A Phase III, 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 Identifier:
992-05
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
Recruitment Complete
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Study Summary
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.
To evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC.
To evaluate the safety and efficacy of pembrolizumab + CRT in patients with previously untreated MIBC who opt for bladder preservation.
Efficacy will be assessed by cystoscopy (± biopsy), by CT or MRI with blinded independent central review, and by urine cytology at 10 weeks after CRT, then every 12 weeks until the end of year 2, and every 24 weeks thereafter.
Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs).
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.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
III
Sex
Female & Male
Age
18+ years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Recruitment Complete
Requirements information
Inclusion criteria
- Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (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 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
- Adults (> or = 18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible.
- Patients will be stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 or 1 vs 2), PD-L1 combined positive score (<10 vs > or = 10), T stage (T2 vs T3 or T4), and geographic region (US vs Europe vs rest of world). CRT regimen must be determined before randomization. The following radiotherapy (RT) regimens are permitted: conventional RT consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated RT consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only)
- Adults who have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted.
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> or =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
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Carolinas
Myrtle Beach, SC, United States, 29572
Investigator
Neal Shore
Status
Recruitment Complete
Condition(s) Treated at Site
Bladder