Study of Pembrolizumab (MK-3475) and Pembrolizumab With Other Investigational Agents in Participants With High Risk Non-muscle Invasive Bladder Cancer (MK-3475-057/KEYNOTE-057)

Phase 2

Active, not recruiting

• Conditions: Bladder Cancer
• Interventions: Biological: Pembrolizumab; Biological: Pembrolizumab/vibostolimab coformulation; Biological: Favezelimab/pembrolizumab coformulation

• Registration Number: NCT02625961
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

In this study, participants with high risk non-muscle-invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette Guerin (BCG) therapy and who are considered ineligible for or have refused to undergo radical cystectomy, will receive pembrolizumab therapy or pembrolizumab in combination with other investigational agents. The primary study hypothesis is that treatment with pembrolizumab will result in a clinically meaningful response.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-12-07
• Study First Submitted QC: 2015-12-07
• Study First Posted: 2015-12-09
• Study Start: 2016-02-10
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-06
• Last Update Posted: 2025-01-07
• Primary Completion: 2026-08-30
• Study Completion: 2030-08-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 320

Inclusion Criteria

• Histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, high grade Ta and / or carcinoma in situ [CIS]) transitional cell carcinoma of the bladder (mixed histology tumors allowed if transitional cell histology is predominant histology).
• Fully resected disease at study entry (residual CIS acceptable)
• BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy
• Ineligible for radical cystectomy or refusal of radical cystectomy
• Available tissue from a newly obtained core biopsy of a tumor lesion not previously irradiated
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate organ function
• Female participants of childbearing potential have a negative urine or serum pregnancy test and must be willing to use an adequate method of contraception
• Male participants must be willing to use an adequate method of contraception

Exclusion criteria:

• Centrally assessed muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and / or stage IV)
• Centrally assessed concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium
• Currently participating or has participated in a study of an investigational agent and received study therapy or received investigational device within 4 weeks prior to the first dose of study treatment
• Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy / Transurethral Resection of Bladder Tumor (TURBT) to starting study treatment
• Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent
• Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤7 and prostatic-specific antigen (PSA) undetectable for at least 1 year while off androgen deprivation therapy that was either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial through 120 days after the last dose of study treatment
• Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor
• Known human immunodeficiency virus (HIV)
• Known active Hepatitis B or C infection
• Received a live virus vaccine within 30 days of planned start of study treatment
• Has had an allogeneic tissue/solid organ transplant

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pembrolizumab	Pembrolizumab	Participants with carcinoma-in-situ (CIS) with or without papillary tumors (Cohort A) and participants with papillary tumors only, without CIS (Cohort B) will receive pembrolizumab, 200 mg, intravenously, every 3 weeks (Q3W) for up to 24 months.
Pembrolizumab coformulation	Favezelimab/pembrolizumab coformulation	Participants with CIS with or without papillary tumors (Cohort C) will receive either pembrolizumab/vibostolimab or favezelimab/pembrolizumab coformulation intravenously Q3W for up to 24 months
Pembrolizumab coformulation	Pembrolizumab/vibostolimab coformulation	Participants with CIS with or without papillary tumors (Cohort C) will receive either pembrolizumab/vibostolimab or favezelimab/pembrolizumab coformulation intravenously Q3W for up to 24 months

Primary Outcome Measures

Name	Time	Method
Cohort C: 12-month CR Rate of High-Risk NMIBC	Up to approximately 12 months	The 12-month CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 12 months.
All Cohorts: Number of Participants Who Discontinue Study Treatment Due to an AE	Up to approximately 24 months	An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Cohort A: Complete Response (CR) Rate of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC)	Up to approximately 6 months	The CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review.
Cohort B: 12-month Disease-Free Survival (DFS) Rate of High-Risk NMIBC	Up to approximately 12 months	DFS of high-risk NMIBC is defined as the time from the first dose to the first occurrence of high-risk NMIBC or worse per central pathology and radiology review. The 12-month DFS rate is the percentage of participants remaining free from high-risk NMIBC or worse at 12 months.
All Cohorts: Number of Participants Who Experience an Adverse Event (AE)	Up to approximately 27 months	An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

Secondary Outcome Measures

Name	Time	Method
Cohort C: CR Rate of High-Risk NMIBC at 3 Months	Up to approximately 3 months	The CR rate of high-risk NMIBC at 3 months is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 3 months.
Cohort B: DFS Rate of Any Disease	Up to approximately 60 months	DFS of any disease is defined as the time from the first dose to the first occurrence of any disease or worse per central pathology and radiology review. The DFS rate is the percentage of participants remaining free of any disease or worse.
Cohort A: CR Rate of Any Disease	Up to approximately 6 months	The CR rate of any disease is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of any disease or worse per central pathology and radiology review.
Cohort C: CR Rate of High-Risk NMIBC at 6 Months	Up to approximately 6 months	The CR rate of high-risk NMIBC at 6 months is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at 6 months.
Cohort A: CR Rate of High-Risk NMIBC in Programmed Cell Death 1 (PDL-1) Positive Participants	Up to approximately 6 months	The CR of high-risk NMIBC is defined as the proportion of PDL-1 positive participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review.
All Cohorts: Progression-Free Survival (PFS)	Up to approximately 60 months	PFS is defined as the time from the first dose to progression to worsening of grade or stage or death or to muscle invasive or metastatic disease or death per central urology, pathology, and radiology review.
Cohort A and C: Duration of Response (DOR)	Up to approximately 60 months	The DOR is defined as the time from the first documented evidence of CR until the recurrence of disease or worse per clinical pathology and radiology review.
Cohort B: 12-month DFS Rate of High-Risk NMIBC in PDL-1 Positive Participants	Up to approximately 12 months	DFS of high-risk NMIBC is defined as the time from the first dose to the first occurrence of high-risk NMIBC or worse per central pathology and radiology review. The 12-month DFS rate is the percentage of participants remaining free from high-risk NMIBC or worse at 12 months. The 12-month DFS rate of high-risk NMIBC in PDL-1 positive participants will be reported.
Cohort C: Overall CR Rate of High-Risk NMIBC	Up to approximately 6 months	The overall CR rate of high-risk NMIBC is defined as the proportion of participants in the analysis population whose tumors are in response to treatment and who are then free of high-risk NMIBC or worse per central pathology and radiology review at first evaluable efficacy assessment.
All Cohorts: Overall Survival (OS)	Up to approximately 60 months	OS is defined as the time from first dose to death due to any cause.
Cohort B: 12-month DFS Rate of Any Disease	Up to approximately 12 months	DFS of any disease is defined as the time from the first dose to the first occurrence of any disease or worse per central pathology and radiology review. The 12-month DFS rate of any disease is the percentage of participants remaining free of any disease or worse at 12 months.

Trial Locations

Locations (25)

Call for Information (Investigational Site 0083); 🇺🇸 Los Angeles, California, United States

Call for Information (Investigational Site 0021); 🇺🇸 Orange, California, United States

Call for Information (Investigational Site 0085); 🇺🇸 Chicago, Illinois, United States

Call for Information (Investigational Site 0084); 🇺🇸 Indianapolis, Indiana, United States

Call for Information (Investigational Site 0081); 🇺🇸 Wichita, Kansas, United States

Call for Information (Investigational Site 0023); 🇺🇸 Minneapolis, Minnesota, United States

Call for Information (Investigational Site 0002); 🇺🇸 Hackensack, New Jersey, United States

Call for Information (Investigational Site 0018); 🇺🇸 New Brunswick, New Jersey, United States

Call for Information (Investigational Site 0004); 🇺🇸 New York, New York, United States

Call for Information (Investigational Site 0072); 🇺🇸 Cincinnati, Ohio, United States

Call for Information (Investigational Site 0009); 🇺🇸 Cleveland, Ohio, United States

Call for Information (Investigational Site 0074); 🇺🇸 Bala-Cynwyd, Pennsylvania, United States

Call for Information (Investigational Site 0078); 🇺🇸 Myrtle Beach, South Carolina, United States

Call for Information (Investigational Site 0080); 🇺🇸 Houston, Texas, United States

MSD Australia; 🇦🇺 North Ryde, Australia

MSD Brasil; 🇧🇷 Sao Paulo, Brazil

MSD Finland Oy; 🇫🇮 Espoo, Finland

MSD France; 🇫🇷 Paris, France

MSD Italia S.r.l.; 🇮🇹 Rome, Italy

Merck Sharp & Dohme BV; 🇳🇱 Haarlem, Netherlands

Call for Information (Investigational Site 2402); 🇵🇷 Ponce, Puerto Rico

Call for Information (Investigational Site 2400); 🇵🇷 Rio Piedras, Puerto Rico

Merck Sharp & Dohme (I.A.) Corp; 🇸🇬 Singapore, Singapore

Merck Sharp and Dohme de Espana S.A.; 🇪🇸 Madrid, Spain

Merck Sharp & Dohme Ilaclari Ltd. Sti; 🇹🇷 Istanbul, Turkey