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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT04241185
Ethics application status
Date submitted
22/01/2020
Date registered
27/01/2020
Date last updated
20/04/2021

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) - 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 post-CRT, radical cystectomy, or death due to any cause. The BI-EFS for all participants will be presented.
Timepoint [1] 0 0
Up to approximately 71 months
Secondary outcome [1] 0 0
Overall Survival (OS) - Time from randomization to death due to any cause.
Timepoint [1] 0 0
Up to approximately 83 months
Secondary outcome [2] 0 0
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 computerized tomography (CT) or magnetic resonance imaging (MRI) per blinded independent central review (BICR) and/or biopsy results assessed by central pathology review. If biopsy is not feasible due to participant safety, CT/MRI alone will be sufficient.
Timepoint [2] 0 0
Up to approximately 83 months
Secondary outcome [3] 0 0
Time to Cystectomy - Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.
Timepoint [3] 0 0
Up to approximately 83 months
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Up to approximately 83 months
Secondary outcome [5] 0 0
Number of Participants Who Experienced One or More Adverse Events (AEs) - 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.
Timepoint [5] 0 0
Up to approximately 83 months
Secondary outcome [6] 0 0
Number of Participants Who Discontinued Study Intervention Due to 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 discontinue study treatment due to an AE will be presented.
Timepoint [6] 0 0
Up to approximately 1 year
Secondary outcome [7] 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) - 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.
Timepoint [7] 0 0
Baseline and up to approximately 83 months
Secondary outcome [8] 0 0
Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (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.
Timepoint [8] 0 0
Baseline and up to approximately 83 months
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Baseline and up to approximately 83 months
Secondary outcome [10] 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) - 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.
Timepoint [10] 0 0
Baseline and up to approximately 83 months
Secondary outcome [11] 0 0
Time to Deterioration (TTD) 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. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation.
Timepoint [11] 0 0
Up to approximately 83 months
Secondary outcome [12] 0 0
Time to Deterioration (TTD) in Physical Functioning (Items 1-5) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (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. TTD in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score is defined as the time from baseline (at randomization) to the first onset of a =10-point decrease with confirmation by the subsequent visit of a =10-point decrease in physical functioning Items 1 to 5 scale scores.
Timepoint [12] 0 0
Up to approximately 83 months
Secondary outcome [13] 0 0
Time to Deterioration (TTD) 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. TTD in BCI is defined as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule.
Timepoint [13] 0 0
Up to approximately 83 months
Secondary outcome [14] 0 0
Time to Deterioration (TTD) 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". TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule.
Timepoint [14] 0 0
Up to approximately 83 months

Eligibility
Key inclusion criteria
- Has a histologically confirmed diagnosis of MIBC with predominant urothelial histology

- Has clinically non-metastatic 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 180 days after the last dose of study
intervention:

- 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 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
Minimum age
18 Years
Maximum age
No limit
Gender
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 co-inhibitory 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 prior to the first dose of study drug

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention

- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or the selected
chemotherapy regimen, and/or any of their excipients

- 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 prior to the first dose of study drug

- 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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Northern Cancer Institute ( Site 0217) - St Leonards
Recruitment hospital [2] 0 0
Monash Health-Monash Medical Centre ( Site 0216) - Clayton
Recruitment hospital [3] 0 0
Austin Health ( Site 0218) - Heidelberg
Recruitment hospital [4] 0 0
Sir Charles Gairdner Hospital ( Site 0223) - Nedlands
Recruitment postcode(s) [1] 0 0
2065 - St Leonards
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
3084 - Heidelberg
Recruitment postcode(s) [4] 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
Missouri
Country [5] 0 0
United States of America
State/province [5] 0 0
New Jersey
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
South Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Wisconsin
Country [10] 0 0
Czechia
State/province [10] 0 0
Olomouc
Country [11] 0 0
Czechia
State/province [11] 0 0
Praha 5
Country [12] 0 0
Czechia
State/province [12] 0 0
Praha 8
Country [13] 0 0
Denmark
State/province [13] 0 0
Hovedstaden
Country [14] 0 0
Denmark
State/province [14] 0 0
Syddanmark
Country [15] 0 0
Estonia
State/province [15] 0 0
Harjumaa
Country [16] 0 0
Estonia
State/province [16] 0 0
Tartumaa
Country [17] 0 0
France
State/province [17] 0 0
Provence-Alpes-Cote-d Azur
Country [18] 0 0
France
State/province [18] 0 0
Somme
Country [19] 0 0
France
State/province [19] 0 0
Paris
Country [20] 0 0
Guatemala
State/province [20] 0 0
Quetzaltenango
Country [21] 0 0
Guatemala
State/province [21] 0 0
Guatemala
Country [22] 0 0
Hungary
State/province [22] 0 0
Bacs-Kiskun
Country [23] 0 0
Hungary
State/province [23] 0 0
Borsod-Abauj-Zemplen
Country [24] 0 0
Hungary
State/province [24] 0 0
Gyor-Moson-Sopron
Country [25] 0 0
Hungary
State/province [25] 0 0
Debrecen
Country [26] 0 0
Hungary
State/province [26] 0 0
Kaposvar
Country [27] 0 0
Israel
State/province [27] 0 0
Afula
Country [28] 0 0
Israel
State/province [28] 0 0
Jerusalem
Country [29] 0 0
Israel
State/province [29] 0 0
Ramat Gan
Country [30] 0 0
Israel
State/province [30] 0 0
Tel Aviv
Country [31] 0 0
Italy
State/province [31] 0 0
Firenze
Country [32] 0 0
Italy
State/province [32] 0 0
Milano
Country [33] 0 0
Italy
State/province [33] 0 0
Modena
Country [34] 0 0
Italy
State/province [34] 0 0
Napoli
Country [35] 0 0
Japan
State/province [35] 0 0
Aomori
Country [36] 0 0
Japan
State/province [36] 0 0
Ibaraki
Country [37] 0 0
Japan
State/province [37] 0 0
Osaka
Country [38] 0 0
Japan
State/province [38] 0 0
Nagasaki
Country [39] 0 0
Japan
State/province [39] 0 0
Tokyo
Country [40] 0 0
Korea, Republic of
State/province [40] 0 0
Kyonggi-do
Country [41] 0 0
Korea, Republic of
State/province [41] 0 0
Taejon-Kwangyokshi
Country [42] 0 0
Korea, Republic of
State/province [42] 0 0
Seoul
Country [43] 0 0
Latvia
State/province [43] 0 0
Riga
Country [44] 0 0
Malaysia
State/province [44] 0 0
Kelantan
Country [45] 0 0
Malaysia
State/province [45] 0 0
Pulau Pinang
Country [46] 0 0
Malaysia
State/province [46] 0 0
Kuala Lumpur
Country [47] 0 0
Netherlands
State/province [47] 0 0
Noord-Holland
Country [48] 0 0
Netherlands
State/province [48] 0 0
Zuid-Holland
Country [49] 0 0
Poland
State/province [49] 0 0
Zachodniopomorskie
Country [50] 0 0
Portugal
State/province [50] 0 0
Lisboa
Country [51] 0 0
Puerto Rico
State/province [51] 0 0
Ponce
Country [52] 0 0
Puerto Rico
State/province [52] 0 0
Rio Piedras
Country [53] 0 0
Romania
State/province [53] 0 0
Cluj
Country [54] 0 0
Romania
State/province [54] 0 0
Dolj
Country [55] 0 0
Romania
State/province [55] 0 0
Timis
Country [56] 0 0
Romania
State/province [56] 0 0
Iasi
Country [57] 0 0
Spain
State/province [57] 0 0
Barcelona
Country [58] 0 0
Spain
State/province [58] 0 0
Valenciana, Comunitat
Country [59] 0 0
Taiwan
State/province [59] 0 0
Kaohsiung
Country [60] 0 0
Taiwan
State/province [60] 0 0
Tainan
Country [61] 0 0
Taiwan
State/province [61] 0 0
Taipei
Country [62] 0 0
Taiwan
State/province [62] 0 0
Taoyuan
Country [63] 0 0
Turkey
State/province [63] 0 0
Ankara
Country [64] 0 0
Turkey
State/province [64] 0 0
Istanbul
Country [65] 0 0
Turkey
State/province [65] 0 0
Izmir
Country [66] 0 0
Turkey
State/province [66] 0 0
Trabzon
Country [67] 0 0
Ukraine
State/province [67] 0 0
Dnipropetrovska Oblast
Country [68] 0 0
Ukraine
State/province [68] 0 0
Kharkivska Oblast
Country [69] 0 0
Ukraine
State/province [69] 0 0
Kirovohradska Oblast
Country [70] 0 0
Ukraine
State/province [70] 0 0
Kyivska Oblast
Country [71] 0 0
Ukraine
State/province [71] 0 0
Kyiv

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
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/show/NCT04241185
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
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
Trialsites@merck.com
Contact person for scientific queries

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