Muscle Invasive Bladder Cancer MedDRA version: 20.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: LLT Classification code 10022877 Term: Invasive bladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: PEMBROLIZUMAB
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration uni
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has a histologically confirmed diagnosis of MIBC with predominant urothelial histology (histology and presence of muscle invasion to be confirmed by BICR) obtained via a diagnostic or maximal TURBT performed within 60 days prior to enrollment (signing of ICF). 2. Has clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT of the chest and CTU/MRU of abdomen and pelvis), confirmed by BICR. 3. Has provided tumor specimen to the central vendor to determine PD-L1 status prior to randomization. 4. Has planned and is eligible to receive CRT and one of the protocol-specified radiosensitizing chemotherapy regimens. 5. Has an ECOG performance status of 0, 1, or 2 assessed within 7 days prior to randomization. 6. Demonstrates adequate organ function. All screening laboratory tests should be performed within 14 days prior to randomization. 7. Is male or female, at least 18 years of age, at the time of signing the informed consent. 8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of study intervention. • Refrain from donating sperm PLUS either: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below: ? Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a WOCBP OR - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention. - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. - The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (
Exclusion criteria
Exclusion criteria: 1. Has the presence of diffuse CIS (multiple foci of CIS) throughout the bladder. 2. Has the presence of UC at any site outside of the urinary bladder in the previous 2 years except for Ta/T1/CIS of the upper tract if the patient has undergone a complete nephroureterectomy. 3. Has the presence of any small cell or neuroendocrine component in the tumor tissue sample. 4. Has a known additional malignancy that is progressing or has required active therapy within the past 3 years. 5. Has the presence of bilateral hydronephrosis during the Screening period. 6. Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter. 7. Has received prior pelvic/local radiation therapy or any antineoplastic treatment for MIBC. 8. 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 co-inhibitory T-cell receptor (eg, CTLA-4, OX- 40, CD137). 9. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. 11. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or the selected chemotherapy regimen, and/or any of their excipients. 12. 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 prior to the first dose of study drug. 13. 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). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 15. Has an active infection requiring systemic therapy. 16. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority. 17. 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. 18. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). No TB testing is required unless mandated by local health authority. 19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To compare bladder intact event-free survival in participants from Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy), based on cystoscopy, biopsy with central pathology review (if applicable), urine cytology and radiographic assessment by blinded independent central review.;Secondary Objective: 1. To compare overall survival between Arm A (pembrolizumab + chemoradiotherapy) and Arm B (placebo + chemoradiotherapy). 2. To evaluate rate of metastasis-free survival. 3. To evaluate time to occurrence of non–muscle-invasive bladder cancer (NMIBC). 4. To evaluate the safety and tolerability of pembrolizumab + chemoradiotherapy. 5. To evaluate changes from baseline in health-related quality of life and time to deterioration, using 2 general instruments (European Organization for Research and Treatment of Cancer [EORTC] QoL questionnaire-Core 30 [QLQ-C30], and European Quality of Life [EuroQoL]-5 Dimensions, 5-level Questionnaire [EQ-5D-5L]) and one disease-specific instrument (Bladder Cancer Index [BCI]). 6. To evaluate time to cystectomy. ;Primary end point(s): 1. Bladder Intact Event-Free Survival;Timepoint(s) of evaluation of this end point: 1. Up to approximately 5 years. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall Survival (OS) 2. Metastasis-Free Survival (MFS) 3. Time to Occurrence of Non–Muscle-Invasive Bladder Cancer (NMIBC) 4. Number of Participants Who Experienced One or More Adverse Events (AEs) 5. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) 6. Change from Baseline in Global Health Status (GHS) and Quality of Life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score 7. Change from Baseline in Physical Functioning Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 8. Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI) 9. Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) 10. Time to Deterioration in Global Health Status (GHS) and Quality of Life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score 11. Time to Deterioration in Physical Functioning Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) 12. Time to Deterioration in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI) 13. Time to Deterioration in the Visual Analog Score (VAS) of the European Quality of Life [EuroQoL]-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) ;Timepoint(s) of evaluation of this end point: 1. Up to approximately 5 years. 2. Up to approximately 5 years. 3. Up to approximately 5 years. 4. Up to approximately 5 years. 5. Up to approximately 5 years. 6. Baseline and up to approximately 2 years. 7. Baseline and up to approximately 2 years. 8. Baseline and up to approximately 2 years. 9. Baseline and up to approximately 2 years. 10. Baseline and up to approximat | — |
Countries
Australia, Czech Republic, Denmark, Estonia, France, Guatemala, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Malaysia, Netherlands, Poland, Portugal, Puerto Rico, Romania, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactJames Luke Godwin
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Outcome results
None listed