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)
- Conditions
- Urinary Bladder Neoplasms
- Interventions
- Radiation: Conventional Radiotherapy (Bladder only)Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)Radiation: Hypofractionated Radiotherapy (Bladder only)
- Registration Number
- NCT04241185
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
Researchers are looking for new ways to treat muscle-invasive bladder cancer (MIBC). MIBC is a type of cancer that has not spread from the muscles in the bladder to other parts of the body.
MIBC is treated by having surgery to remove the bladder (cystectomy). Not all people choose to have surgery and want to keep their bladder using other treatments.
Chemoradiotherapy (CRT)- is a type of non-surgical treatment for MIBC which combines Chemotherapy (a treatment with medicine to destroy cancer cells or stop them growing) and Radiation therapy (a treatment that uses beams of intense energy \[like X-rays\] to shrink or get rid of tumors).
Pembrolizumab is an immunotherapy, which is a treatment that helps the immune system fight cancer.
A placebo looks like the study medicine but has no study medicine in it. Using a placebo helps researchers better understand if the study medicine works.
The goal of this study is to learn: 1. If a study medicine pembrolizumab given with Chemoradiotherapy (CRT) can help people live longer without their cancer growing, spreading, or coming back compared to placebo given with CRT. 2.About the safety and how well people tolerate CRT alone or in combination with pembrolizumab.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 520
-
Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology
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Has clinically nonmetastatic bladder cancer (N0M0)
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Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens
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Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
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Demonstrates adequate organ function
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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
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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
- 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 for any reason 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Chemotherapy + Radiotherapy Mitomycin C (MMC) Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Fluorouracil (5-FU) Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Conventional Radiotherapy (Bladder only) Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Conventional Radiotherapy (Bladder and pelvic nodes) Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Mitomycin C (MMC) Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Pembrolizumab Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Hypofractionated Radiotherapy (Bladder only) Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Conventional Radiotherapy (Bladder and pelvic nodes) Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Hypofractionated Radiotherapy (Bladder only) Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Conventional Radiotherapy (Bladder only) Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Fluorouracil (5-FU) Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Placebo to Pembrolizumab Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Cisplatin Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Pembrolizumab + Chemotherapy + Radiotherapy Gemcitabine Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Cisplatin Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator. Placebo + Chemotherapy + Radiotherapy Gemcitabine Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.
- Primary Outcome Measures
Name Time Method Bladder Intact Event-Free Survival (BI-EFS) Up to approximately 76 months 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.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Up to approximately 95 months Time from randomization to death due to any cause.
Metastasis-Free Survival (MFS) Up to approximately 95 months 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.
Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC) Up to approximately 95 months Time to occurrence of low-grade disease, defined as the time from randomization until the development of NMIBC, will be presented.
Number of Participants Who Experienced an Adverse Event (AE) Up to approximately 95 months 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.
Number of Participants Who Discontinued Study Intervention Due to an AE Up to approximately 1 year 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.
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) Baseline and up to approximately 24 months 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.
Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 Baseline and up to approximately 24 months 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.
Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Baseline and up to approximately 24 months 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.
Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI) Baseline and up to approximately 24 months 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.
Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30 Up to approximately 24 months 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.
TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 Up to approximately 24 months 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.
TTD in Urinary, Bowel, and Sexual Domains of the BCI Up to approximately 24 months 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.
TTD in the VAS of the EQ-5D-5L Up to approximately 24 months 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.
Time to Cystectomy Up to approximately 95 months Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.
Trial Locations
- Locations (126)
Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga ( Site 0095)
🇭🇺Budapest, Hungary
Institute of Science Tokyo Hospital ( Site 0601)
🇯🇵Tokyo, Japan
Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)
🇺🇸Washington, District of Columbia, United States
Bay Pines VA Medical Center ( Site 0055)
🇺🇸Bay Pines, Florida, United States
AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlandoc ( Site 0004)
🇺🇸Orlando, Florida, United States
Norton Cancer Institute ( Site 0044)
🇺🇸Louisville, Kentucky, United States
Pikeville Medical Center ( Site 0009)
🇺🇸Pikeville, Kentucky, United States
Baltimore VA Medical Center ( Site 0054)
🇺🇸Baltimore, Maryland, United States
Washington University ( Site 0003)
🇺🇸Saint Louis, Missouri, United States
Summit Medical Group Cancer Center ( Site 6008)
🇺🇸Florham Park, New Jersey, United States
Scroll for more (116 remaining)Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga ( Site 0095)🇭🇺Budapest, Hungary