A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to
Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With
Chemoradiotherapy (CRT) versus CRT Alone in Participants with Muscle-invasive Bladder Cancer (MIBC)
Chemoradiotherapy +/- pembrolizumab in participants with MIBC
-Has a histologically confirmed initial diagnosis of MIBC with predominant urothelial histology (histology and presence of muscle invasion to be confirmed by blinded independent central review [BICR]) obtained via a diagnostic or maximal TURBT
-Has clinically nonmetastatic bladder cancer (N0M0) determined by imaging and verified by BICR
-Has planned and is eligible to receive CRT and one of the protocol-specified radiosensitizing chemotherapy regimens
-Has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2
-Demonstrates adequate organ function
-Male participants are eligible to participate if they agree to use a method of birth control as detailed in the protocol during the intervention period and for at least 90 days after the last CRT treatment
-A female participant is eligible to participate if she is not pregnant or breastfeeding, and if she agrees to use a method of birth control as detailed in the protocol and agrees not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during the intervention period and for at least 180 days after the last CRT treatment/at least 120 days after the last dose of MK-3475
-Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder
-Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years
-Has a known additional malignancy that is progressing or has required active therapy within the past 3 years
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) who have undergone potentially curative therapy are not excluded.
-Has the presence of bilateral hydronephrosis during the Screening period
-Has limited bladder function with frequency of small amounts of urine (<30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter
-Has received prior pelvic/local radiation therapy or any antineoplastic treatment for MIBC
-Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
-Has received a live vaccine within 30 days before the first dose of study medication
-Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention
-Has known severe hypersensitivity (>=Grade 3) to the selected chemotherapy regimen and/or any of their excipients and excipients of pembrolizumab
-Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication
-Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
-Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
-Has an active infection requiring systemic therapy
-Has a known history of human immunodeficiency virus (HIV) infection
-Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
-Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
-Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
-Has had an allogenic tissue/solid organ transplant
18age old over
No limit
Both
Muscle-invasive Bladder Cancer (MIBC)
Participants will receive either pembrolizumab 400 mg (Active Comparator) or placebo (Placebo Comparator) Q6W.
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.
The radiosensitizing chemotherapy will consist of 1 of 3 regimens:
-Cisplatin monotherapy (35 mg/m2 IV weekly, concurrent with radiation therapy, 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 radiation therapy), or
-Gemcitabine monotherapy (27 mg/m2 IV twice weekly, concurrent with radiation therapy, planned 12 doses).
BI-EFS: The time from randomization to the first documented occurrence of any of the following events:
-Residual/recurrent MIBC (as assessed by cystoscopy, cytology, and biopsy results by central pathology review)
-Nodal or distant metastases as assessed by CT of chest and CTU or MRU of the abdomen and pelvis per BICR and/or biopsy results assessed by central pathology review. If biopsy is not feasible due to participant safety, the imaging alone will be sufficient.
-Radical cystectomy
-Death from any cause
-OS: The time from randomization to death from any cause
-MFS: The time from randomization to the first documented evidence of nodal or distant metastases
-The time to occurrence of non-muscle-invasive bladder cancer (NMIBC)
-Number of participants who experienced an Adverse Event (AE)
-Number of participants who discontinued study intervention due to an AE
-Change from baseline in:
-The global health status/quality of life of the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire-Core 30 (QLQ-C30) (Items 29 and 30)
-The physical functioning scale of the EORTC QLQ-C30
-Bladder Cancer Index (BCI): urinary, bowel, and sexual domains
-EQ-5D-5L VAS
-The time to deterioration, defined as the time from baseline to first onset of patient-reported outcome deterioration based on established minimal important differences threshold, in:
-The global health status/quality of life of the EORTC QLQ-C30
-The physical functioning scale of the EORTC QLQ-C30
-BCI: urinary, bowel, and sexual domains
-EQ-5D-5L VAS
-Time from randomization to the date of cystectomy
MSD K.K.
Institutional Review Board of Hirosaki University Hospital
