A Study of Efficacy and Safety of Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)

NCT05845814 | Active Not Recruiting Phase 1 FDA Drug

• 5 other identifiers: 3475-04BMK-3475-04B2023-506385-30-00U1111-1293-75642022-001371-14
• Study Type: interventional
• Target: 390
• Locations: 12 countries
• Sites: 47

Brief Summary

This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus EV. There will be no comparison of coformulated favezelimab/pembrolizumab plus EV versus coformulated vibostolimab/pembrolizumab plus EV. If ORR and/or DRR are substantially better on coformulated favezelimab/pembrolizumab plus EV and/or coformulated vibostolimab/pembrolizumab plus EV compared with pembrolizumab plus EV, after evaluation of the totality of data, the sponsor might consider Part 2 (expansion) to further characterize the efficacy and safety of the treatment arms under study.

Conditions

Metastatic Urothelial Carcinoma; Urothelial Neoplasms

Outcome Measures

Primary Outcomes (5)

• Part 1: Objective Response Rate (ORR)

  ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). ORR will be reported for participants in Part 1.

  Up to ~4 years

• Part 1: Percentage of Participants experiencing an Adverse Event (AE)

  An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported.

  Up to ~4 years

• Part 1: Percentage of Participants who Discontinue study interventions due to an AE

  An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study interventions due to an AE in Part 1 will be reported.

  Up to ~4 years

• Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)

  A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported.

  Up to 21 days

• Part 2: Progression Free Survival (PFS)

  PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. PFS will be reported for participants in Part 2.

  Up to ~4 years

Secondary Outcomes (20)

• Part 1: PFS

  Up to ~4 years

• Part 1: Duration of Response (DOR)

  Up to ~4 years

• Part 2: Overall Survival (OS)

  Up to ~4 years

• Part 2: ORR

  Up to ~4 years

• Part 2: DOR

  Up to ~4 years

Study Arms (3)

Arm A: Coformulated favezelimab/pembrolizumab plus EV

EXPERIMENTAL

Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) as an intravenous (IV) infusion on Day 1 of every 3-week cycle for up to \~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.

Biological: Coformulated favezelimab/pembrolizumab; Combination Product: EV

Arm B: Coformulated vibostolimab/pembrolizumab plus EV

EXPERIMENTAL

Participants will receive coformulated vibostolimab/pembrolizumab (200 mg/200 mg) as an IV infusion on Day 1 of every 3-week cycle, for up to \~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.

Biological: Coformulated vibostolimab/pembrolizumab; Combination Product: EV

Arm C: Pembrolizumab plus EV

ACTIVE COMPARATOR

Participants will receive 200 mg pembrolizumab as an IV infusion on Day 1 of every 3-week cycle for up to \~2 years (35 cycles) and EV at 1.25 mg/kg, administered as an IV infusion on Days 1 and 8 of every 3-week cycle, until disease progression, intolerable toxicity, or investigator decision.

Combination Product: EV; Biological: Pembrolizumab

Interventions

Coformulated favezelimab/pembrolizumab BIOLOGICAL

Coformulated favezelimab/pembrolizumab (800 mg/200 mg) IV infusion

Also known as: MK-4280A

Arm A: Coformulated favezelimab/pembrolizumab plus EV

Coformulated vibostolimab/pembrolizumab BIOLOGICAL

Coformulated vibostolimab/pembrolizumab (200 mg/200 mg) IV infusion

Also known as: MK-7684A

Arm B: Coformulated vibostolimab/pembrolizumab plus EV

EV COMBINATION_PRODUCT

1.25 mg/kg IV infusion

Also known as: Padcev, ASG-22CE, ASG-22ME

Arm A: Coformulated favezelimab/pembrolizumab plus EV; Arm B: Coformulated vibostolimab/pembrolizumab plus EV; Arm C: Pembrolizumab plus EV

Pembrolizumab BIOLOGICAL

200 mg IV infusion

Also known as: MK-3475, KEYTRUDA®

Arm C: Pembrolizumab plus EV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
• Participants with mixed histology are eligible provided the urothelial component is ≥50% (and \<10% plasmacytoid component)
• Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally)
• Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:
• Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
• Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence \>12 months from completion of therapy are permitted.
• Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
• Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with \<Grade 2 neuropathy are eligible.

You may not qualify if:

• Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
• Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
• Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
• Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
• Has a history of uncontrolled diabetes.
• Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has hepatitis B or hepatitis C virus infection.
• Has had major surgery within 4 weeks prior to first dose of study intervention.
• Has had an allogenic tissue/solid organ transplant

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (47)

Moores Cancer Center ( Site 3028)

La Jolla, California, 92093-0698, United States

Location

University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 3045)

Orange, California, 92868, United States

Location

UCSF Medical Center at Mission Bay ( Site 3044)

San Francisco, California, 94158, United States

Location

Anschutz Cancer Pavilion ( Site 3017)

Aurora, Colorado, 80045, United States

Location

Emory University School of Medicine ( Site 3043)

Atlanta, Georgia, 30322, United States

Location

Indiana University Melvin and Bren Simon Cancer Center ( Site 3011)

Indianapolis, Indiana, 46202, United States

Location

Dana-Farber Cancer Institute ( Site 3047)

Boston, Massachusetts, 02115, United States

Location

Siteman Cancer Center ( Site 3038)

St Louis, Missouri, 63108, United States

Location

Icahn School of Medicine at Mount Sinai ( Site 3018)

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center ( Site 3031)

New York, New York, 10065, United States

Location

Duke Cancer Institute ( Site 3027)

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic-Taussig Cancer Center ( Site 3036)

Cleveland, Ohio, 44195, United States

Location

UPMC Hillman Cancer Center ( Site 3014)

Pittsburgh, Pennsylvania, 15232, United States

Location

Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 3041)

Salt Lake City, Utah, 84112, United States

Location

Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Site 3951)

Brisbane, Queensland, 4029, Australia

Location

Austin Health-Cancer Clinical Trials Centre ( Site 3950)

Heidelberg, Victoria, 3084, Australia

Location

The Ottawa Hospital - General Campus-The Ottawa Hospital Cancer Centre ( Site 3105)

Ottawa, Ontario, K1H 8L6, Canada

Location

Sunnybrook Research Institute - Odette Cancer Centre ( Site 3108)

Toronto, Ontario, M4N 3M5, Canada

Location

Princess Margaret Cancer Centre ( Site 3106)

Toronto, Ontario, M5G 2M9, Canada

Location

FALP-UIDO ( Site 3151)

Santiago, Region M. de Santiago, 7500921, Chile

Location

Bradfordhill-Clinical Area ( Site 3155)

Santiago, Region M. de Santiago, 8420383, Chile

Location

ONCOCENTRO APYS-ACEREY ( Site 3158)

Viña del Mar, Región de Valparaíso, 2520598, Chile

Location

Bradford Hill Norte ( Site 3152)

Antofagasta, 1240000, Chile

Location

CHU de Bordeaux Hop St ANDRE ( Site 3607)

Bordeaux, Aquitaine, 33075, France

Location

Centre Georges François Leclerc-Centre de recherche clinique ( Site 3608)

Dijon, Cote-d Or, 21079, France

Location

Oncopole Claudius Regaud ( Site 3610)

Toulouse, Haute-Garonne, 31059, France

Location

centre hospitalier lyon sud ( Site 3606)

Pierre-Bénite, Rhone, 69310, France

Location

Hôpital Européen Georges Pompidou ( Site 3605)

Paris, 75015, France

Location

Rambam Health Care Campus-Oncology Division ( Site 3501)

Haifa, 3109601, Israel

Location

Rabin Medical Center-Oncology ( Site 3504)

Petah Tikva, 4941492, Israel

Location

Sheba Medical Center-ONCOLOGY ( Site 3503)

Ramat Gan, 5265601, Israel

Location

Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 3406)

Napoli, Campania, 80131, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 3405)

Milan, Lombardy, 20133, Italy

Location

Ospedale San Raffaele-Oncologia Medica ( Site 3403)

Milan, 20132, Italy

Location

Maastricht UMC+ ( Site 3304)

Maastricht, Limburg, 6229 HX, Netherlands

Location

Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 3302)

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Erasmus Medisch Centrum-Medical Oncology ( Site 3303)

Rotterdam, South Holland, 3015 GD, Netherlands

Location

Severance Hospital, Yonsei University Health System-Medical oncology ( Site 3903)

Seoul, 03722, South Korea

Location

Asan Medical Center-Department of Oncology ( Site 3901)

Seoul, 05505, South Korea

Location

Samsung Medical Center ( Site 3902)

Seoul, 06351, South Korea

Location

Hospital Universitari Vall d'Hebron ( Site 3767)

Barcelona, Catalonia, 08035, Spain

Location

Hospital Clinico San Carlos ( Site 3765)

Madrid, 28040, Spain

Location

Chang Gung Memorial Hospital at Kaohsiung-Oncology and Hematology ( Site 3802)

Kaohsiung City, 83301, Taiwan

Location

National Cheng Kung University Hospital-Clinical Trial Center ( Site 3803)

Tainan, 704, Taiwan

Location

National Taiwan University Hospital-Oncology ( Site 3801)

Taipei, 10002, Taiwan

Location

St Bartholomew's Hospital-Centre for Experimental Cancer Medicine ( Site 3206)

London, London, City of, EC1A 7BE, United Kingdom

Location

ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 3201)

London, London, City of, SW3 6JJ, United Kingdom

Location

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In Part 1, participants will be randomized in a 1:1:1 ratio to receive either Arm A (coformulated favezelimab/pembrolizumab plus EV), Arm B (coformulated vibostolimab/pembrolizumab plus EV), or Arm C (pembrolizumab plus EV). If Part 2 is conducted, participants will be randomized in a 1:1:1 ratio to Arms A, B, and C or in a 1:1 ratio to Arms A and C or B and C, depending on the treatment arm(s) that are expanded in Part 2.

Study Record Dates

• First Submitted: April 26, 2023
• First Posted: May 6, 2023
• Study Start: June 23, 2023
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027
• Last Updated: September 10, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

US (14); GB (2); IT (3); AU (2); TW (3); IL (3); KR (3); CL (4); CA (3); FR (5); NL (3); ES (2)