A Study of Chemotherapy and Radiation Therapy Compared to Chemotherapy and Radiation Therapy Plus MEDI4736 (Durvalumab) Immunotherapy for Bladder Cancer Which Has Spread to the Lymph Nodes (The INSPIRE Study)

Summary

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PRIMARY OBJECTIVE: I. To compare the clinical complete response rate (cCR) after chemoradiotherapy (chemoRT) with or without MEDI4736 (durvalumab) in node-positive bladder cancer patients. SECONDARY OBJECTIVES: I. To compare the toxicity profile in both arms using the Common Terminology Criteria for...

PRIMARY OBJECTIVE: I. To compare the clinical complete response rate (cCR) after chemoradiotherapy (chemoRT) with or without MEDI4736 (durvalumab) in node-positive bladder cancer patients. SECONDARY OBJECTIVES: I. To compare the toxicity profile in both arms using the Common Terminology Criteria for Adverse Events (CTCAE). II. To estimate the progression-free survival (PFS) in both arms. III. To estimate overall survival (OS) post randomization in both arms. IV. To estimate the bladder intact event free survival (BIEFS) in both arms. V. To estimate the metastasis free survival (MFS) in both arms. VI. To estimate bladder cancer specific survival in both arms. VII. To estimate the complete clinical response duration in both arms. VIII. To estimate salvage cystectomy rates in both arms. EXPLORATORY OBJECTIVE: I. Planned subgroup analyses for clinical outcome (clinical complete response [CR] rate post chemoRT+/- MEDI4736 [durvalumab], MFS, OS, PFS) based on stratification factors. TRANSLATIONAL OBJECTIVE: I. To collect and bank tumor tissue and blood specimens at pre-and post-treatment with chemoRT +/- MEDI4736 to determine predictive or prognostic markers. OUTLINE: STEP 1 - REGISTRATION: Patients are assigned to 1 of 2 arms. ARM A: Patients registered after completion of >= 3 cycles of induction chemotherapy proceed to Step 2 - Randomization. ARM B: Chemotherapy naive patients receive 1 of 4 chemotherapy regimens: gemcitabine hydrochloride intravenously (IV) over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; carboplatin IV over 30-60 minutes on day 1 and gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 every 21 days for 3 cycles; gemcitabine hydrochloride IV over 30-60 minutes on days 1 and 8 and cisplatin IV 30-60 minutes on day 1 every 21 days for 3 cycles; or methotrexate IV over 3 minutes, vinblastine sulfate IV over 3 minutes, doxorubicin hydrochloride IV over 5 minutes, and cisplatin IV over 30-60 minutes on day 1 every 14 days for 3 cycles. Cycles repeat in the absence of disease progression or unacceptable toxicity. STEP 2 - RANDOMIZATION: Patients are randomized to 1 of 2 arms. ARM C: Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. ARM D: Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes twice weekly for 6 weeks; cisplatin IV over 30-60 minutes for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. STEP 3 - REGISTRATION (POST CONCURRENT CHEMORT +/- DURVALUMAB): Patients are assigned to 1 of 2 arms. ARM E: Patients previously randomized to Arm C (chemoradiation and durvalumab) who achieve clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. ARM F: Patients previously randomized to Arm D who achieve clinical CR or clinical benefit, or patients previously randomized to Arm C with no clinical CR or clinical benefit undergo observation. After completion of study treatment, patients are followed up every 12 weeks for 1 year, every 6 months for 1 year, and then annually for 1 year.

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