Clinical trial NCT04241185: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Urinary Bladder Neoplasms
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-01-27
Enrollment: 520
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Bladder Intact Event-Free Survival (BI-EFS)
timeFrame: Up to approximately 76 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 95 months
measure: Metastasis-Free Survival (MFS)
timeFrame: Up to approximately 95 months
measure: Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC)
timeFrame: Up to approximately 95 months
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 95 months
measure: Number of Participants Who Discontinued Study Intervention Due to an AE
timeFrame: Up to approximately 1 year
measure: 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)
timeFrame: Baseline and up to approximately 24 months
measure: Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
timeFrame: Baseline and up to approximately 24 months
measure: Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
timeFrame: Baseline and up to approximately 24 months
measure: Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
timeFrame: Baseline and up to approximately 24 months
measure: Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30
timeFrame: Up to approximately 24 months
measure: TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
timeFrame: Up to approximately 24 months
measure: TTD in Urinary, Bowel, and Sexual Domains of the BCI
timeFrame: Up to approximately 24 months
measure: TTD in the VAS of the EQ-5D-5L
timeFrame: Up to approximately 24 months
measure: Time to Cystectomy
timeFrame: Up to approximately 95 months
Other outcomes:
Locations:
city: Washington
country: United States
facility: Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)
state: District of Columbia
city: Bay Pines
country: United States
facility: Bay Pines VA Medical Center ( Site 0055)
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlandoc ( Site 0004)
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute ( Site 0044)
state: Kentucky
city: Pikeville
country: United States
facility: Pikeville Medical Center ( Site 0009)
state: Kentucky
city: Baltimore
country: United States
facility: Baltimore VA Medical Center ( Site 0054)
state: Maryland
city: Saint Louis
country: United States
facility: Washington University ( Site 0003)
state: Missouri
city: Florham Park
country: United States
facility: Summit Medical Group Cancer Center ( Site 6008)
state: New Jersey
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)
state: New Jersey
city: Albany
country: United States
facility: New York Oncology Hematology P.C ( Site 0024)
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute ( Site 6009)
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital ( Site 0069)
state: New York
city: New York
country: United States
facility: New York University Perlmutter Cancer Center ( Site 0001)
state: New York
city: Cleveland
country: United States
facility: Fairview Hospital-Moll Cancer Center ( Site 6013)
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Main ( Site 0062)
state: Ohio
city: Mayfield Heights
country: United States
facility: Cleveland Clinic - Hillcrest Hospital-Hillcrest Hospital Cancer Center ( Site 6012)
state: Ohio
city: Bala-Cynwyd
country: United States
facility: MidLantic urology ( Site 0070)
state: Pennsylvania
city: Greenville
country: United States
facility: Saint Francis Cancer Center ( Site 0026)
state: South Carolina
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center ( Site 0002)
state: South Carolina
city: San Antonio
country: United States
facility: Urology San Antonio Research ( Site 6010)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 6006)
state: Virginia
city: Charleston
country: United States
facility: West Virginia University - Charleston Area Medical Center ( Site 6003)
state: West Virginia
city: Milwaukee
country: United States
facility: Froedtert and Medical College of Wisconsin ( Site 0022)
state: Wisconsin
city: Liverpool
country: Australia
facility: Liverpool Hospital ( Site 0220)
state: New South Wales
city: St Leonards
country: Australia
facility: GenesisCare North Shore ( Site 0217)
state: New South Wales
city: Clayton
country: Australia
facility: Monash Medical Centre ( Site 0216)
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health ( Site 0218)
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital ( Site 0223)
state: Western Australia
city: Valdivia
country: Chile
facility: Oncocentro Valdivia ( Site 7055)
state: Los Rios
city: Santiago
country: Chile
facility: FALP ( Site 7056)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 7051)
state: Region M. De Santiago
city: Viña del Mar
country: Chile
facility: ONCOCENTRO APYS-ACEREY ( Site 7054)
state: Valparaiso
city: Antofagasta
country: Chile
facility: Bradford Hill Norte ( Site 7052)
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc ( Site 0559)
city: Praha 5
country: Czechia
facility: 2. LF UK a FN Motol ( Site 0555)
city: Praha 8
country: Czechia
facility: Nemocnice Na Bulovce ( Site 0556)
city: Herlev
country: Denmark
facility: Herlev og Gentofte Hospital. ( Site 0401)
state: Hovedstaden
city: Odense
country: Denmark
facility: Odense Universitetshospital ( Site 0403)
state: Syddanmark
city: Tallin
country: Estonia
facility: North Estonia Medical Centre Foundation ( Site 0081)
state: Harjumaa
city: Tartu
country: Estonia
facility: Tartu University Hospital ( Site 0079)
state: Tartumaa
city: Avignon
country: France
facility: Institut Sainte Catherine ( Site 0121)
state: Provence-Alpes-Cote-d Azur
city: Amiens
country: France
facility: CHU Amiens Picardie Site Sud Amiens ( Site 0123)
state: Somme
city: Paris
country: France
facility: Institut Curie ( Site 0112)
city: Paris
country: France
facility: A.P.H. Paris. Hopital Bichat Claude Bernard ( Site 0115)
city: Guatemala
country: Guatemala
facility: Centro de Investigaciones Clinicas de Latinoamerica S.A. - CELAN ( Site 0146)
city: Guatemala
country: Guatemala
facility: Oncomedica ( Site 0145)
city: Guatemala
country: Guatemala
facility: Grupo Medico Angeles ( Site 0143)
city: Guatemala
country: Guatemala
facility: Medi-K Cayala ( Site 0142)
city: Quetzaltenango
country: Guatemala
facility: Centro Medico Integral De Cancerología (CEMIC) ( Site 0144)
city: Miskolc
country: Hungary
facility: BAZ Megyei Korhaz. Klinikai Onkologia es Sugarterapias Centrum ( Site 0092)
state: Borsod-Abauj-Zemplen
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz ( Site 0099)
state: Gyor-Moson-Sopron
city: Budapest
country: Hungary
facility: Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga ( Site 0095)
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont ( Site 0097)
city: Kaposvar
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz ( Site 0091)
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center-Oncology ( Site 7031)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology Division ( Site 0088)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center. Ein Kerem ( Site 0086)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center ( Site 7032)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 0087)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 0089)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Campus Bio-Medico-Radiation Oncology ( Site 7041)
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0186)
state: Lombardia
city: Bari
country: Italy
facility: IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0193)
state: Puglia
city: Firenze
country: Italy
facility: AOU Careggi ( Site 0191)
city: Macerata
country: Italy
facility: Ospedale Civile di Macerata ( Site 0190)
city: Milano
country: Italy
facility: Ospedale San Raffaele ( Site 0194)
city: Modena
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico di Modena ( Site 0188)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0192)
city: Hirosaki
country: Japan
facility: Hirosaki University Hospital ( Site 0602)
state: Aomori
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital ( Site 0605)
state: Ibaraki
city: Takatsuki
country: Japan
facility: Osaka Medical and Pharmaceutical University Hospital ( Site 0604)
state: Osaka
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital ( Site 0600)
city: Tokyo
country: Japan
facility: Institute of Science Tokyo Hospital ( Site 0601)
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Komagome Hospital ( Site 0606)
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center ( Site 0202)
state: Kyonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital ( Site 0204)
state: Kyonggi-do
city: Songpagu
country: Korea, Republic of
facility: Asan Medical Center ( Site 0200)
state: Seoul
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital ( Site 0203)
state: Taejon-Kwangyokshi
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital ( Site 0205)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0201)
city: Riga
country: Latvia
facility: Pauls Stradins Clinical University Hospital ( Site 0073)
city: Kubang Kerian
country: Malaysia
facility: Hospital Universiti Sains Malaysia ( Site 0237)
state: Kelantan
city: Penang
country: Malaysia
facility: Hospital Pulau Pinang ( Site 0239)
state: Pulau Pinang
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur ( Site 0238)
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre ( Site 0236)
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute (NKI) ( Site 0183)
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus MC ( Site 0182)
state: Zuid-Holland
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 0153)
state: Malopolskie
city: Siedlce
country: Poland
facility: Mazowiecki Szpital Wojewódzki w Siedlcach ( Site 0154)
state: Mazowieckie
city: Koszalin
country: Poland
facility: Szpital Wojewodzki im. Mikolaja Kopernika ( Site 0152)
state: Zachodniopomorskie
city: Loures
country: Portugal
facility: Unidade Local de Saude Loures-Odivelas - Hospital Beatriz Angelo ( Site 0303)
state: Lisboa
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitario de Coimbra ( Site 0306)
city: Lisboa
country: Portugal
facility: Unidade Local de Saude Lisboa Ocidental - Hospital de São Francisco Xavier ( Site 0302)
city: Lisboa
country: Portugal
facility: Unidade Local de Saude de Santa Maria - Hospital de Santa Maria ( Site 0305)
city: Ponce
country: Puerto Rico
facility: Advance Urology and Laparoscopic Center ( Site 0281)
city: San Juan, Rio Piedras
country: Puerto Rico
facility: PAN American Center Oncologic ( Site 0280)
city: Cluj Napoca
country: Romania
facility: Institutul Oncologic Prof.Dr. Ion Chiricuta Cluj-Napoca ( Site 0249)
state: Cluj
city: Cluj-Napoca
country: Romania
facility: S.C. Radiotherapy Center Cluj S.R.L ( Site 0252)
state: Cluj
city: Craiova
country: Romania
facility: S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 0248)
state: Dolj
city: Timisoara
country: Romania
facility: Policlinica Oncomed SRL ( Site 0254)
state: Timis
city: Bucuresti
country: Romania
facility: MEMORIAL HEALTHCARE INTERNATIONAL S.R.L. ( Site 0253)
city: Cluj
country: Romania
facility: Institutul Oncologic-Oncologie Medicala ( Site 0256)
city: Iasi
country: Romania
facility: Institutul Regional de Oncologie Iasi ( Site 0255)
city: L Hospitalet De Llobregat
country: Spain
facility: Instituto Catalan de Oncologia - ICO ( Site 0103)
state: Barcelona
city: Valencia
country: Spain
facility: Hospital La Fe de Valencia ( Site 0105)
state: Valenciana, Comunitat
city: Sevilla
country: Spain
facility: HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO-Medical Oncology ( Site 0106)
city: Ankara
country: Turkey
facility: University of Health Sciences,Gulhane School of Medicine-Oncology ( Site 0509)
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi. ( Site 0502)
city: Istanbul
country: Turkey
facility: Istanbul Uni. Cerrahpasa Tip Fakultesi ( Site 0501)
city: Istanbul
country: Turkey
facility: T.C. Saglik Bakanligi Turkiye Kamu Hastaneleri Kurumu - Baki-Istanbul Bakirkoy Sadi Konuk Training (
city: Istanbul
country: Turkey
facility: Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 0504)
city: Izmir
country: Turkey
facility: Ege University Medical Faculty ( Site 0508)
city: Trabzon
country: Turkey
facility: Karadeniz Teknik Universitesi Tip Fakultesi ( Site 0503)
city: Dnipro
country: Ukraine
facility: Clinical oncology dispensary of Dnipro ( Site 0133)
state: Dnipropetrovska Oblast
city: Kharkiv
country: Ukraine
facility: Grigoriev Institute for medical Radiology NAMS of Ukraine ( Site 0139)
state: Kharkivska Oblast
city: Kharkiv
country: Ukraine
facility: MNPE Regional Center of Oncology ( Site 0134)
state: Kharkivska Oblast
city: Kropyvnytskiy
country: Ukraine
facility: Ukranian Center of TomoTherapy ( Site 0140)
state: Kirovohradska Oblast
city: Kyiv
country: Ukraine
facility: SNPE National Cancer Institute ( Site 0136)
state: Kyivska Oblast
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Oncology Center ( Site 0135)
city: Rhyl
country: United Kingdom
facility: Betsi Cadwaladr University Health Board ( Site 0447)
state: Denbighshire
city: Torquay
country: United Kingdom
facility: South Devon Healthcare Foundation Trust. Torbay Hospital ( Site 0444)
state: Devon
city: Preston
country: United Kingdom
facility: Royal Preston Hospital ( Site 0449)
state: Lancashire
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust ( Site 0445)
state: London, City Of
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust. ( Site 0442)
state: London, City Of
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital NHS Trust ( Site 0250)
state: Nottinghamshire
city: Darlington
country: United Kingdom
facility: Darlington Memorial Hospital NHS Trust ( Site 0446)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: