular adjuvants. We conducted a phase I/II trial of human GM-CSF DNA in conjunction with a multipeptide vaccine (gp100 and tyrosinase) in stage III/IV melanoma patients. Nineteen human leukocyte antigen (HLA)-A*0201(+) patients were treated. Three dose levels were studied: 100, 400, and 800 mcg DNA/injection, administered subcutaneously (SQ) every month with 500 mcg of each peptide. In the dose-ranging study, 3 patients were treated at each dose level. The remaining patients were then treated at the highest dose. Most toxicities were grade 1 injection site reactions. Eight patients (42%) developed CD8+ T-cell responses, defined by a ≥3 SD increase in baseline reactivity to tyrosinase or gp100 peptide in tetramer or intracellular cytokine staining assays. There was no relationship between dose and T-cell response. Responding T cells had an effector memory cell phenotype. Polyfunctional T cells were also demonstrated. At a median of 31 months follow-up, median survival has not been reached. Human GM-CSF DNA was found to be a safe adjuvant. PMID:18797450

  14. Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma.

    PubMed

    Rini, Brian I; Tomita, Yoshihiko; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Uemura, Hirotsugu; Oya, Mototsugu; Bair, Angel H; Andrews, Glen I; Rosbrook, Brad; Jonasch, Eric

    2016-12-01

    In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first-line mRCC. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

    PubMed

    Franceschi, E; Cavallo, G; Lonardi, S; Magrini, E; Tosoni, A; Grosso, D; Scopece, L; Blatt, V; Urbini, B; Pession, A; Tallini, G; Crinò, L; Brandes, A A

    2007-04-10

    To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

  16. A phase II study of oxaliplatin and prednisone for patients with relapsed or refractory marginal zone lymphoma: Consortium for Improving Survival of Lymphoma trial.

    PubMed

    Oh, Sung Yong; Kim, Won Seog; Kim, Jin Seok; Chae, Yee Soo; Lee, Gyeong-Won; Eom, Hyeon Seok; Ryoo, Hun Mo; Lee, Suee; Kim, Seok Jin; Yoon, Dok Hyun; Won, Jong Ho; Hong, Junshik; Park, Jinny; Lee, Sang-Min; Hong, Jung Yong; Park, Eunkyung; Kim, Hyo Jung; Yang, Deok-Hwan; Kim, Hyo-Jin; Suh, Cheolwon

    2016-01-01

    Overall, more than 50% of marginal zone lymphoma (MZL) patients experience a relapse within 10 years. This phase II trial was conducted to assess the efficacy and safety of oxaliplatin-prednisone (Ox-P) chemotherapy for patients with relapsed or refractory MZL. Patients received oxaliplatin 130 mg/m(2) on day 1 and prednisone 100 mg/day on days 1-5 of each cycle. A total of 38 patients were enrolled. The median age of the 34 (16 males, 18 females) evaluated patients was 53 (range = 27-74) years. There were seven complete responses (20.6%) and 15 partial responses (44.1%) (Overall response rate = 64.7%). No treatment-related deaths occurred. The median progression-free survival was 14.2 months (95% CI = 2.1-26.3 months); 3-year overall survival rate was 77.7%. Thus, salvage Ox-P chemotherapy for patients with relapsed or refractory MZL at the stated dosage and schedule showed moderate clinical activity and was considerable in very few selected patients (NCT01068392).

  17. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris--A randomized phase II study.

    PubMed

    Koo, John; Tyring, Stephen; Werschler, William P; Bruce, Suzanne; Olesen, Martin; Villumsen, John; Bagel, Jerry

    2016-01-01

    An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment. To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks. In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician's global assessment of disease severity. In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference -0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch). Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment.

  18. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris – A randomized phase II study

    PubMed Central

    Koo, John; Tyring, Stephen; Werschler, William P.; Bruce, Suzanne; Olesen, Martin; Villumsen, John; Bagel, Jerry

    2016-01-01

    Abstract Background: An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment. Objectives: To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks. Methods: In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician’s global assessment of disease severity. Results: In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference –0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch). Conclusions: Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment. PMID:26444907

  19. Clinical activity of everolimus in relapsed/refractory marginal zone B-cell lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group.

    PubMed

    Conconi, Annarita; Raderer, Markus; Franceschetti, Silvia; Devizzi, Liliana; Ferreri, Andrés J M; Magagnoli, Massimo; Arcaini, Luca; Zinzani, Pier Luigi; Martinelli, Giovanni; Vitolo, Umberto; Kiesewetter, Barbara; Porro, Elena; Stathis, Anastasios; Gaidano, Gianluca; Cavalli, Franco; Zucca, Emanuele

    2014-07-01

    The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose-limiting toxicity or progression. Median age was 71 years (range, 51-88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty-four patients had stage III-IV. Median number of prior therapies was two (range 1-5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4.5 (range, 1-16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10-47). Grade 3-4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6.8 months (range, 1.4-11.1+). After a median follow-up of 14.5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent-to-treat analysis, the projected median progression-free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.

  20. Second-line treatment with intravenous gemcitabine and oral etoposide in platinum-resistant advanced ovarian cancer patients: results of a phase II study.

    PubMed

    Bruzzone, M; Centurioni, M G; Giglione, P; Gualco, M; Merlo, D F; Miglietta, L; Cosso, M; Giannelli, F; Cristoforoni, P; Ferrarini, M

    2011-01-01

    The outcome of advanced ovarian cancer patients has not significantly improved since the introduction of platinum. One of the major reasons for this failure is the lack of an effective second-line treatment. In this phase II trial we tested the combination of gemcitabine and etoposide in 2 different groups of patients. Group 1 consisted of patients showing disease progression or relapse within 6 months of first-line platinum-based chemotherapy. Group 2 comprised heavily pretreated patients showing progression during the last chemotherapy attempt. Thirty-four patients were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) on days 1 and 8 and etoposide was administered orally at 100 mg/day on days 8-12 for 6 courses. Eighteen patients (52.9%) had an objective response and the median duration of the response was 10.3 months. Our chemotherapy regimen showed a low toxicity and good patient compliance. In 5 patients the treatment had to be delayed and in only 2 patients it was discontinued. The combination of gemcitabine and oral etoposide seems to be a safe and effective second-line treatment for platinum-resistant ovarian cancer patients. Additional data on larger series are warranted to better define the activity of this combination regimen. Copyright © 2011 S. Karger AG, Basel.

  1. Chemoneuroendocrine therapy of metastatic breast cancer with persistent thrombocytopenia with weekly low-dose epirubicin plus melatonin: a phase II study.

    PubMed

    Lissoni, P; Tancini, G; Paolorossi, F; Mandalà, M; Ardizzoia, A; Malugani, F; Giani, L; Barni, S

    1999-04-01

    Thrombocytopenia is a frequent complication of cancer and constitutes an absolute contraindication for chemotherapy. Recent studies have demonstrated that platelet generation may be influenced by both cytokines and neurohormones. In particular, the pineal indole melatonin has been proven to enhance platelet number in patients with thrombocytopenia due to different reasons. On this basis, we have evaluated the effects of a concomitant administration of melatonin in thrombocytopenic cancer patients undergoing chemotherapy. The study was performed in 14 metastatic breast cancer women treated by weekly epirubicin. Each cycle consisted of epirubicin at 25 mg/m2 i.v. at weekly intervals. Melatonin was given orally at 20 mg/day in the evening every day, starting 7 days prior to chemotherapy. Patients were considered as evaluable when they received at least four cycles of chemotherapy. Evaluable patients were 12/14. The induction phase with melatonin induced a normalization of platelet number in 9/12 evaluable patients, and no further platelet decline occurred in chemotherapy. Objective tumor regression was achieved in 5/12 (41%) patients. This preliminary study would suggest that melatonin may be effective in the treatment of cancer-related thrombocytopenia and to prevent chemotherapy-induced platelet decline. Until now, melatonin therapy of cancer has been generally considered as an alternative treatment to chemotherapy. In contrast, this study would suggest that melatonin may contribute to the realization of chemotherapy in metastatic cancer patients unable to tolerate the chemotherapeutic approach because of persistent thrombocytopenia.

  2. Gefitinib or Placebo in Combination with Tamoxifen in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: a Randomized Phase II Study

    PubMed Central

    Osborne, C. Kent; Neven, Patrick; Dirix, Luc Y.; Mackey, John R.; Robert, Jean; Underhill, Craig; Schiff, Rachel; Gutierrez, Carolina; Migliaccio, Ilenia; Anagnostou, Valsamo K.; Rimm, David L.; Magill, Patrick; Sellers, Mark

    2011-01-01

    Purpose Increased growth factor signaling may contribute to tamoxifen resistance. This randomized Phase II trial assessed tamoxifen plus placebo or the EGFR inhibitor gefitinib in ER-positive metastatic breast cancer. Experimental Design Patients with newly metastatic disease or recurring after adjuvant tamoxifen (Stratum 1, St1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (Stratum 2, St2) were eligible. Primary variables were progression-free survival (PFS) (St1) and clinical benefit rate (CBR) (St2). A ≥ 5% improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor. Results In St1 (n=206), the PFS hazard ratios (HR, gefitinib:placebo) were 0.84 (95% CI, 0.59 to 1.18; median PFS 10.9 v 8.8 months). In the St1 endocrine therapy naïve subset (n=158) the HR was 0.78 (95% CI, 0.52 to 1.15), and the prior endocrine-treated subgroup (n=48) 1.47 (95% CI, 0.63 to 3.45). In St1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In St2 (n=84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in St1 there was greater benefit with gefitinib in patients who were ER negative or had lower levels of ER protein. Conclusions In St1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria sufficient to warrant further investigation of this strategy. In St2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. PMID:21220480

  3. Front-line Treatment with Gemcitabine, Paclitaxel and Doxorubicin for Patients with Unresectable or Metastatic Urothelial Cancer and Poor Renal Function: Final Results from a Phase II Study

    PubMed Central

    Siefker-Radtke, Arlene O.; Campbell, Matthew T.; Munsell, Mark F.; Harris, Deborah R.; Carolla, Robert L.; Pagliaro, Lance C.

    2016-01-01

    Objectives To estimate the response rate to gemcitabine, paclitaxel, and doxorubicin in patients with advanced urothelial carcinoma, we conducted a phase II clinical trial. Patients with renal insufficiency cannot receive standard cisplatin-based chemotherapy for urothelial carcinoma, and carboplatin-based regimens have proved unsatisfactory. Secondary end points for this study included overall survival, safety of the regimen, and safety of same-day pegfilgrastim dosing. Methods A two-stage design was chosen with target response rate of 40%. Key inclusion criteria were metastatic or unresectable urothelial carcinoma, no prior chemotherapy, glomerular filtration rate <60 mL/min, and no dialysis. Gemcitabine (900 mg/m2), paclitaxel (135 mg/m2), and doxorubicin (40 mg/m2) were administered on day 1 of each 14-day cycle. Pegfilgrastim was given with every cycle on either day 1 or optionally day 2. Results Forty patients were enrolled and 39 were treated. Median age was 72 years (range, 51–89). There were 7 complete and 15 partial responses, for a response rate of 56.4% (95% CI, 39.6-72.2). Most (82.8%) cycles were given with same-day pegfilgrastim. Notable grade 3 and 4 non-hematologic toxicities were fatigue and mucositis (10.3% each). There were 4 episodes of neutropenic fever (4/198 cycles [2%]; 4/39 patients [10.3%]) and no treatment related deaths. Median overall survival was 14.4 months. Conclusions The combination of gemcitabine, paclitaxel, and doxorubicin is effective first-line chemotherapy for patients with advanced urothelial carcinoma and renal insufficiency. Neutropenic prophylaxis was acceptable whether pegfilgrastim was given immediately or 24 hours after chemotherapy. PMID:26723185

  4. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Ko, Andrew H.; Venook, Alan P.

    2007-07-01

    Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

  5. A Randomized Phase I/II Study of ABT-888 in Combination with Temozolomide in Recurrent Temozolomide Resistant Glioblastoma: An NRG Oncology RTOG Group Study

    PubMed Central

    Robins, H Ian; Zhang, Peixin; Gilbert, Mark R; Chakravarti, Arnab; de Groot, John F; Grimm, Sean A; Wang, Fen; Lieberman, Frank S; Krauze, Andra; Trotti, Andy M; Mohile, Nimish; Kee, Andrew Y J; Colman, Howard; Cavaliere, Robert; Kesari, Santosh; Chmura, Steven J; Mehta, Minesh

    2015-01-01

    This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using 2 randomized schedules (5 versus 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m2 (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m2) schedule was known from prior trials (arm 2). Two cohorts were studied: bevacizumab (BEV) naïve (n=151), and BEV refractory (n=74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0%. For the BEV refractory cohort, the PFS 6 was 4.4%; for the BEV naïve cohort, PFS6 was 17%. Overall survival was similar for both arms in both the BEV naïve (median survival time (MST) 10.3M; 95% CI, 8.4-12) and BEV refractory cohort (MST 4.7 M; 95%CI, 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0M (95% CI, 1.9-2.1). PMID:26508094

  6. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study.

    PubMed

    Becker, Richard C; Moliterno, David J; Jennings, Lisa K; Pieper, Karen S; Pei, Jinglan; Niederman, Alan; Ziada, Khaled M; Berman, Gail; Strony, John; Joseph, Diane; Mahaffey, Kenneth W; Van de Werf, Frans; Veltri, Enrico; Harrington, Robert A

    2009-03-14

    An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist. We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912. 257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561). Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

  7. Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: final report of RTOG phase I/II study

    SciTech Connect

    Spanos, W.J. Jr.; Wasserman, T.; Meoz, R.; Sala, J.; Kong, J.; Stetz, J.

    1987-10-01

    Between October 1979 and June 1982 forty-six patients were entered on a non-randomized Phase I-II protocol for the evaluation of Misonidazole combined with high dose per fraction radiation for the treatment of advanced pelvic malignancies. Pelvic radiation consisted of 1000 cGy in one fraction repeated at 4-week intervals for a total of three treatments. Oral Misonidazole at a dose of 4 gm/m2 was administered 4-6 hr prior to radiation (total dose 12 g/m2). The distribution of histology consisted of 20 gynecologic, 24 bowel, and 2 prostate malignancies. Of the thirty-seven patients completing the three treatments; there were 6 complete responses (14% CR), 10 partial responses (27% PR) 19 minimal or no response (32% NR), and 4 unevaluable. One patient remains NED 5.5 years following radiation. Toxicity directly related to Misonidazole was minimal and consisted primarily of transcient Grade 1, 2 peripheral neuropathy (20% Grade 1, 4% Grade 2) and Grade 2 ototoxicity (4%). Radiation toxicity was significant for late bowel damage. There were 4 (11%) Grade 3 and 7 (19%) Grade 4 gastro-intestinal (GI) toxicities. Kaplan-Meier plot of GI toxicity showed a progressive increase in incidence with time for projected rate of 49% Grade 3, 4 by 12-month. GI toxicity (Grade 3, 4) was also related to tumor response. The complication rate was 80% (4/6) for CR, 30% (3/10) for PR and 26% (5/19) for NR or progression. Because of the GI complication rate, this protocol for palliation of advanced pelvic malignancies has been replaced by a protocol that uses 4 fractions over 2 days (b.i.d.) of 370 cGy per fraction repeated at 3-week intervals for a total of 3 courses.

  8. A phase II study of REOLYSIN(®) (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma.

    PubMed

    Mahalingam, Devalingam; Fountzilas, Christos; Moseley, Jennifer; Noronha, Nicole; Tran, Hue; Chakrabarty, Romit; Selvaggi, Giovanni; Coffey, Matthew; Thompson, Brad; Sarantopoulos, John

    2017-04-01

    REOLYSIN(®) (pelareorep) is an investigational new drug, consisting of a live, replication-competent, Reovirus Type 3 Dearing strain in a proprietary formulation. Several preclinical and clinical trials with REOLYSIN(®) on a wide range of cancer indications have demonstrated antineoplastic activity on cells with activated RAS-signaling pathway. Furthermore, long-term survival benefits were evident in post-treatment patients indicating a potential antitumor immune response triggered by REOLYSIN(®). Numerous mono and/or combination therapy studies with the agent showed a consistent safety profile. The current study is a phase II, single-arm, open label trial of REOLYSIN(®) in combination with carboplatin and paclitaxel for patients with advanced melanoma. Results from the 14 patients enrolled in the study exhibited no grade 4 adverse events or deaths but manageable grade-3 toxicities commonly attributed to REOLYSIN(®), including pyrexia, chills, myalgia, pain, fatigue, and nausea. The number of treatment cycles ranged from 2 to 20 with a median of 6 cycles. The study met its treatment and efficacy goal for the first stage with three partial responses (ORR was 21%). No complete responses were noted. The median PFS and OS were 5.2 and 10.9 months, respectively. The 1-year OS was 43% with a disease control rate of 85%. In conclusion, REOLYSIN(®) combined with carboplatin and paclitaxel is a safe and potentially efficacious therapy for patients with advanced malignant melanoma. Additional combination studies using REOLYSIN(®) with chemo/immunotherapy drugs may support more favorable outcomes for patients in this indication.

  9. Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group.

    PubMed

    Villablanca, Judith G; London, Wendy B; Naranjo, Arlene; McGrady, Patrick; Ames, Matthew M; Reid, Joel M; McGovern, Renee M; Buhrow, Sarah A; Jackson, Hollie; Stranzinger, Enno; Kitchen, Brenda J; Sondel, Paul M; Parisi, Marguerite T; Shulkin, Barry; Yanik, Gregory A; Cohn, Susan L; Reynolds, C Patrick

    2011-11-01

    To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Patients received 7 days of fenretinide: 2,475 mg/m(2)/d divided TID (<18 years) or 1,800 mg/m(2)/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible. Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies. ©2011 AACR

  10. Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer.

    PubMed

    Strumberg, Dirk; Schultheis, Beate; Scheulen, M E; Hilger, R A; Krauss, J; Marschner, N; Lordick, F; Bach, F; Reuter, D; Edler, L; Mross, K

    2012-06-01

    Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43-7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t(1/2) was calculated to 45 h. These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.

  11. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study.

    PubMed

    Martín-Richard, Marta; Massutí, Bartomeu; Pineda, Eva; Alonso, Vicente; Marmol, Maribel; Castellano, Daniel; Fonseca, Emilio; Galán, Antonio; Llanos, Marta; Sala, Maria Angeles; Pericay, Carlos; Rivera, Fernando; Sastre, Javier; Segura, Angel; Quindós, Maria; Maisonobe, Pascal

    2013-09-20

    Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.

  12. Phase II Study of Cetuximab in Combination With Chemoradiation in Patients With Stage IIIA/B Non–Small-Cell Lung Cancer: RTOG 0324

    PubMed Central

    Blumenschein, George R.; Paulus, Rebecca; Curran, Walter J.; Robert, Francisco; Fossella, Frank; Werner-Wasik, Maria; Herbst, Roy S.; Doescher, Philip O.; Choy, Hak; Komaki, Ritsuko

    2011-01-01

    Purpose Non–small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC. Patients and Methods Eligibility criteria included unresectable stage III NSCLC, Zubrod performance status ≤ 1, weight loss ≤ 5%, forced expiratory volume in 1 second ≥ 1.2 L, and adequate organ function. Patients received an initial dose of cetuximab (400 mg/m2) on day 1 of week 1 and then weekly doses of cetuximab (250 mg/m2) until completion of therapy (weeks 2 through 17). During week 2, patients started CRT (63 Gy in 35 fractions) with weekly carboplatin at area under the [concentration-time] curve (AUC) 2 and six doses of paclitaxel at 45 mg/m2 followed by carboplatin (AUC 6) and two cycles of paclitaxel (200 mg/m2) during weeks 12 through 17. Primary end points included safety and compliance of concurrent cetuximab and CRT. Results In all, 93 patients were enrolled and 87 were evaluable. Median follow-up was 21.6 months. Response rate was 62% (n = 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events. Conclusion The combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group. PMID:21555682

  13. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia

    PubMed Central

    Zeidner, Joshua F.; Foster, Matthew C.; Blackford, Amanda L.; Litzow, Mark R.; Morris, Lawrence E.; Strickland, Stephen A.; Lancet, Jeffrey E.; Bose, Prithviraj; Levy, M. Yair; Tibes, Raoul; Gojo, Ivana; Gocke, Christopher D.; Rosner, Gary L.; Little, Richard F.; Wright, John J.; Doyle, L. Austin; Smith, B. Douglas; Karp, Judith E.

    2015-01-01

    Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972. PMID:26022709

  14. Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study)

    PubMed Central

    Takeuchi, K.; Togashi, Y.; Kamihara, Y.; Fukuyama, T.; Yoshioka, H.; Inoue, A.; Katsuki, H.; Kiura, K.; Nakagawa, K.; Seto, T.; Maemondo, M.; Hida, T.; Harada, M.; Ohe, Y.; Nogami, N.; Yamamoto, N.; Nishio, M.; Tamura, T.

    2016-01-01

    Background Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. Patients and methods In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. Result ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Conclusions Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. Registration number JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center). PMID:26487585

  15. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study.

    PubMed

    Cooper, C L; Davis, H L; Morris, M L; Efler, S M; Adhami, M Al; Krieg, A M; Cameron, D W; Heathcote, J

    2004-11-01

    Oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) act as potent Th1-like immune enhancers with many antigens in animal models. We have extended these observations to the first clinical evaluation of the safety, tolerability and immunogenicity of CPG 7909 when added to a commercial HBV vaccine. In a randomized, double-blind phase I dose escalation study, healthy volunteers aged 18-35 years were vaccinated at 0, 4 and 24 weeks by intramuscular injection with Engerix-B (GlaxoSmithKline). The regular adult dose of 20 microg recombinant hepatitis B surface antigen (HBsAg) adsorbed to alum was administered mixed with saline (control) or with CPG 7909 at one of three doses (0.125, 0.5 or 1.0 mg). HBsAg-specific antibody responses (anti-HBs) appeared significantly sooner and were significantly higher at all timepoints up to and including 24 weeks in CPG 7909 recipients compared to control subjects (p< or = 0.001). Strikingly, most CpG 7909-vaccinated subjects developed protective levels of anti-HBs IgG within just two weeks of the priming vaccine dose. A trend towards higher rates of positive cytotoxic T cell lymphocyte responses was noted in the two higher dose groups of CPG 7909 compared to controls. The most frequently reported adverse events were injection site reactions, flu-like symptoms and headache. While these were more frequent in CPG 7909 groups than in the control group (p<0.0001), most were reported to be of mild to moderate intensity regardless of group. In summary, CPG 7909 as an adjuvant to Engerix-B was well-tolerated and enhanced vaccine immunogenicity. CPG 7909 may allow the development of a two-dose prophylactic HBV vaccine.

  16. 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

  17. Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

    PubMed

    Lobo, Christopher; Lopes, Gilberto; Baez, Odalys; Castrellon, Aurelio; Ferrell, Annapoorna; Higgins, Connie; Hurley, Erin; Hurley, Judith; Reis, Isildinha; Richman, Stephen; Seo, Pearl; Silva, Orlando; Slingerland, Joyce; Tukia, Keleni; Welsh, Catherine; Glück, Stefan

    2010-09-01

    In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study.

  18. Pharmacodynamic markers and clinical results from the Phase II Study of the SMAC-Mimetic Birinapant in Women with Relapsed Platinum-Resistant or Refractory Epithelial Ovarian Cancer

    PubMed Central

    Chen, Jin-Qiu; Herrmann, Michelle A.; Lee, Jung-min; Kohn, Elise C.; O’Sullivan, Ciara C.; Jordan, Elizabeth; Houston, Nicole; Takebe, Naoko; Kinders, Robert J.; Cao, Liang; Peer, Cody J.; Figg, W. Douglas; Annunziata, Christina M.

    2015-01-01

    Background Inhibitors of Apoptosis Proteins (IAPs) are key regulators of apoptosis, and are frequently dysregulated in ovarian cancer. We hypothesized that blocking IAPs with birinapant would increase tumor cell death resulting in objective response for women with platinum-refractory and resistant ovarian cancer. Methods In this phase II CTEP-sponsored study, patients received birinapant 47mg/m2 on days 1, 8, 15 of 28-day cycles. Pharmacokinetics were obtained in cycle 1. Plasma, peripheral blood mononuclear cells (PBMC) and percutaneous tumor biopsies were collected prior to cycle 1, and after 6 weeks. The primary endpoint was objective response or progression-free survival lasting greater than 6 months in a mini-max design. Results Eleven patients received birinapant, after which accrual was terminated for lack of clinical benefit. Birinapant was well-tolerated, with predominantly grade 2 adverse events (AE) and one grade 3 lymphopenia. Pre-treatment biopsies and PBMCs were collected; paired post-treatment biopsies and PBMC were collected from 7 and 10 patients, respectively. There was consistent downregulation of cIAP1 in tumor (P=0.016) and PBMC (P<0.01). Pro-caspase3 also decreased in tumors (P=0.031) and PBMC (P<0.01); cleaved caspase3 co-localized with gamma-H2AX in tumors after birinapant exposure. Peripheral T- and B-cells decreased significantly post-treatment, but NK-cells did not (P=0.04, P=0.05, P=0.43 respectively). Conclusion Birinapant shows consistent target suppression in vivo, without single agent anti-tumor activity in this small population. Single agent pharmacodynamics were necessary to understand drug mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials. PMID:26566079

  19. Phase II Study of the AKT inhibitor MK-2206 plus Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer who Previously Progressed on Erlotinib

    PubMed Central

    Lara, Primo N.; Longmate, Jeff; Mack, Philip C.; Kelly, Karen; Socinski, Mark A.; Salgia, Ravi; Gitlitz, Barbara; Li, Tianhong; Koczywas, Mariana; Reckamp, Karen L.; Gandara, David R.

    2015-01-01

    Purpose Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the epidermal-growth factor receptor (EGFR) inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK2206, a highly selective inhibitor of AKT, in NSCLC patients. Experimental Design Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg po QD + MK-2206 45 mg po QOD on a 28 day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild type). Results Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were respectively 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. Conclusions Combination MK2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild type NSCLC. While activity was seen in EGFR mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild type NSCLC. PMID:26106072

  20. Phase II Study of Chemoembolization With Drug-Eluting Beads in Patients With Hepatic Neuroendocrine Metastases: High Incidence of Biliary Injury

    SciTech Connect

    Bhagat, Nikhil Reyes, Diane K.; Lin, Mingde; Kamel, Ihab; Pawlik, Timothy M.; Frangakis, Constantine; Geschwind, J. F.

    2013-04-15

    To evaluate safety in an interim analysis of transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) in 13 patients with hepatic metastases from neuroendocrine tumors (NETs) as part of a phase II trial. Institutional Review Board approval and informed consent were obtained. Thirteen patients completed preliminary safety analysis. Their mean age was 65 years, Eastern Cooperative Oncology Group status was 0/1, tumor burden range was 4-75 %, and mean targeted tumor size was 5.9 cm. Up to four DEB-TACE sessions (100-300 {mu}m beads loaded with {<=}100 mg doxorubicin) within 6 months were allowed. Tumor response was assessed by magnetic resonance imaging 1 month after treatment using contrast-enhancement [European Association for the Study of the Liver (EASL) and size Response Evaluation Criteria in Solid Tumors (RECIST)] criteria. Safety was assessed by National Cancer Institute Common Terminology Criteria. DEB-TACE was successfully performed in all 13 patients. At 1 month follow-up, there was a mean 12 % decrease in tumor size (p < 0.0003) and a 56 % decrease in tumor enhancement (p < 0.0001). By EASL criteria, the targeted lesion objective response rate was 78 %. Grade 3 to 4 toxicities were fatigue (23 %), increased alanine amino transferase (15 %), hyperglycemia (15 %), and abdominal pain (8 %). Seven patients developed bilomas (54 %); all of these patients had multiple small (<4 cm) lesions. Subsequently, four underwent percutaneous drainage, three for abscess formation and one for symptoms related to mass effect. Although biloma and liver abscess are known risks after TACE, the high incidence in our study population was unexpected and forced interruption of the trial. Although this occurred in a small group of patients, we have changed our technique and patient selection as a result of these findings, thus allowing resumption of the trial.

  1. A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study.

    PubMed

    Robins, H Ian; Zhang, Peixin; Gilbert, Mark R; Chakravarti, Arnab; de Groot, John F; Grimm, Sean A; Wang, Fen; Lieberman, Frank S; Krauze, Andra; Trotti, Andy M; Mohile, Nimish; Kee, Andrew Y J; Colman, Howard; Cavaliere, Robert; Kesari, Santosh; Chmura, Steven J; Mehta, Minesh

    2016-01-01

    This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1).

  2. A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C.

    PubMed

    Almhanna, Khaldoun; Wright, David; Mercade, Teresa Macarulla; Van Laethem, Jean-Luc; Gracian, Antonio Cubillo; Guillen-Ponce, Carmen; Faris, Jason; Lopez, Carolina Muriel; Hubner, Richard A; Bendell, Johanna; Bols, Alain; Feliu, Jaime; Starling, Naureen; Enzinger, Peter; Mahalingham, Devalingham; Messersmith, Wells; Yang, Huyuan; Fasanmade, Adedigbo; Danaee, Hadi; Kalebic, Thea

    2017-05-19

    Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

  3. Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.

    PubMed

    Mawad, Raya; Becker, Pamela S; Hendrie, Paul; Scott, Bart; Wood, Brent L; Dean, Carol; Sandhu, Vicky; Deeg, Hans Joachim; Walter, Roland; Wang, Lixia; Myint, Han; Singer, Jack W; Estey, Elihu; Pagel, John M

    2016-01-01

    Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients ≥60 years old (median age 70 years; range, 60-83) were randomized to receive tosedostat (120 mg on days 1-21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2 /d) or decitabine (20 mg/m2 /d) every 35 d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 11.2 months (range, 0.5-22.3), and median survival was 11.5 months (95% confidence interval, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.

  4. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.

    PubMed

    Zeidner, Joshua F; Foster, Matthew C; Blackford, Amanda L; Litzow, Mark R; Morris, Lawrence E; Strickland, Stephen A; Lancet, Jeffrey E; Bose, Prithviraj; Levy, M Yair; Tibes, Raoul; Gojo, Ivana; Gocke, Christopher D; Rosner, Gary L; Little, Richard F; Wright, John J; Doyle, L Austin; Smith, B Douglas; Karp, Judith E

    2015-09-01

    Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.

  5. Ledipasvir/sofosbuvir-based treatment of patients with chronic genotype-1 HCV infection and cirrhosis: results from two Phase II studies.

    PubMed

    Lawitz, Eric; Poordad, Fred; Hyland, Robert H; Wang, Jing; Liu, Lin; Dvory-Sobol, Hadas; Brainard, Diana M; McHutchison, John G; Gutierrez, Julio A

    2016-01-01

    Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis. In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRILOGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety. In both studies, most patients were male (each 65%) and white (92-96%), infected with HCV genotype-1a (62-70%) and had IL28B non-CC genotypes (82-87%). In total, 37-39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRILOGY-1 (82-91%) and TRILOGY-2 (88-95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent. All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.

  6. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972.

    PubMed

    van den Bent, M J; Chinot, O; Boogerd, W; Bravo Marques, J; Taphoorn, M J B; Kros, J M; van der Rijt, C C D; Vecht, C J; De Beule, N; Baron, B

    2003-04-01

    Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.

  7. Phase II study of bevacizumab, capecitabine, and oxaliplatin followed by bevacizumab plus erlotinib as first-line therapy in metastatic colorectal cancer.

    PubMed

    Muñoz, Alberto; Pericay, Carles; García-Girón, Carlos; Alonso, Vicente; Dueñas, Rosario; Cirera, Luis; Rivera, Fernando; Falcó, Esther; Bustos, Iñaki Alvarez; Salud, Antonieta

    2013-01-01

    This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m(2) on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progression-free survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 [95% confidence interval (CI): 7.9-11.9] months, and the median overall survival was 25.8 (95% CI: 18.0-30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0-15.7) months, and the median overall survival was 29.5 (95% CI: 23.7-36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX-bevacizumab for 6 cycles followed by bevacizumab-erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer.

  8. A phase II study of sequential 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel in advanced breast cancer (Protocol PV BC 97/01)

    PubMed Central

    Riccardi, A; Pugliese, P; Danova, M; Brugnatelli, S; Grasso, D; Giordano, M; Bernardo, G; Giardina, G; Fava, S; Montanari, G; Pedrotti, C; Trotti, G; Rinaldi, E; Poli, M A; Tinelli, C

    2001-01-01

    Sequential administration of the association of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel could be better tolerated than the association of an anthracycline and paclitaxel while having a similar antitumour effect. 69 patients with advanced breast cancer previously untreated with anthracyclines or paclitaxel entered a phase II multicentre study in which FEC was followed by paclitaxel. Both regimens were administered 4 times every 21 days. The median follow-up is 20 months and 38/69 patients have died. Grade III–IV toxicity was acceptable. Leukopenia occurred in 26% of patients, thrombocytopenia in 2% and anaemia in 4%. One patient had reversible heart failure during FEC therapy. Peripheral neuropathy and arthralgia-myalgia occurred in 9% and 4% of patients, respectively and one patient had respiratory hypersensitivity during paclitaxel treatment. 9 patients did not complete therapy because of: treatment refusal (n= 1), cardiac toxicity (n= 1), early death during FEC chemotherapy (n= 1), major protocol violations (n= 4), hypersensitivity reaction (n= 1) and early death during paclitaxel chemotherapy (n= 1). The overall response rate was 65% (95% CI = 53–76), and 7% of patients had stable disease. Therapy was defined as having failed in 28% of patients because they were not evaluable (13%) or had progressive disease (15%). The median time to progression and survival are 13.2 and 23.5 months, respectively. Sequential FEC-paclitaxel is a suitable strategy for patients with metastatic breast cancer who have not been previously treated with anthracyclines and/or taxanes. In fact, it avoids major haematologic toxicity and has a good antitumour effect. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11461067

  9. Immunogenicity and safety of tetravalent dengue vaccine in 2-11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru.

    PubMed

    Lanata, Claudio F; Andrade, Teresa; Gil, Ana I; Terrones, Cynthia; Valladolid, Omar; Zambrano, Betzana; Saville, Melanie; Crevat, Denis

    2012-09-07

    In a randomized, placebo-controlled, monocenter, observer blinded study conducted in an area where dengue is endemic, we assessed the safety and immunogenicity of a recombinant, live, attenuated, tetravalent dengue vaccine candidate (CYD-TDV) in 2-11 year-olds with varying levels of pre-existing yellow-fever immunity due to vaccination 1-7 years previously. 199 children received 3 injections of CYD-TDV (months 0, 6 and 12) and 99 received placebo (months 0 and 6) or pneumococcal polysaccharide vaccine (month 12). One month after the third dengue vaccination, serotype specific neutralizing antibody GMTs were in the range of 178-190 (1/dil) (versus 16.7-38.1 in the control group), a 10-20 fold-increase from baseline, and 94% of vaccines were seropositive to all four serotypes (versus 39% in the control group). There were no vaccine-related SAEs. The observed reactogenicity profile was consistent with phase I studies, with severity grade 1-2 injection site pain, headache, malaise and fever most frequently reported and no increase after subsequent vaccinations. Virologically confirmed dengue cases were seen after completion of the 3 doses: 1 in the CYD-TDV group (N=199), and 3 in the control group (N=99). A 3-dose regimen of CYD-TDV had a good safety profile in 2-11 year olds with a history of YF vaccination and elicited robust antibody responses that were balanced against the four serotypes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Randomized Phase II Study of the X-linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC).

    PubMed

    Lee, Francis A S; Zee, Benny Chung-Ying; Cheung, Foon Yiu; Kwong, Philip; Chiang, Chi Leung; Leung, Kwong Chuen; Siu, Steven W K; Lee, Conrad; Lai, Maria; Kwok, Chloe; Chong, Marc; Jolivet, Jacques; Tung, Steward

    2016-12-01

    This multicenter, randomized, open-label, phase II trial evaluated the efficacy and safety of AEG35156 in addition to sorafenib in patients with advanced hepatocellular carcinoma (HCC), as compared with sorafenib alone. Eligible patients were randomly assigned in a 2:1 ratio to receive AEG35156 (300 mg weekly intravenous infusion) in combination with sorafenib (400 mg twice daily orally) or sorafenib alone. The primary endpoint was progression-free survival (PFS). Other endpoints include overall survival (OS), objective response rates (ORR), and safety profile. A total of 51 patients were enrolled; of them, 48 were evaluable. At a median follow-up of 16.2 months, the median PFS and OS were 4.0 months (95% CI, 1.2-4.1) and 6.5 months (95% CI, 3.9-11.5) for combination arm, and 2.6 (95% CI, 1.2-5.4) and 5.4 months (95% CI, 4.3-11.2) for sorafenib arm. Patients who had the study treatment interrupted or had dose modifications according to protocol did significantly better, in terms of PFS and OS, than those who had no dose reduction in combination arm and those in sorafenib arm. The ORR based on Choi and RECIST criteria were 16.1% and 9.7% in combination arm, respectively. The ORR was 0 in control arm. One drug-related serious adverse event of hypersensitivity occurred in the combination arm, whereas 2 gastrointestinal serious adverse events in the sorafenib arm. AEG35156 in combination with sorafenib showed additional activity in terms of ORR and was well tolerated. The benefit on PFS is moderate but more apparent in the dose-reduced subgroups.

  11. A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007.

    PubMed

    Miller, Kathy D; Althouse, Sandra K; Nabell, Lisle; Rugo, Hope; Carey, Lisa; Kimmick, Gretchen; Jones, David R; Merino, Maria J; Steeg, Patricia S

    2014-11-01

    Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.

  12. Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Carcinoma: Four-Year Results of a Prospective Phase II Study

    SciTech Connect

    Fakiris, Achilles J.; McGarry, Ronald C.; Yiannoutsos, Constantin T.; Papiez, Lech; Williams, Mark; Henderson, Mark A.; Timmerman, Robert

    2009-11-01

    Purpose: The 50-month results of a prospective Phase II trial of stereotactic body radiation therapy (SBRT) in medically inoperable patients are reported. Methods and Materials: A total of 70 medically inoperable patients had clinically staged T1 (34 patients) or T2 (36 patients) (<=7 cm), N0, M0, biopsy-confirmed non-small-cell lung carcinoma (NSCLC) and received SBRT as per our previously published reports. The SBRT treatment dose of 60-66 Gy was prescribed to the 80% isodose volume in three fractions. Results: Median follow-up was 50.2 months (range, 1.4-64.8 months). Kaplan-Meier local control at 3 years was 88.1%. Regional (nodal) and distant recurrence occurred in 6 (8.6%) and 9 (12.9%) patients, respectively. Median survival (MS) was 32.4 months and 3-year overall survival (OS) was 42.7% (95% confidence interval [95% CI], 31.1-54.3%). Cancer-specific survival at 3 years was 81.7% (95% CI, 70.0-93.4%). For patients with T1 tumors, MS was 38.7 months (95% CI, 25.3-50.2) and for T2 tumors MS was 24.5 months (95% CI, 18.5-37.4) (p = 0.194). Tumor volume (<=5 cc, 5-10 cc, 10-20 cc, >20 cc) did not significantly impact survival: MS was 36.9 months (95% CI, 18.1-42.9), 34.0 (95% CI, 16.9-57.1), 32.8 (95% CI, 21.3-57.8), and 21.4 months (95% CI, 17.8-41.6), respectively (p = 0.712). There was no significant survival difference between patients with peripheral vs. central tumors (MS 33.2 vs. 24.4 months, p = 0.697). Grade 3 to 5 toxicity occurred in 5 of 48 patients with peripheral lung tumors (10.4%) and in 6 of 22 patients (27.3%) with central tumors (Fisher's exact test, p = 0.088). Conclusion: Based on our study results, use of SBRT results in high rates of local control in medically inoperable patients with Stage I NSCLC.

  13. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.

    PubMed

    Kang, Y-K; Yau, T; Park, J-W; Lim, H Y; Lee, T-Y; Obi, S; Chan, S L; Qin, Sk; Kim, R D; Casey, M; Chen, C; Bhattacharyya, H; Williams, J A; Valota, O; Chakrabarti, D; Kudo, M

    2015-12-01

    The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification

  14. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

    SciTech Connect

    Vuky, Jacqueline; Badiozamani, Kasra; Song Guobin

    2012-03-15

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  15. A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

    PubMed Central

    Krasner, C N; McMeekin, D S; Chan, S; Braly, P S; Renshaw, F G; Kaye, S; Provencher, D M; Campos, S; Gore, M E

    2007-01-01

    The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis®) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m−2) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (⩾6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2–41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8–6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1–14.2%). Median PFS was 2.0 months (95% CI: 1.7–3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (⩾2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile. PMID

  16. Randomized open-label phase II study comparing oxycodone-naloxone with oxycodone in early return of gastrointestinal function after laparoscopic colorectal surgery.

    PubMed

    Creamer, F; Balfour, A; Nimmo, S; Foo, I; Norrie, J D; Williams, L J; Fearon, K C; Paterson, H M

    2017-01-01

    Combined oral modified-release oxycodone-naloxone may reduce opioid-induced postoperative gut dysfunction. This study examined the feasibility of a randomized trial of oxycodone-naloxone within the context of enhanced recovery for laparoscopic colorectal resection. In a single-centre open-label phase II feasibility study, patients received analgesia based on either oxycodone-naloxone or oxycodone. Primary endpoints were recruitment, retention and protocol compliance. Secondary endpoints included a composite endpoint of gut function (tolerance of solid food, low nausea/vomiting score, passage of flatus or faeces). Eighty-two patients were screened and 62 randomized (76 per cent); the attrition rate was 19 per cent (12 of 62), leaving 50 patients who received the allocated intervention with 100 per cent follow-up and retention (modified intention-to-treat cohort). Protocol compliance was more than 90 per cent. Return of gut function by day 3 was similar in the two groups: 13 (48 per cent) of 27 in the oxycodone-naloxone group and 15 (65 per cent) of 23 in the control group (95 per cent c.i. for difference -10·0 to 40·7 per cent; P = 0·264). However, patients in the oxycodone-naloxone group had a shorter time to first bowel movement (mean(s.d.) 87(38) h versus 111(37) h in the control group; 95 per cent c.i. for difference 2·3 to 45·4 h, P = 0·031) and reduced total (oral plus parenteral) opioid consumption (mean(s.d.) 78(36) versus 94(56) mg respectively; 95 per cent c.i. for difference -10·2 to 42·8 mg, P = 0·222). High participation, retention and protocol compliance confirmed feasibility. Potential benefits of oxycodone-naloxone in reducing time to bowel movement and total opioid consumption could be tested in a randomized trial. Registration number: NCT02109640 (https://www.clinicaltrials.gov/). © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

  17. 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study.

    PubMed

    Yanik, Gregory A; Villablanca, Judith G; Maris, John M; Weiss, Brian; Groshen, Susan; Marachelian, Araz; Park, Julie R; Tsao-Wei, Denice; Hawkins, Randall; Shulkin, Barry L; Jackson, Hollie; Goodarzian, Fariba; Shimada, Hiro; Courtier, Jesse; Hutchinson, Raymond; Haas-Koga, Daphne; Hasenauer, C Beth; Czarnecki, Scarlett; Katzenstein, Howard M; Matthay, Katherine K

    2015-04-01

    (131)I-Metaiodobenzylguanidine ((131)I-MIBG) has been used as a single agent or in combination with chemotherapy for the treatment of high-risk neuroblastoma. The activity and toxicity of (131)I-MIBG when combined with carboplatin, etoposide, and melphalan (CEM) and autologous stem cell transplantation (SCT) are now investigated in a phase II multicenter study. Fifty patients with MIBG-avid disease were enrolled into 2 cohorts, stratified by response to induction therapy. The primary study endpoint was response of patients with refractory (n = 27) or progressive disease (n = 15). A second cohort of patients (n = 8) with a partial response (PR) to induction therapy was included to obtain preliminary response data. (131)I-MIBG was administered on day -21 to all patients, with CEM given days -7 to -4, and SCT given on day 0. (131)I-MIBG dosing was determined by pre-therapy glomerular filtration rate (GFR), with 8 mCi/kg given if GFR was 60 to 99 mL/minute/1.73 m(2) (n = 13) and 12 mCi/kg if GFR ≥ 100 mL/minute/1.73 m(2) (n = 37). External beam radiotherapy was delivered to the primary and metastatic sites, beginning approximately 6 weeks after SCT. Responses (complete response + PR) were seen in 4 of 41 (10%) evaluable patients with primary refractory or progressive disease. At 3 years after SCT, the event-free survival (EFS) was 20% ± 7%, with overall survival (OS) 62% ± 8% for this cohort of patients. Responses were noted in 3 of 8 (38%) of patients with a PR to induction, with 3-year EFS 38% ± 17% and OS 75% ± 15%. No statistically significant difference was found comparing EFS or OS based upon pre-therapy GFR or disease cohort. Six of 50 patients had nonhematologic dose-limiting toxicity (DLT); 1 of 13 in the low GFR and 5 of 37 in the normal GFR cohorts. Hepatic sinusoidal obstructive syndrome (SOS) was seen in 6 patients (12%), with 5 events defined as dose-limiting SOS. The median times to neutrophil and platelet engraftment were 10 and 15 days

  18. A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer.

    PubMed

    Lacouture, M E; Keefe, D M; Sonis, S; Jatoi, A; Gernhardt, D; Wang, T; Doherty, J P; Giri, N; Nadanaciva, S; O'Connell, J; Sbar, E; Piperdi, B; Garon, E B

    2016-09-01

    ARCHER 1042, a randomized phase II trial, explored the impact of prophylactic treatment on select dermatologic adverse events of interest (SDAEI), diarrhea, and mucositis associated with dacomitinib, an oral irreversible pan-human epidermal growth factor receptor (HER) inhibitor, in development for advanced non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC treated with dacomitinib were enrolled in two cohorts. Cohort I patients were randomized 1:1 to receive oral doxycycline or placebo (4 weeks). Cohort II patients received oral VSL#3 probiotic plus topical alclometasone. Primary end points for Cohorts I and II were incidence of all grade and grade ≥2 SDAEI in the first 8 weeks of treatment and quality of life (QoL) assessed by the Skindex-16 survey. Additional primary end points for Cohort II were incidence of all grade and grade ≥2 diarrhea and mucositis in the first 8 weeks of treatment; QoL regarding diarrhea and mucositis incidence was assessed by the modified-Oral Mucositis Daily Questionnaire. Cohort I randomized 114 evaluable patients: 56 in the doxycycline arm, 58 in the placebo arm. Cohort II enrolled 59 evaluable patients. Doxycycline significantly reduced the incidence of grade ≥2 SDAEI by 50% (P = 0.016) compared with placebo. The incidence of all grade SDAEI was lower with doxycycline than with placebo but did not reach statistical significance. Doxycycline was associated with less deterioration in QoL compared with placebo. Alclometasone was associated with less deterioration in QoL compared with placebo but did not statistically significantly reduce the incidence of all grade or grade ≥2 SDAEI. VSL#3 did not reduce the incidence of all grade or grade ≥2 diarrhea and did not impact mucositis scores. Doxycycline was effective as a prophylactic treatment for dacomitinib-induced grade ≥2 SDAEI. Both doxycycline and alclometasone reduced the negative impact in patient-reported dermatologic AEs. The probiotic was not effective

  19. Efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma when combined with oral tegafur-uracil modulated with leucovorin: results from a phase II study.

    PubMed

    Uzcudun, Ana Escribano; Batlle, Jaime Feliu; Velasco, Jesús Calvillo; Sánchez Santos, María Elena; Carpeño, Javier De Castro; Grande, Antonio García; Juberías, Alberto Mata; Piñeiro, Elena Hernández; Olivar, Lara Miralles; García, Alfredo García

    2002-10-01

    ). With a median follow-up of 37 (range, 10-62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). this protocol needs to be tested in a phase-III clinical trial with a larger sample size.

  20. Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study.

    PubMed

    Thaler, Josef; Karthaus, Meinolf; Mineur, Laurent; Greil, Richard; Letocha, Henry; Hofheinz, Ralf; Fernebro, Eva; Gamelin, Erick; Baños, Ana; Köhne, Claus-Henning

    2012-09-29

    Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity. ClinicalTrials.gov NCT00508404.

  1. A FDG-PET driven consolidation strategy in diffuse large B-cell lymphoma: Final results of a randomized phase II study.

    PubMed

    Casasnovas, Rene-Olivier; Ysebaert, Loic; Thieblemont, Catherine; Bachy, Emmanuel; Feugier, Pierre; Delmer, Alain; Tricot, Sabine; Gabarre, Jean; Andre, Marc; Fruchart, Christophe; Mounier, Nicolas; Delarue, Richard; Meignan, Michel; Berriolo-Riedinger, Alina; Bardet, Stephane; Emile, Jean-Francois; Jais, Jean-Philippe; Haioun, Corinne; Tilly, Herve; Morschhauser, Franck

    2017-07-12

    Dose-dense induction and upfront consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating high-risk diffuse large B cell lymphoma patients. GELA designed a randomized phase II trial evaluating the efficacy of either R-ACVBP or R-CHOP14 induction and a PET-driven ASCT or standard immunochemotherapy (SIC) consolidation in aaIPI2-3 patients. PET was done at baseline, after 2 (PET2) and 4 induction cycles (PET4) and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- ASCT and PET4+ patients treated with investigator' choice. The primary end-point was the 2007 international working group CR rate after induction. ΔSUVmax PET assessment was explored. 211 patients were randomized to R-ACVBP (n=109) or R-CHOP14 (n=102). PET4-/CR rates were 53/47% with R-ACVBP and 41/39% with R-CHOP14 (CR 95%CI: 38%-67% v 28%-54%; p=0.076). Consolidation in the R-ACVBP and R-CHOP14 arms was SIC in 26% and 23% of patients and ASCT in 28% and 18%, respectively. PET4 positivity was higher with R-CHOP14 (54% v 41%; p=0.08) leading to more salvage therapy (37% v 26%; p=0.07) and lower EFS (4y-EFS= 31% v 43%; p<0.01) but PFS and OS were similar in both arms. PET2-/PET4- and PET2+/PET4- patients had similar outcome. Using ΔSUVmax, 79% patients were PET2-/PET4-. ΔSUVmaxPET0-4>70% was associated with better outcome (4y-PFS: 84% v 35%; 4y-OS: 91% v 57%, p<0.0001) whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing alternative to SIC, including ASCT. Copyright © 2017 American Society of Hematology.

  2. Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Shaffer, Brian C; Le Luduec, Jean-Benoit; Forlenza, Christopher; Jakubowski, Ann A; Perales, Miguel-Angel; Young, James W; Hsu, Katharine C

    2016-04-01

    We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT.

  3. Sequential (gemcitabine/vinorelbine) and concurrent (gemcitabine) radiochemotherapy with FDG-PET-based target volume definition in locally advanced non-small cell lung cancer: first results of a phase I/II study

    PubMed Central

    Gagel, Bernd; Piroth, Marc; Pinkawa, Michael; Reinartz, Patrick; Krohn, Thomas; Kaiser, Hans J; Stanzel, Sven; Breuer, Christian; Asadpour, Branka; Schmachtenberg, Axel; Eble, Michael J

    2007-01-01

    Background The aim of the study was to determine the maximal tolerated dose (MTD) of gemcitabine every two weeks concurrent to radiotherapy, administered during an aggressive program of sequential and simultaneous radiochemotherapy for locally advanced, unresectable non-small cell lung cancer (NSCLC) and to evaluate the efficacy of this regime in a phase II study. Methods 33 patients with histologically confirmed NSCLC were enrolled in a combined radiochemotherapy protocol. 29 patients were assessable for evaluation of toxicity and tumor response. Treatment included two cycles of induction chemotherapy with gemcitabine (1200 mg/m2) and vinorelbine (30 mg/m2) at day 1, 8 and 22, 29 followed by concurrent radiotherapy (2.0 Gy/d; total dose 66.0 Gy) and chemotherapy with gemcitabine every two weeks at day 43, 57 and 71. Radiotherapy planning included [18F] fluorodeoxyglucose positron emission tomography (FDG PET) based target volume definition. 10 patients were included in the phase I study with an initial gemcitabine dose of 300 mg/m2. The dose of gemcitabine was increased in steps of 100 mg/m2 until the MTD was realized. Results MTD was defined for the patient group receiving gemcitabine 500 mg/m2 due to grade 2 (next to grade 3) esophagitis in all patients resulting in a mean body weight loss of 5 kg (SD = 1.4 kg), representing 8% of the initial weight. These patients showed persisting dysphagia 3 to 4 weeks after completing radiotherapy. In accordance with expected complications as esophagitis, dysphagia and odynophagia, we defined the MTD at this dose level, although no dose limiting toxicity (DLT) grade 3 was reached. In the phase I/II median follow-up was 15.7 months (4.1 to 42.6 months). The overall response rate after completion of therapy was 64%. The median overall survival was 19.9 (95% CI: [10.1; 29.7]) months for all eligible patients. The median disease-free survival for all patients was 8.7 (95% CI: [2.7; 14.6]) months. Conclusion After induction

  4. Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

    PubMed

    Yokota, T; Ogawa, T; Takahashi, S; Okami, K; Fujii, T; Tanaka, K; Iwae, S; Ota, I; Ueda, T; Monden, N; Matsuura, K; Kojima, H; Ueda, S; Sasaki, K; Fujimoto, Y; Hasegawa, Y; Beppu, T; Nishimori, H; Hirano, S; Naka, Y; Matsushima, Y; Fujii, M; Tahara, M

    2017-05-05

    Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March

  5. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors.

    PubMed

    Pusceddu, Sara; de Braud, Filippo; Concas, Laura; Bregant, Cristina; Leuzzi, Livia; Formisano, Barbara; Buzzoni, Roberto

    2014-01-01

    Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.

  6. Phase II Study of Everolimus Beyond Progression

    ClinicalTrials.gov

    2016-09-23

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  7. Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O(6)-Methylguanine-DNA Methyltransferase Biomarker Analyses.

    PubMed

    Cloughesy, Timothy; Finocchiaro, Gaetano; Belda-Iniesta, Cristóbal; Recht, Lawrence; Brandes, Alba A; Pineda, Estela; Mikkelsen, Tom; Chinot, Olivier L; Balana, Carmen; Macdonald, David R; Westphal, Manfred; Hopkins, Kirsten; Weller, Michael; Bais, Carlos; Sandmann, Thomas; Bruey, Jean-Marie; Koeppen, Hartmut; Liu, Bo; Verret, Wendy; Phan, See-Chun; Shames, David S

    2017-01-20

    Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O(6)-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O(6)-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with

  8. A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer

    PubMed Central

    Jones, R L; Walsh, G; Ashley, S; Chua, S; Agarwal, R; O'Brien, M; Johnston, S; Smith, I E

    2009-01-01

    Accelerated (dose-dense) chemotherapy, in which the frequency of administration is increased without changing total dose or duration, may increase the efficacy of cancer chemotherapy. We performed a randomised Phase II study to assess the safety and relative toxicity of AC (doxorubicin; cyclophosphamide) vs E(epirubicin)C given by conventional or accelerated schedules as neoadjuvant or adjuvant chemotherapy for early breast cancer. Furthermore, the relative toxicity of doxorubicin and epirubicin remains uncertain. Patients were randomised to one of four arms; four courses of standard 3 weekly cyclophosphamide 600 mg m−2 in combination with doxorubicin 60 mg m−2 (AC) vs epirubicin 90 mg m−2 (EC) 3 weekly vs the same regimens administered every 2 weeks with pegfilgrastim (G-CSF). A total of 126 patients were treated, 42 with standard AC, 42 with accelerated AC, 19 with standard EC and 23 with accelerated EC. Significantly more grade 3/4 day one neutropenia was seen with standard (6/61, 10%) compared to accelerated (0/65,) regimens (P=0.01). A trend towards more neutropenic sepsis was seen in the combined standard and accelerated AC arms (12/84, 14%) compared to the combined EC arms (1/42, 2%), P=0.06. Falls in left ventricular ejection fraction were not increased with accelerated treatment. Accelerated AC and EC with pegfilgrastim are safe and feasible regimens in the treatment of early breast cancer with less neutropenia than conventional 3 weekly schedules. PMID:19165198

  9. Fluosol and oxygen breathing as an adjuvant to radiation therapy in the treatment of locally advanced non-small cell carcinoma of the lung: Results of a phase I/II study

    SciTech Connect

    Lustig, R.; Lowe, N.; Prosnitz, L.; Spaulding, M.; Cohen, M.; Stitt, J.; Brannon, R. )

    1990-07-01

    Fluosol, a perflourcarbon emulsion, has the ability to carry oxygen in solution. In conjunction with oxygen breathing and radiation, fluosol has been shown in animal models to enhance local tumor control. In September 1985, a Phase I/II Study was instituted to evaluate the effect of this adjuvant therapy with radiation in non-small cell carcinomas of the lung. Of the 49 patients administered Fluosol, 34 mild moderate adverse reactions were noted in 22 patients to either the test dose/infusion or post infusion. Flushing, dyspnea and hypertension and chills and/or fever were the typical symptoms. Transient elevation of blood chemistries were noted in some patients. Six patients had transient depression of WBC counts and two patients had transient depression of platelets. None of these altered treatment. Forty-five patients received Fluosol of which 34 completed the planned therapy. Six patients were diagnosed with metastatic disease during therapy and three patients died of their disease during treatment. Radiation therapy was administered at a daily fraction of 165 to 200 cGy per fraction to a total dose of 5940 to 6800 cGy.

  10. Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study

    PubMed Central

    Siena, S.; Crinò, L.; Danova, M.; Del Prete, S.; Cascinu, S.; Salvagni, S.; Schiavetto, I.; Vitali, M.; Bajetta, E.

    2010-01-01

    Background: Brain metastases reduce survival because therapeutic options are limited. This phase II study evaluated the efficacy of single-agent therapy with alternating weekly, dose-dense temozolomide in pretreated patients with brain metastases prospectively stratified by primary tumor type. Methods: Eligible patients had bidimensionally measurable brain metastases from histologically/cytologically confirmed melanoma, breast cancer (BC), or non-small-cell lung cancer (NSCLC). Prior chemotherapy, radiotherapy, and whole-brain radiotherapy (WBRT) were allowed. Patients received temozolomide 150 mg/m2/day (days 1–7 and 15–21 every 28- or 35-day cycle). Results: In the intent-to-treat population (N = 157; 53 melanoma, 51 BC, and 53 NSCLC), one patient had complete response, nine (6%) had partial responses, and 31 (20%) had stable disease in the brain. Median progression-free survival was 56, 58, and 66 days for melanoma, BC, and NSCLC, respectively. Median overall survival was 100 days for melanoma, 172 days for NSCLC, and not evaluable in the BC group. Thrombocytopenia was the most common adverse event causing dose modification or treatment discontinuation. Grade 4 toxic effects were rare. Conclusions: This alternating weekly, dose-dense temozolomide regimen was well tolerated and clinically active in heavily pretreated patients with brain metastases, particularly in patients with melanoma. Combining temozolomide with WBRT or other agents may improve clinical outcomes. PMID:19767314

  11. A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis.

    PubMed

    Greenberg, Richard N; Hurley, Maria Yadira; Hurley, Yadira; Dinh, Dinh V; Mraz, Serena; Vera, Javier Gomez; von Bredow, Dorothea; von Krempelhuber, Alfred; Roesch, Siegfried; Virgin, Garth; Arndtz-Wiedemann, Nathaly; Meyer, Thomas Peter; Schmidt, Darja; Nichols, Richard; Young, Philip; Chaplin, Paul

    2015-01-01

    Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers. This Phase II study compared the safety and immunogenicity of MVA enrol