Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04241185




Registration number
NCT04241185
Ethics application status
Date submitted
22/01/2020
Date registered
27/01/2020
Date last updated
10/05/2024

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
State/province [30] 0 0
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
State/province [35] 0 0
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
State/province [41] 0 0
Tel Aviv
Country [42] 0 0
Italy
State/province [42] 0 0
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
Country [53] 0 0
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
Country [57] 0 0
Korea, Republic of
State/province [57] 0 0
Taejon-Kwangyokshi
Country [58] 0 0
Latvia
State/province [58] 0 0
Riga
Country [59] 0 0
Malaysia
State/province [59] 0 0
Kelantan
Country [60] 0 0
Malaysia
State/province [60] 0 0
Pulau Pinang
Country [61] 0 0
Malaysia
State/province [61] 0 0
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
State/province [80] 0 0
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
This study is designed to assess the antitumor efficacy and safety of pembrolizumab in
combination with chemoradiotherapy (CRT) versus CRT alone in participants with
muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab +
chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact
event-free survival.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04241185
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04241185