This phase II trial studies the side effects and how well radiation therapy and durvalumab with or without tremelimumab work in treating participants with bladder cancer that cannot be removed by surgery, has spread to nearby tissue or lymph nodes, or that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and durvalumab with or without tremelimumab will work better in treating participants with bladder cancer.
PRIMARY OBJECTIVES: I. To determine the safety profile of radiation therapy (RT) and durvalumab with or without tremelimumab. (Safety lead-in cohort) II. To determine the median progression-free survival with RT and durvalumab with or without tremelimumab. (Expansion cohort) SECONDARY OBJECTIVES: I. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of local control of irradiated bladder tumor. II. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of pathologic complete response (CR) rate of irradiated bladder tumor. III. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms overall response rate. IV. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of abscopal response rate. V. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of duration of response. VI. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of disease specific survival. VII. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of overall survival. VIII. To further determine the safety and tolerability of RT + durvalumab with or without tremelimumab (expansion cohorts). EXPLORATORY OBJECTIVES: I. To explore the immunologic changes associated with the combination of durvalumab and RT +/- tremelimumab. OUTLINE: Participants are randomized to 1 of 2 regimens. REGIMEN A: Participants receive durvalumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo external beam radiation therapy (EBRT) for 5 fractions beginning on day 8 of course 1. REGIMEN B: Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1. After completion of study treatment, participants are followed up at 8 weeks and then every 12 and 16 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
13
Given IV
Undergo EBRT
Given IV
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria (Safety lead-in cohort)
Observed toxicities will be tabulated using frequencies and percentages based on the CTCAE v 4.03.
Time frame: Up to 90 days after last dose of investigation product
Progression- free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (Expansion cohort)
PFS will be estimated in each study arm by Kaplan-Meier estimate, where PFS is a composite endpoint based on radiologic progression, clinical deterioration or death. A log rank test will be used to test if there is significant difference in PFS between two arms. PFS will be also estimated for localized patients and metastatic patients separately within each arm and stratified log rank test will be used as well.
Time frame: From the first day of the treatment to the first occurrence of disease progression or death, assessed up to 3 years
Local control at the primary irradiate site determined by RECIST v 1.1
The stratified Kaplan Meier method will be used to describe local control for each arm along with their median.
Time frame: Up to 3 years
Pathologic complete rate (CR) of primary irradiated tumor
The point estimate and its 95% confidence interval will be obtained for the pathologic CR rate of the primary irradiated tumor for each arm and for localized patients and metastatic patients separately within each arm. A two-sample proportion test will be used to test if there is significant difference in pathologic CR (pCR) rates between two arms and the CochranMantel-Haenszel test will be used when accounting for the stratified design.
Time frame: Up to 3 years
Overall response rate (ORR) defined as the number (%) of patients with at least 1 visit response of CR or partial response (PR) determined by RECIST v 1.1
The point estimate and its 95% confidence interval of ORR will be obtained by arm and for localized patients and metastatic patients separately within each arm. A two-sample proportion test will be used to test if there is significant difference in ORR rates between two arms and the Cochran-Mantel-Haenszel test will be used when accounting for the stratified design.
Time frame: Up to 3 years
Abscopal response (in patients with metastatic disease) determined by RECIST v 1.1 with response (PR and CR) sites away from the primary irradiated tumor
The point estimate and its 95% confidence interval will be obtained by arm and for localized patients and metastatic patients separately within each arm. Furthermore, a two-sample proportion test will be used to test if there is significant difference between two arms and the Cochran-Mantel-Haenszel test will be used when accounting for the stratified design.
Time frame: Up to 3 years
Duration of response
The stratified Kaplan Meier method will be used to describe the duration of response for each arm along with their median.
Time frame: From date of the first documented response until the first date of documented progression or death, assessed up to 3 years
Disease-specific survival
The stratified Kaplan Meier method will be used to describe disease-specific survival for each arm along with their median.
Time frame: From the date of randomization to the date of death related to treatment and/or disease determined, assessed up to 3 years
Overall survival
The stratified Kaplan Meier method will be used to describe overall survival for each arm along with their median.
Time frame: From the date of randomization to the date of to the date of death due to any cause, assessed up to 3 years
Incidence of adverse events assessed by National Cancer Institute CTCAE v4.0
Will be summarized according to the subjects? baseline grade and maximum grade for each cycle of therapy.
Time frame: Up to 3 years
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