This phase III trial studies how well chemotherapy and radiation therapy work with or without atezolizumab in treating patients with localized muscle invasive bladder cancer. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as gemcitabine, cisplatin, fluorouracil and mitomycin-C, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with radiation therapy may kill more tumor cells. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab with radiation therapy and chemotherapy may work better in treating patients with localized muscle invasive bladder cancer compared to radiation therapy and chemotherapy without atezolizumab.
PRIMARY OBJECTIVE: I. To compare bladder intact event-free survival (BI-EFS) for concurrent chemoradiation therapy (CRT) with and without atezolizumab in localized muscle invasive bladder cancer (MIBC). SECONDARY OBJECTIVES: I. To compare overall survival between the two arms. II. To compare modified bladder intact event-free survival including cancer related death between arms. III. To compare complete and partial pathologic response between arms at 3 months after completing chemoradiation therapy. IV. To estimate metastases-free survival by arm. V. To compare the qualitative and quantitative adverse events from each arm. VI. To estimate the rate of non-muscle invasive bladder cancer recurrence by arm. VII. To estimate the rate of salvage cystectomy and reasons for cystectomy by arm. VIII. To compare mean patient-reported global quality of life (QOL) at week 54 using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 Global Health Status (GHS) subscale score between patients with localized muscle-invasive bladder cancer randomized to chemoradiation with versus (vs.) without atezolizumab. TRANSLATIONAL MEDICINE OBJECTIVES: I. To test the hypothesis that a panel of validated biomarkers of concurrent CRT involving nuclear MRE11, impaired deoxyribonucleic acid damage response (DDR) function and tumor subtyping will be prognostic for BI-EFS among patients receiving either concurrent CRT or chemoimmuno-radiotherapy (CIRT) of the primary tumor. II. To test the hypothesis that tumor total mutation burden, neoantigen burden, infiltrating immune response, PD-L1 expression and T cell response are associated with augmented response after concurrent CIRT. III. To bank urine specimens for future use. PATIENT-REPORTED OUTCOMES (PROs) OBJECTIVES: I. To compare mean patient-reported global QOL as measured by the EORTC QLQ-C30 Global Health Status subscale scores at week 54 between patients with localized muscle-invasive bladder cancer randomized to chemoradiation with vs. without atezolizumab. (Primary) II. To compare mean patient-reported bowel symptoms at each assessment time by arm using the Expanded Prostate Cancer Index Composite (EPIC) Bowel Assessment from the Expanded Prostate Index, the bladder-specific supplement to the QLQ-C30, the EORTC QLQ-Muscle Invasive Bladder Cancer (BLM30), the Physical Functioning subscale of the EORTC QLQ-C30, and overall health status using the EuroQol Five Dimension Five Level Scale (EQ-5D-5L). (Exploratory) III. To compare longitudinal change over time by arm in patient-reported global QOL using the EORTC QLQ-C30, the Bowel Domain of the Expanded Prostate Index (EPIC Bowel Assessment), the bladder-specific supplement to the QLQ-C30, the EORTC QLQ-BLM30, the Physical Functioning subscale of the EORTC QLQ-C30, and overall health status using the EQ-5D-5L. (Exploratory) OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo radiation therapy (RT) (3 dimensional \[D\] CRT or intensity-modulated radiation therapy \[IMRT\]) daily Monday-Friday for up to 7-8 weeks. Patients also receive chemotherapy based on physician's choice of gemcitabine intravenously (IV) twice weekly for 6 weeks concurrent with RT, or cisplatin IV weekly for 6 weeks concurrent with RT, or fluorouracil IV on same days as doses 1-5 and 16-20 of radiation therapy and mitomycin IV on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. Patients also undergo a transurethral resection of bladder tumor (TURBT) at randomization and week 18 as well as cystoscopy at randomization, at weeks 18, 30, 42, 54, then every 3 months through year 2, followed by every 6 months through year 5 and computed tomography (CT) or magnetic resonance imaging (MRI) at randomization, at weeks 18, 30, 42, 54, then every 6 months through year 2, followed by every 12 months through year 5. ARM II: Patients undergo RT (3DCRT or IMRT) daily Monday-Friday for up to 7-8 weeks and receive chemotherapy based on physician's choice as in Arm I. Patients also receive atezolizumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a TURBT with bladder biopsy at randomization and week 18 as well as cystoscopy at randomization, at weeks 18, 30, 42, 54, then every 3 months through year 2, followed by every 6 months through year 5 and CT or MRI at randomization, at weeks 18, 30, 42, 54, then every 6 months through year 2, followed by every 12 months through year 5. After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
475
Given IV
Undergo a bladder biopsy
Given IV
Undergo CT or MRI
Undergo a cystoscopy
Given IV
Given IV
Undergo CT or MRI
Given IV
Ancillary studies
Undergo 3DCRT or IMRT
Ancillary studies
Undergo a TURBT
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Banner University Medical Center - Tucson
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Sutter Auburn Faith Hospital
Auburn, California, United States
Bladder intact event-free survival (BI-EFS)
At each time point, futility will be evaluated, and in the latter two analyses, efficacy will also be evaluated as specified. The final BI-EFS intent-to-treat analysis will be conducted using a stratified logrank test stratifying on stratification factors, and testing treatment at the one-sided significance level of 0.022 to account for multiple interim testing. The hazard ratio (HR) will be estimated using a stratified Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median BI-EFS for each treatment arm.
Time frame: From the date of randomization to the first documentation of a BI-EFS event, assessed up to 5 years
Overall survival (OS)
Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS.
Time frame: From date of randomization to death from any cause, assessed up to 5 years
Modified bladder intact event-free survival (mBI-EFS)
Analysis of modified BI-EFS, i.e., a sensitivity analysis of BI-EFS, where bladder cancer event is defined as histologically proven presence of muscle invasive bladder cancer, clinical evidence of nodal or metastatic disease, radical cystectomy, or death within 90 days of receiving protocol specified treatment, will also be conducted.
Time frame: From date of randomization to the first documentation of a mBI-EFS event, assessed within 90 days
Biopsy response
The Cochran-Mantel-Haenszel statistic will be used with modified ridit scores to evaluate the biopsy outcomes of complete response versus (vs.) down-staging vs. no response for the two treatment arms.
Time frame: At 18 weeks
Complete response duration
For the subset of patients who achieve a complete response during the week 18 biopsy window, complete response duration is defined from the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause. Will be analyzed using a similar method as for BI-EFS.
Time frame: From the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause, assessed at 18 weeks
Progression-free survival
Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS.
Time frame: From date of randomization to first radiologic or histologic evidence of local progression, nodal or distant metastasis, or death due to any cause, assessed up to 5 years
Metastasis-free survival
Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS.
Time frame: From date of randomization to first radiologic or histologic evidence of metastatic disease or death due to any cause, assessed up to 5 years
Cancer-specific survival
Time frame: From date of randomization to date of death due to bladder cancer, assessed up to 5 years
Quality of life
Assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ)-C30. Will be examined using linear mixed models with patient considered as the random effect. The baseline physical function score and the stratification factors will be included in the regression model as adjustment covariates.
Time frame: Baseline up to 5 years
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Sutter Cancer Centers Radiation Oncology Services-Auburn
Auburn, California, United States
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
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Carmichael, California, United States
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Carmichael, California, United States
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