Perlmutter Cancer Center

This is a Phase 3, randomized, placebo-controlled, parallel-group, multi-site, double-blind (with in-house blinding) study of pembrolizumab + CRT versus placebo + CRT in participants with MIBC (T2-T4aN0M0) who are deemed eligible for and have elected to be treated with CRT (Section 5.1). Approximately 636 participants with previously untreated MIBC who have elected to be treated with CRT will be randomized. A biopsy demonstrating MIBC must have been performed within 60 days prior to enrolling into the study (signing the ICF), and tumor tissue must be available for central pathology review (to confirm histology and the presence of muscle invasion, and for evaluation of PD-L1 status) prior to randomization. A maximal TURBT to remove all resectable/visible disease must occur prior to randomization; this may have occurred prior to enrollment (within 60 days prior to signing the ICF), or may be performed during Screening prior to randomization after confirmation of eligibility. All participants will also undergo baseline screening imaging (CTU or MRU of the abdomen and pelvis and a CT of the chest) for clinical staging (reviewed by BICR) prior to randomization to confirm eligibility. The radiation treatment plan must also be submitted for central review prior to randomization. Eligible participants will be randomized in a 1:1 ratio to receive CRT with either pembrolizumab (Arm A) or placebo (Arm B). Randomization will be stratified based on the following factors: - ECOG PS of 0 & 1 versus 2 - PD-L1 CPS <10 versus =10 - T stage: T2 versus T3 and T4 - US versus EU versus Rest-of-the-World All participants will receive CRT. The radiotherapy will consist of 1 of 3 regimens based upon local standards of care: - Conventional radiotherapy to the bladder consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks, - Conventional radiotherapy to the bladder (including pelvic nodes) consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks, or - Hypofractionated radiotherapy to the bladder consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks. Details related to the required equipment, treatment planning, and site credentialing with regards to radiotherapy are contained within the Radiotherapy Guidelines and the Radiotherapy Quality Assurance Manual. The radiosensitizing chemotherapy will consist of 1 of 3 regimens: - Cisplatin monotherapy (35 mg/m2 IV weekly, concurrent with RT, planned 6 doses) - 5-FU+MMC (500 mg/m2 on Days 1 to 5 and Days 22 to 26 and MMC 12 mg/m2 on Day 1, concurrent with RT), or - Gemcitabine monotherapy (27 mg/m2 IV twice weekly, concurrent with RT, planned 12 doses). The Investigator’s choice of chemotherapy must be specified prior to randomization. The use of gemcitabine monotherapy will be capped at a maximum of approximately 20% of participants, as this is not a routine standard of care in all of the countries that treat patients with MIBC using CRT. Participants will receive either pembrolizumab or placebo Q6W for up to a maximum of 9 doses (approximately 1 year total). Treatment will be discontinued for the reasons specified in Section 7.1.