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)

A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) and Pembrolizumab in Combination With Other Investigational Agents in Subjects With High Risk Non-muscle-Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

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.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Pembrolizumab/vibostolimab coformulation; Biological: Favezelimab/pembrolizumab coformulation

• Study Type: Interventional
• Enrollment (Estimated): 320
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839

Study Locations

• Brazil
  • Sao Paulo, Brazil
    • Recruiting
    • MSD Brasil
    • Contact: MSD Online; Phone Number: 0800 012 22 32
• Canada
  • Quebec
    • Kirkland, Quebec, Canada, H9H 4M7
      • Recruiting
      • Merck Canada
      • Contact: Medical Information Centre Centre d'information medicale Merck Canada Inc.; Phone Number: 514-428-8600 / 1-800-567-2594
• Finland
  • Espoo, Finland
    • Recruiting
    • MSD Finland Oy
    • Contact: Michael Pasternack; Phone Number: 358 20 7570300
• France
  • Paris, France
    • Recruiting
    • MSD France
    • Contact: Dominique Blazy; Phone Number: 33 147548990
• Italy
  • Rome, Italy
    • Recruiting
    • MSD Italia S.r.l.
    • Contact: Barbara Capaccetti; Phone Number: 39 06361911
• Netherlands
  • Haarlem, Netherlands
    • Recruiting
    • Merck Sharp & Dohme BV
    • Contact: Caroline Doornebos; Phone Number: 31 23 515 3362
• Puerto Rico
  • Ponce, Puerto Rico, 00717
    • Recruiting
    • Call for Information (Investigational Site 2402)
  • Rio Piedras, Puerto Rico, 00935
    • Recruiting
    • Call for Information (Investigational Site 2400)
• Singapore
  • Singapore, Singapore
    • Recruiting
    • Merck Sharp & Dohme (I.A.) Corp
    • Contact: Cesar Recto; Phone Number: 632 784 9500
• Spain
  • Madrid, Spain
    • Recruiting
    • Merck Sharp and Dohme de Espana S.A.
    • Contact: Lourdes Lopez-Bravo; Phone Number: (0034) 913210654
• Turkey
  • Istanbul, Turkey
    • Recruiting
    • Merck Sharp & Dohme Ilaclari Ltd. Sti
    • Contact: Alev Eren; Phone Number: 90 212 336 12 63
• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • Call for Information (Investigational Site 0021)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • Call for Information (Investigational Site 0085)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Call for Information (Investigational Site 0084)
  • Kansas
    • Wichita, Kansas, United States, 67226
      • Recruiting
      • Call for Information (Investigational Site 0081)
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Call for Information (Investigational Site 0023)
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Call for Information (Investigational Site 0002)
    • New Brunswick, New Jersey, United States, 08903
      • Recruiting
      • Call for Information (Investigational Site 0018)
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • Call for Information (Investigational Site 0004)
  • Ohio
    • Cincinnati, Ohio, United States, 45212
      • Recruiting
      • Call for Information (Investigational Site 0072)
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Call for Information (Investigational Site 0009)
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • Recruiting
      • Call for Information (Investigational Site 0074)
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Recruiting
      • Call for Information (Investigational Site 0078)
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Call for Information (Investigational Site 0080)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Biological: Pembrolizumab; Participants with CIS with or without papillary tumors (Cohort A) and participants with papillary tumors only, without CIS (Cohort B) receive pembrolizumab 200mg via IV infusion once every 3 weeks for up to 35 administrations; Other Names: KEYTRUDA; MK-3475
Experimental: 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	Biological: Pembrolizumab/vibostolimab coformulation; Participants with CIS with or without papillary tumors (Cohort C) receive pembrolizumab/vibostolimab (coformulation of 200 mg pembrolizumab and 200 mg vibostolimab) via IV infusion once every 3 weeks for up to 35 administrations; Other Names: MK-7684A; Biological: Favezelimab/pembrolizumab coformulation; Participants with CIS with or without papillary tumors (Cohort C) receive favezelimab/pembrolizumab (coformulation of 800mg favezelimab and 200 mg pembrolizumab) via IV infusion once every 3 weeks for up to 35 administrations; Other Names: MK-4280A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A: Complete Response (CR) Rate of High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC)	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.	Up to approximately 6 months
Cohort B: 12-month Disease-Free Survival (DFS) Rate of High-Risk NMIBC	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.	Up to approximately 12 months
Cohort C: 12-month CR Rate of High-Risk NMIBC	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.	Up to approximately 12 months
All Cohorts: Number of Participants Who Experience an Adverse Event (AE)	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.	Up to approximately 27 months
All Cohorts: Number of Participants Who Discontinue Study Treatment Due to an AE	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.	Up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A: CR Rate of Any Disease	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.	Up to approximately 6 months
Cohort C: CR Rate of High-Risk NMIBC at 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.	Up to approximately 3 months
Cohort C: CR Rate of High-Risk NMIBC at 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.	Up to approximately 6 months
Cohort C: Overall CR Rate of High-Risk NMIBC	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.	Up to approximately 6 months
Cohort A: CR Rate of High-Risk NMIBC in Programmed Cell Death 1 (PDL-1) Positive Participants	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.	Up to approximately 6 months
Cohort A and C: Duration of Response (DOR)	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.	Up to approximately 60 months
All Cohorts: Progression-Free Survival (PFS)	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.	Up to approximately 60 months
All Cohorts: Overall Survival (OS)	OS is defined as the time from first dose to death due to any cause.	Up to approximately 60 months
Cohort B: DFS Rate of Any Disease	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.	Up to approximately 60 months
Cohort B: 12-month DFS Rate of Any Disease	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.	Up to approximately 12 months
Cohort B: 12-month DFS Rate of High-Risk NMIBC in PDL-1 Positive Participants	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.	Up to approximately 12 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguie M, Krieger LEM, Singer EA, Bajorin DF, Grivas P, Seo HK, Nishiyama H, Konety BR, Li H, Nam K, Kapadia E, Frenkl T, de Wit R. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930. doi: 10.1016/S1470-2045(21)00147-9. Epub 2021 May 26. Erratum In: Lancet Oncol. 2021 Aug;22(8):e347.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2016
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): August 31, 2030

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 7, 2015
• First Posted (Estimated): December 9, 2015

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: PD-1; PD-L1; PD1; PDL1
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 3475-057; 163236 (Registry Identifier: JAPAC-CTI); 2014-004026-17 (EudraCT Number); 2022-502526-41 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf