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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04241185




Registration number
NCT04241185
Ethics application status
Date submitted
22/01/2020
Date registered
27/01/2020

Titles & IDs
Public title
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)
Scientific 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)
Secondary ID [1] 0 0
MK-3475-992
Secondary ID [2] 0 0
3475-992
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Urinary Bladder Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bladder - transitional cell cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pembrolizumab
Treatment: Other - Conventional Radiotherapy (Bladder only)
Treatment: Other - Conventional Radiotherapy (Bladder and pelvic nodes)
Treatment: Other - Hypofractionated Radiotherapy (Bladder only)
Treatment: Drugs - Cisplatin
Treatment: Drugs - Fluorouracil (5-FU)
Treatment: Drugs - Mitomycin C (MMC)
Treatment: Drugs - Gemcitabine
Treatment: Drugs - Placebo to Pembrolizumab

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.

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.


Treatment: Drugs: Pembrolizumab
400 mg of IV (intravenous) pembrolizumab once every 6 weeks.

Treatment: Other: Conventional Radiotherapy (Bladder only)
64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.

Treatment: Other: 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.

Treatment: Other: Hypofractionated Radiotherapy (Bladder only)
55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.

Treatment: Drugs: Cisplatin
35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.

Treatment: Drugs: 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.

Treatment: Drugs: Mitomycin C (MMC)
MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.

Treatment: Drugs: Gemcitabine
Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.

Treatment: Drugs: Placebo to Pembrolizumab
Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Bladder Intact Event-Free Survival (BI-EFS)
Timepoint [1] 0 0
Up to approximately 71 months
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Up to approximately 83 months
Secondary outcome [2] 0 0
Metastasis-Free Survival (MFS)
Timepoint [2] 0 0
Up to approximately 83 months
Secondary outcome [3] 0 0
Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC)
Timepoint [3] 0 0
Up to approximately 83 months
Secondary outcome [4] 0 0
Number of Participants Who Experienced an Adverse Event (AE)
Timepoint [4] 0 0
Up to approximately 83 months
Secondary outcome [5] 0 0
Number of Participants Who Discontinued Study Intervention Due to an AE
Timepoint [5] 0 0
Up to approximately 1 year
Secondary outcome [6] 0 0
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)
Timepoint [6] 0 0
Baseline and up to approximately 83 months
Secondary outcome [7] 0 0
Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
Timepoint [7] 0 0
Baseline and up to approximately 83 months
Secondary outcome [8] 0 0
Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)
Timepoint [8] 0 0
Baseline and up to approximately 83 months
Secondary outcome [9] 0 0
Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)
Timepoint [9] 0 0
Baseline and up to approximately 83 months
Secondary outcome [10] 0 0
Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30
Timepoint [10] 0 0
Up to approximately 83 months
Secondary outcome [11] 0 0
TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30
Timepoint [11] 0 0
Up to approximately 83 months
Secondary outcome [12] 0 0
TTD in Urinary, Bowel, and Sexual Domains of the BCI
Timepoint [12] 0 0
Up to approximately 83 months
Secondary outcome [13] 0 0
TTD in the VAS of the EQ-5D-5L
Timepoint [13] 0 0
Up to approximately 83 months
Secondary outcome [14] 0 0
Time to Cystectomy
Timepoint [14] 0 0
Up to approximately 83 months

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/05/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
10/06/2031
Actual
Sample size
Target
636
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Liverpool Hospital ( Site 0220) - Liverpool
Recruitment hospital [2] 0 0
GenesisCare North Shore ( Site 0217) - St Leonards
Recruitment hospital [3] 0 0
Monash Medical Centre ( Site 0216) - Clayton
Recruitment hospital [4] 0 0
Austin Health ( Site 0218) - Heidelberg
Recruitment hospital [5] 0 0
Sir Charles Gairdner Hospital ( Site 0223) - Nedlands
Recruitment postcode(s) [1] 0 0
2170 - Liverpool
Recruitment postcode(s) [2] 0 0
2065 - St Leonards
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
3084 - Heidelberg
Recruitment postcode(s) [5] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
District of Columbia
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Kentucky
Country [4] 0 0
United States of America
State/province [4] 0 0
Maryland
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
New Jersey
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Ohio
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
South Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Virginia
Country [13] 0 0
United States of America
State/province [13] 0 0
West Virginia
Country [14] 0 0
United States of America
State/province [14] 0 0
Wisconsin
Country [15] 0 0
Chile
State/province [15] 0 0
Los Rios
Country [16] 0 0
Chile
State/province [16] 0 0
Region M. De Santiago
Country [17] 0 0
Chile
State/province [17] 0 0
Valparaiso
Country [18] 0 0
Chile
State/province [18] 0 0
Antofagasta
Country [19] 0 0
Czechia
State/province [19] 0 0
Olomouc
Country [20] 0 0
Czechia
State/province [20] 0 0
Praha 5
Country [21] 0 0
Czechia
State/province [21] 0 0
Praha 8
Country [22] 0 0
Denmark
State/province [22] 0 0
Hovedstaden
Country [23] 0 0
Denmark
State/province [23] 0 0
Syddanmark
Country [24] 0 0
Estonia
State/province [24] 0 0
Harjumaa
Country [25] 0 0
Estonia
State/province [25] 0 0
Tartumaa
Country [26] 0 0
France
State/province [26] 0 0
Provence-Alpes-Cote-d Azur
Country [27] 0 0
France
State/province [27] 0 0
Somme
Country [28] 0 0
France
State/province [28] 0 0
Paris
Country [29] 0 0
Guatemala
State/province [29] 0 0
Guatemala
Country [30] 0 0
Guatemala
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Quetzaltenango
Country [31] 0 0
Hungary
State/province [31] 0 0
Bacs-Kiskun
Country [32] 0 0
Hungary
State/province [32] 0 0
Borsod-Abauj-Zemplen
Country [33] 0 0
Hungary
State/province [33] 0 0
Gyor-Moson-Sopron
Country [34] 0 0
Hungary
State/province [34] 0 0
Debrecen
Country [35] 0 0
Hungary
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Kaposvar
Country [36] 0 0
Israel
State/province [36] 0 0
Be'er Sheva
Country [37] 0 0
Israel
State/province [37] 0 0
Haifa
Country [38] 0 0
Israel
State/province [38] 0 0
Jerusalem
Country [39] 0 0
Israel
State/province [39] 0 0
Petah Tikva
Country [40] 0 0
Israel
State/province [40] 0 0
Ramat Gan
Country [41] 0 0
Israel
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Tel Aviv
Country [42] 0 0
Italy
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Lazio
Country [43] 0 0
Italy
State/province [43] 0 0
Lombardia
Country [44] 0 0
Italy
State/province [44] 0 0
Puglia
Country [45] 0 0
Italy
State/province [45] 0 0
Firenze
Country [46] 0 0
Italy
State/province [46] 0 0
Macerata
Country [47] 0 0
Italy
State/province [47] 0 0
Milano
Country [48] 0 0
Italy
State/province [48] 0 0
Modena
Country [49] 0 0
Italy
State/province [49] 0 0
Napoli
Country [50] 0 0
Japan
State/province [50] 0 0
Aomori
Country [51] 0 0
Japan
State/province [51] 0 0
Ibaraki
Country [52] 0 0
Japan
State/province [52] 0 0
Osaka
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Japan
State/province [53] 0 0
Nagasaki
Country [54] 0 0
Japan
State/province [54] 0 0
Tokyo
Country [55] 0 0
Korea, Republic of
State/province [55] 0 0
Kyonggi-do
Country [56] 0 0
Korea, Republic of
State/province [56] 0 0
Seoul
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Korea, Republic of
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Taejon-Kwangyokshi
Country [58] 0 0
Latvia
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Riga
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Malaysia
State/province [59] 0 0
Kelantan
Country [60] 0 0
Malaysia
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Pulau Pinang
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Malaysia
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Kuala Lumpur
Country [62] 0 0
Netherlands
State/province [62] 0 0
Noord-Holland
Country [63] 0 0
Netherlands
State/province [63] 0 0
Zuid-Holland
Country [64] 0 0
Poland
State/province [64] 0 0
Malopolskie
Country [65] 0 0
Poland
State/province [65] 0 0
Mazowieckie
Country [66] 0 0
Poland
State/province [66] 0 0
Zachodniopomorskie
Country [67] 0 0
Portugal
State/province [67] 0 0
Lisboa
Country [68] 0 0
Portugal
State/province [68] 0 0
Coimbra
Country [69] 0 0
Puerto Rico
State/province [69] 0 0
Ponce
Country [70] 0 0
Puerto Rico
State/province [70] 0 0
San Juan, Rio Piedras
Country [71] 0 0
Romania
State/province [71] 0 0
Cluj
Country [72] 0 0
Romania
State/province [72] 0 0
Dolj
Country [73] 0 0
Romania
State/province [73] 0 0
Timis
Country [74] 0 0
Romania
State/province [74] 0 0
Bucuresti
Country [75] 0 0
Romania
State/province [75] 0 0
Iasi
Country [76] 0 0
Spain
State/province [76] 0 0
Barcelona
Country [77] 0 0
Spain
State/province [77] 0 0
Valenciana, Comunitat
Country [78] 0 0
Spain
State/province [78] 0 0
Sevilla
Country [79] 0 0
Taiwan
State/province [79] 0 0
Tainan
Country [80] 0 0
Taiwan
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Kaohsiung
Country [81] 0 0
Taiwan
State/province [81] 0 0
Taichung
Country [82] 0 0
Taiwan
State/province [82] 0 0
Taipei
Country [83] 0 0
Taiwan
State/province [83] 0 0
Taoyuan
Country [84] 0 0
Turkey
State/province [84] 0 0
Ankara
Country [85] 0 0
Turkey
State/province [85] 0 0
Istanbul
Country [86] 0 0
Turkey
State/province [86] 0 0
Izmir
Country [87] 0 0
Turkey
State/province [87] 0 0
Trabzon
Country [88] 0 0
Ukraine
State/province [88] 0 0
Dnipropetrovska Oblast
Country [89] 0 0
Ukraine
State/province [89] 0 0
Kharkivska Oblast
Country [90] 0 0
Ukraine
State/province [90] 0 0
Kirovohradska Oblast
Country [91] 0 0
Ukraine
State/province [91] 0 0
Kyivska Oblast
Country [92] 0 0
Ukraine
State/province [92] 0 0
Kyiv
Country [93] 0 0
United Kingdom
State/province [93] 0 0
Denbighshire
Country [94] 0 0
United Kingdom
State/province [94] 0 0
Devon
Country [95] 0 0
United Kingdom
State/province [95] 0 0
Lancashire
Country [96] 0 0
United Kingdom
State/province [96] 0 0
London, City Of
Country [97] 0 0
United Kingdom
State/province [97] 0 0
Nottinghamshire
Country [98] 0 0
United Kingdom
State/province [98] 0 0
Darlington

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04241185