Chemoradiotherapy with or without Atezolizumab in Treating Patients with Localized Muscle Invasive Bladder Cancer

Summary

Objectives

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) 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 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.