Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Muscle-invasive Bladder Cancer (MIBC) (MK-3475-992/KEYNOTE-992)

Study Overview
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Brief Summary
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This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Official Title
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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) (KEYNOTE-992)

Conditions
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Urinary Bladder Neoplasms

Intervention / Treatment
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* Drug: Pembrolizumab
* Radiation: Conventional Radiotherapy (Bladder only)
* Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)
* Radiation: Hypofractionated Radiotherapy (Bladder only)
* Drug: Cisplatin
* Drug: Fluorouracil (5-FU)
* Drug: Mitomycin C (MMC)
* Drug: Gemcitabine
* Drug: Placebo to Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology Has clinically nonmetastatic bladder cancer (N0M0) Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Demonstrates adequate organ function Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of CRT treatment: Refrain from donating sperm 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 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 woman of childbearing potential (WOCBP) 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 the time needed to eliminate each study intervention 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 length of time required to continue contraception for each study intervention is as follows: MK-3475 - 120 days and CRT - 180 days Exclusion Criteria: 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 except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy Has the presence of bilateral hydronephrosis 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 muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted. Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137]) 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 medication 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). 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 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 or known active hepatitis C virus 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Chemotherapy + Radiotherapy<br>Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. | Drug: Pembrolizumab<br>* 400 mg of IV (intravenous) pembrolizumab once every 6 weeks.<br>* Other names: KEYTRUDA®;Radiation: Conventional Radiotherapy (Bladder only)<br>* 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.<br>Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)<br>* 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.<br>Radiation: Hypofractionated Radiotherapy (Bladder only)<br>* 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.<br>Drug: Cisplatin<br>* 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.<br>Drug: Fluorouracil (5-FU)<br>* 5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.<br>Drug: Mitomycin C (MMC)<br>* MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.<br>Drug: Gemcitabine<br>* Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.<br>|
| Placebo Comparator: Placebo + Chemotherapy + Radiotherapy<br>Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. | Radiation: Conventional Radiotherapy (Bladder only)<br>* 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.<br>Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)<br>* 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.<br>Radiation: Hypofractionated Radiotherapy (Bladder only)<br>* 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.<br>Drug: Cisplatin<br>* 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.<br>Drug: Fluorouracil (5-FU)<br>* 5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.<br>Drug: Mitomycin C (MMC)<br>* MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.<br>Drug: Gemcitabine<br>* Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.<br>Drug: Placebo to Pembrolizumab<br>* Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bladder Intact Event-Free Survival (BI-EFS) | BI-EFS is defined as the time from randomization to any of the following events: residual/recurrent MIBC post-chemoradiotherapy (CRT), nodal or distant metastases as assessed by computerized tomography (CT) and CT urography (CTU) or magnetic resonance urography (MRU) per blinded independent central review (BICR) and/or biopsy results assessed by central pathology review, radical cystectomy, or death due to any cause. If biopsy is not feasible due to participant safety, the imaging alone will be sufficient. The BI-EFS for all participants will be presented. | Up to approximately 71 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from randomization to death due to any cause. | Up to approximately 83 months | 
| Metastasis-Free Survival (MFS) | MFS is defined as the time from randomization to the first documented occurrence of nodal or distant metastases as assessed by CT and CTU or MRU 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. | Up to approximately 83 months | 
| Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC) | Time to occurrence of low-grade disease, defined as the time from randomization until the development of NMIBC, will be presented. | Up to approximately 83 months | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented. | Up to approximately 83 months | 
| Number of Participants Who Discontinued Study Intervention Due to an AE | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 1 year | 
| Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented. | Baseline and up to approximately 83 months | 
| Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented. | Baseline and up to approximately 83 months | 
| Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI) | The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. The change from baseline in the combined scores of the urinary, bowel, and sexual domains of the BCI will be presented. | Baseline and up to approximately 83 months | 
| Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) | The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being the worst health you can imagine and 100 being the best health you can imagine. The change from baseline in EQ-5D-5L VAS will be presented. | Baseline and up to approximately 83 months | 
| Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30 | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation. | Up to approximately 83 months | 
| TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. TTD in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score is defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores. | Up to approximately 83 months | 
| TTD in Urinary, Bowel, and Sexual Domains of the BCI | The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. TTD in BCI is defined as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule. | Up to approximately 83 months | 
| TTD in the VAS of the EQ-5D-5L | The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being the worst health you can imagine and 100 being the best health you can imagine. TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule. | Up to approximately 83 months | 
| Time to Cystectomy | Time to cystectomy is defined as time from a participant's randomization to date of cystectomy. | Up to approximately 83 months |