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)

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Urinary Bladder Neoplasms
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Estimated): 520
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital ( Site 0220)
    • St Leonards, New South Wales, Australia, 2065
      • GenesisCare North Shore ( Site 0217)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre ( Site 0216)
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health ( Site 0218)
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital ( Site 0223)
• Chile
  • Antofagasta, Chile, 1240000
    • Bradford Hill Norte ( Site 7052)
  • Los Ríos Region
    • Valdivia, Los Ríos Region, Chile, 5112129
      • Oncocentro Valdivia ( Site 7055)
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7500921
      • FALP ( Site 7056)
    • Santiago, Region M. de Santiago, Chile, 8420383
      • Bradfordhill-Clinical Area ( Site 7051)
  • Valparaiso
    • Viña del Mar, Valparaiso, Chile, 2520598
      • ONCOCENTRO APYS-ACEREY ( Site 7054)
• Czechia
  • Olomouc, Czechia, 77900
    • Fakultni nemocnice Olomouc ( Site 0559)
  • Prague, Czechia, 150 06
    • 2. LF UK a FN Motol ( Site 0555)
  • Prague, Czechia, 180 81
    • Nemocnice Na Bulovce ( Site 0556)
• Denmark
  • Capital Region
    • Herlev, Capital Region, Denmark, 2730
      • Herlev og Gentofte Hospital. ( Site 0401)
  • Region Syddanmark
    • Odense, Region Syddanmark, Denmark, 5000
      • Odense Universitetshospital ( Site 0403)
• Estonia
  • Harju
    • Tallinn, Harju, Estonia, 13419
      • North Estonia Medical Centre Foundation ( Site 0081)
  • Tartu
    • Tartu, Tartu, Estonia, 51014
      • Tartu University Hospital ( Site 0079)
• France
  • Paris, France, 75005
    • Institut Curie ( Site 0112)
  • Paris, France, 75018
    • A.P.H. Paris. Hopital Bichat Claude Bernard ( Site 0115)
  • Provence-Alpes-Côte d'Azur Region
    • Avignon, Provence-Alpes-Côte d'Azur Region, France, 84918
      • Institut Sainte Catherine ( Site 0121)
  • Somme
    • Amiens, Somme, France, 80000
      • CHU Amiens Picardie Site Sud Amiens ( Site 0123)
• Guatemala
  • Guatemala City, Guatemala, 01010
    • Centro de Investigaciones Clinicas de Latinoamerica S.A. - CELAN ( Site 0146)
  • Guatemala City, Guatemala, 01010
    • Oncomedica ( Site 0145)
  • Guatemala City, Guatemala, 01015
    • Grupo Medico Angeles ( Site 0143)
  • Guatemala City, Guatemala, 01009
    • MEDI-K ( Site 0142)
  • Quetzaltenango, Guatemala, 09002
    • Centro Medico Integral De Cancerología (CEMIC) ( Site 0144)
• Hungary
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mor Oktato Korhaz ( Site 0091)
  • Borsod-Abauj Zemplen county
    • Miskolc, Borsod-Abauj Zemplen county, Hungary, 3526
      • BAZ Megyei Korhaz. Klinikai Onkologia es Sugarterapias Centrum ( Site 0092)
  • Bács-Kiskun county
    • Kecskemét, Bács-Kiskun county, Hungary, 6000
      • Bacs-Kiskun Megyei Korhaz-Onkoradiologiai Kozpont ( Site 0095)
  • Győr-Moson-Sopron
    • Győr, Győr-Moson-Sopron, Hungary, 9024
      • Petz Aladar Megyei Oktato Korhaz ( Site 0099)
  • Hajdú-Bihar
    • Debrecen, Hajdú-Bihar, Hungary, 4032
      • Debreceni Egyetem Klinikai Kozpont ( Site 0097)
• Israel
  • Beersheba, Israel, 8400000
    • Soroka Medical Center-Oncology ( Site 7031)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus-Oncology Division ( Site 0088)
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center. Ein Kerem ( Site 0086)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center ( Site 7032)
  • Ramat Gan, Israel, 5262000
    • Chaim Sheba Medical Center ( Site 0087)
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 0089)
• Italy
  • Florence, Italy, 50134
    • AOU Careggi ( Site 0191)
  • Macerata, Italy, 62100
    • Ospedale Civile di Macerata ( Site 0190)
  • Milan, Italy, 20132
    • Ospedale San Raffaele. ( Site 0194)
  • Modena, Italy, 41124
    • Azienda Ospedaliero - Universitaria Policlinico di Modena ( Site 0188)
  • Naples, Italy, 80131
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0192)
  • Apulia
    • Bari, Apulia, Italy, 70124
      • IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0193)
  • Lazio
    • Rome, Lazio, Italy, 00128
      • Fondazione Policlinico Universitario Campus Bio-Medico-Radiation Oncology ( Site 7041)
  • Lombardy
    • Milan, Lombardy, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0186)
• Japan
  • Nagasaki, Japan, 852-8501
    • Nagasaki University Hospital ( Site 0600)
  • Tokyo, Japan, 113-8519
    • Institute of Science Tokyo Hospital ( Site 0601)
  • Tokyo, Japan, 113-8677
    • Tokyo Metropolitan Komagome Hospital ( Site 0606)
  • Aomori
    • Hirosaki, Aomori, Japan, 036-8563
      • Hirosaki University Hospital ( Site 0602)
  • Ibaraki
    • Tsukuba, Ibaraki, Japan, 305-8576
      • University of Tsukuba Hospital ( Site 0605)
  • Osaka
    • Takatsuki, Osaka, Japan, 569-8686
      • Osaka Medical and Pharmaceutical University Hospital ( Site 0604)
• Latvia
  • Riga, Latvia, LV-1002
    • Pauls Stradins Clinical University Hospital ( Site 0073)
• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Hospital Kuala Lumpur ( Site 0238)
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre ( Site 0236)
  • Kelantan
    • Kubang Kerian, Kelantan, Malaysia, 16150
      • Hospital Universiti Sains Malaysia ( Site 0237)
  • Pulau Pinang
    • George Town, Pulau Pinang, Malaysia, 10990
      • Hospital Pulau Pinang ( Site 0239)
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Netherlands Cancer Institute (NKI) ( Site 0183)
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Erasmus MC ( Site 0182)
• Poland
  • Lesser Poland Voivodeship
    • Krakow, Lesser Poland Voivodeship, Poland, 31-826
      • Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 0153)
  • Masovian Voivodeship
    • Siedlce, Masovian Voivodeship, Poland, 08-110
      • Mazowiecki Szpital Wojewódzki w Siedlcach ( Site 0154)
  • West Pomeranian Voivodeship
    • Koszalin, West Pomeranian Voivodeship, Poland, 75-581
      • Szpital Wojewodzki im.M.Kopernika. ( Site 0152)
• Portugal
  • Coimbra, Portugal, 3000-075
    • Centro Hospitalar e Universitario de Coimbra ( Site 0306)
  • Lisbon, Portugal, 1449-005
    • Unidade Local de Saude Lisboa Ocidental - Hospital de São Francisco Xavier ( Site 0302)
  • Lisbon, Portugal, 1649-035
    • Unidade Local de Saude de Santa Maria - Hospital de Santa Maria ( Site 0305)
  • Lisbon District
    • Loures, Lisbon District, Portugal, 2674-514
      • Unidade Local de Saude Loures-Odivelas - Hospital Beatriz Angelo ( Site 0303)
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Advance Urology and Laparoscopic Center ( Site 0281)
  • San Juan, Rio Piedras, Puerto Rico, 00935
    • PAN American Center Oncologic ( Site 0280)
• Romania
  • Bucharest, Romania, 013812
    • MEMORIAL HEALTHCARE INTERNATIONAL S.R.L. ( Site 0253)
  • Cluj-Napoca, Romania, 400015
    • Institutul Oncologic-Oncologie Medicala ( Site 0256)
  • Iași, Romania, 700483
    • Institutul Regional de Oncologie Iasi ( Site 0255)
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 407280
      • S.C. Radiotherapy Center Cluj S.R.L ( Site 0252)
    • Cluj-Napoca, Cluj, Romania, 400015
      • Institutul Oncologic Prof.Dr. Ion Chiricuta Cluj-Napoca ( Site 0249)
  • Dolj
    • Craiova, Dolj, Romania, 200542
      • S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 0248)
  • Timiș County
    • Timișoara, Timiș County, Romania, 300239
      • Policlinica Oncomed SRL ( Site 0254)
• South Korea
  • Seoul, South Korea, 02841
    • Korea University Anam Hospital ( Site 0205)
  • Seoul, South Korea, 03722
    • Severance Hospital Yonsei University Health System ( Site 0201)
  • Seoul, South Korea, 05505
    • Asan Medical Center ( Site 0200)
  • Kyonggi-do
    • Gyeonggi-do, Kyonggi-do, South Korea, 10408
      • National Cancer Center ( Site 0202)
    • Seongnam-si, Kyonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital ( Site 0204)
  • Taejon-Kwangyokshi
    • Daejeon, Taejon-Kwangyokshi, South Korea, 35015
      • Chungnam National University Hospital ( Site 0203)
• Spain
  • Seville, Spain, 41013
    • HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO-Medical Oncology ( Site 0106)
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Instituto Catalan de Oncologia - ICO ( Site 0103)
  • Valenciana, Comunitat
    • Valencia, Valenciana, Comunitat, Spain, 46026
      • Hospital La Fe de Valencia ( Site 0105)
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital ( Site 0209)
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital ( Site 0213)
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital ( Site 0208)
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital ( Site 0210)
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital ( Site 0211)
  • Taoyuan, Taiwan, 333
    • Chang Gung Medical Foundation.Linkou Branch ( Site 0212)
  • Tainan
    • Tainan, Tainan, Taiwan, 71004
      • Chi Mei Medical Center ( Site 0215)
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06010
    • University of Health Sciences,Gulhane School of Medicine-Oncology ( Site 0509)
  • Ankara, Turkey (Türkiye), 06100
    • Ankara Universitesi Tip Fakultesi. ( Site 0502)
  • Istanbul, Turkey (Türkiye), 34098
    • Istanbul Uni. Cerrahpasa Tip Fakultesi ( Site 0501)
  • Istanbul, Turkey (Türkiye), 34722
    • Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 0504)
  • Istanbul, Turkey (Türkiye), 34147
    • T.C. Saglik Bakanligi Turkiye Kamu Hastaneleri Kurumu - Baki-Istanbul Bakirkoy Sadi Konuk Training ( Site 0510)
  • Izmir, Turkey (Türkiye), 35100
    • Ege University Medical Faculty ( Site 0508)
  • Trabzon, Turkey (Türkiye), 61080
    • Karadeniz Teknik Universitesi Tip Fakultesi ( Site 0503)
• Ukraine
  • Kyiv, Ukraine, 03115
    • Kyiv City Clinical Oncology Center ( Site 0135)
  • Kyiv, Ukraine, 03022
    • SNPE National Cancer Institute ( Site 0136)
  • Dnipropetrovsk Oblast
    • Dnipro, Dnipropetrovsk Oblast, Ukraine, 49055
      • Clinical oncology dispensary of Dnipro ( Site 0133)
  • Kharkivs’ka Oblast’
    • Kharkiv, Kharkivs’ka Oblast’, Ukraine, 61024
      • Grigoriev Institute for medical Radiology NAMS of Ukraine ( Site 0139)
    • Kharkiv, Kharkivs’ka Oblast’, Ukraine, 61070
      • MNPE Regional Center of Oncology ( Site 0134)
  • Kirovohrad Oblast
    • Kropyvnytskiy, Kirovohrad Oblast, Ukraine, 25011
      • Ukranian Center of TomoTherapy ( Site 0140)
• United Kingdom
  • Darlington, United Kingdom, DL3 6HX
    • Darlington Memorial Hospital NHS Trust ( Site 0446)
  • Denbighshire
    • Rhyl, Denbighshire, United Kingdom, LL18 5UJ
      • Betsi Cadwaladr University Health Board ( Site 0447)
  • Devon
    • Torquay, Devon, United Kingdom, TQ2 7AA
      • South Devon Healthcare Foundation Trust. Torbay Hospital ( Site 0444)
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Royal Preston Hospital ( Site 0449)
  • London, City of
    • London, London, City of, United Kingdom, NW1 2PG
      • University College London Hospitals NHS Foundation Trust ( Site 0445)
    • London, London, City of, United Kingdom, SW3 6JJ
      • The Royal Marsden NHS Foundation Trust. ( Site 0442)
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Nottingham University Hospital NHS Trust ( Site 0250)
• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)
  • Florida
    • Bay Pines, Florida, United States, 33744
      • Bay Pines VA Medical Center ( Site 0055)
    • Orlando, Florida, United States, 32804
      • AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlandoc ( Site 0004)
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute ( Site 0044)
    • Pikeville, Kentucky, United States, 41501
      • Pikeville Medical Center ( Site 0009)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Baltimore VA Medical Center ( Site 0054)
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University ( Site 0003)
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
      • Summit Medical Group Cancer Center ( Site 6008)
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)
  • New York
    • Albany, New York, United States, 12206
      • New York Oncology Hematology P.C ( Site 0024)
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute ( Site 6009)
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital ( Site 0069)
    • New York, New York, United States, 10016
      • New York University Perlmutter Cancer Center ( Site 0001)
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center ( Site 6014)
  • Ohio
    • Cleveland, Ohio, United States, 44111
      • Fairview Hospital-Moll Cancer Center ( Site 6013)
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Main ( Site 0062)
    • Mayfield Heights, Ohio, United States, 44124
      • Cleveland Clinic - Hillcrest Hospital-Hillcrest Hospital Cancer Center ( Site 6012)
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • MidLantic urology ( Site 0070)
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Saint Francis Cancer Center ( Site 0026)
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center ( Site 0002)
  • Texas
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Research ( Site 6010)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute ( Site 6006)
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University - Charleston Area Medical Center ( Site 6003)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and Medical College of Wisconsin ( Site 0022)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Chemotherapy + Radiotherapy; Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.	Drug: Pembrolizumab; 400 mg of IV (intravenous) pembrolizumab once every 6 weeks.; Other Names: MK-3475; KEYTRUDA®; Radiation: Conventional Radiotherapy (Bladder only); 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.; Radiation: Conventional Radiotherapy (Bladder and pelvic nodes); 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.; Radiation: Hypofractionated Radiotherapy (Bladder only); 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.; Drug: Cisplatin; 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.; Drug: Fluorouracil (5-FU); 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.; Drug: Mitomycin C (MMC); MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.; Drug: Gemcitabine; Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.
Placebo Comparator: Placebo + Chemotherapy + Radiotherapy; 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); 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.; Radiation: Conventional Radiotherapy (Bladder and pelvic nodes); 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.; Radiation: Hypofractionated Radiotherapy (Bladder only); 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.; Drug: Cisplatin; 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.; Drug: Fluorouracil (5-FU); 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.; Drug: Mitomycin C (MMC); MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.; Drug: Gemcitabine; Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.; Drug: Placebo to Pembrolizumab; Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.

What is the study measuring?

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 76 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Overall Survival (OS)	Time from randomization to death due to any cause.	Up to approximately 7 years
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 7 years
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 7 years
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 7 years
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 2 years
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 2 years
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 2 years
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 2 years
Time to Cystectomy	Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.	Up to approximately 7 years

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2020
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): November 1, 2031

Study Registration Dates

• First Submitted: January 22, 2020
• First Submitted That Met QC Criteria: January 22, 2020
• First Posted (Actual): January 27, 2020

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Uracil; Pyrimidinones; Platinum Compounds; Quinones; Azirines; Mitomycins; Indolequinones; Gemcitabine; Fluorouracil; Cisplatin; Mitomycin; pembrolizumab
• Other Study ID Numbers: 3475-992; MK-3475-992 (Other Identifier: MSD); 205383 (Registry Identifier: JAPIC-CTI); 2019-004023-20 (EudraCT Number); U1111-1287-4190 (Registry Identifier: UTN); jRCT2080225287 (Registry Identifier: jRCT); 2023-503500-87-00 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No