A Substudy of Investigational Agents in Programmed Cell Death-1/Ligand 1 (PD-1/L1) Refractory Locally Advanced or Metastatic Urothelial Carcinoma (mUC) (MK-3475-04A)

May 26, 2026 updated by: Merck Sharp & Dohme LLC

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Study of Investigational Agents With or Without Pembrolizumab in Participants With PD-1/L1 Refractory Locally Advanced or Metastatic Urothelial Carcinoma (KEYMAKER-U04): Substudy 04A

This substudy is part of an umbrella platform study which is designed to evaluate investigational agents with or without pembrolizumab in participants with urothelial carcinoma who are in need of new treatment options. Substudy 04A will enroll participants with locally advanced or mUC whose disease is resistant to treatment with programmed cell death-1/ligand 1 (PD-1/L1) inhibitors. The protocol infrastructure will enable the rolling assignment of investigational treatments.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

48

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
    • Queensland
      • Brisbane, Queensland, Australia, 4029
        • Completed
        • Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Site 1952)
  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • Recruiting
        • Princess Margaret Cancer Centre ( Site 1106)
        • Contact:
          • Study Coordinator
          • Phone Number: 4169464501 2662
  • Chile
    • Region M. de Santiago
      • Santiago, Region M. de Santiago, Chile, 7500921
        • Recruiting
        • FALP-UIDO ( Site 1151)
        • Contact:
          • Study Coordinator
          • Phone Number: 56224205098
      • Santiago, Region M. de Santiago, Chile, 8420383
        • Recruiting
        • Bradford Hill ( Site 1155)
        • Contact:
          • Study Coordinator
          • Phone Number: +56229490970
  • Denmark
    • Capital Region
      • Copenhagen, Capital Region, Denmark, 2100
        • Recruiting
        • Rigshospitalet-Dept. of Oncology ( Site 1701)
        • Contact:
          • Study Coordinator
          • Phone Number: 00 45 35 45 35 45
  • Israel
      • Haifa, Israel, 3109601
        • Recruiting
        • Rambam Health Care Campus-Oncology ( Site 1501)
        • Contact:
          • Study Coordinator
          • Phone Number: +972-4-7776234
      • Petah Tikva, Israel, 4941492
        • Recruiting
        • Rabin Medical Center-Oncology ( Site 1504)
        • Contact:
          • Study Coordinator
          • Phone Number: 972 393 78077
      • Ramat Gan, Israel, 5265601
        • Recruiting
        • Sheba Medical Center-ONCOLOGY ( Site 1503)
        • Contact:
          • Study Coordinator
          • Phone Number: 03-5304498
  • Italy
      • Naples, Italy, 80131
        • Recruiting
        • Istituto Nazionale Tumori IRCCS Fondazione Pascale-S.C. Sperimentazioni Cliniche ( Site 1406)
        • Contact:
          • Study Coordinator
          • Phone Number: 00393331891929
    • Lombardy
      • Milan, Lombardy, Italy, 20133
        • Recruiting
        • Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 1408)
        • Contact:
          • Study Coordinator
          • Phone Number: +390223904449
  • Netherlands
    • North Holland
      • Amsterdam, North Holland, Netherlands, 1066 CX
        • Recruiting
        • Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 1302)
        • Contact:
          • Study Coordinator
          • Phone Number: +31 20 512 9111
  • South Korea
      • Seoul, South Korea, 03722
        • Recruiting
        • Severance Hospital, Yonsei University Health System ( Site 1903)
        • Contact:
          • Study Coordinator
          • Phone Number: +82222288138
      • Seoul, South Korea, 05505
        • Recruiting
        • Asan Medical Center ( Site 1901)
        • Contact:
          • Study Coordinator
          • Phone Number: +82230105977
      • Seoul, South Korea, 06351
        • Recruiting
        • Samsung Medical Center ( Site 1902)
        • Contact:
          • Study Coordinator
          • Phone Number: +82234103459
  • Spain
      • Madrid, Spain, 28040
        • Recruiting
        • Hospital Clinico San Carlos ( Site 1765)
        • Contact:
          • Study Coordinator
          • Phone Number: +34913303546
    • Catalonia
      • Barcelona, Catalonia, Spain, 08035
        • Recruiting
        • Hospital Universitari Vall d'Hebron ( Site 1767)
        • Contact:
          • Study Coordinator
          • Phone Number: +34934894158
  • United Kingdom
    • London, City of
      • London, London, City of, United Kingdom, EC1A 7BE
        • Recruiting
        • St Bartholomew's Hospital ( Site 1206)
        • Contact:
          • Study Coordinator
          • Phone Number: +44 0203 416 5000
      • London, London, City of, United Kingdom, SW3 6JJ
        • Recruiting
        • ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 1201)
        • Contact:
          • Study Coordinator
          • Phone Number: +44 20 7352 8171
  • United States
    • California
      • Orange, California, United States, 92868
        • Recruiting
        • University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 1045)
        • Contact:
          • Study Coordinator
          • Phone Number: 714-509-2371
      • San Francisco, California, United States, 94158
        • Recruiting
        • University of California San Francisco ( Site 1044)
        • Contact:
          • Study Coordinator
          • Phone Number: 415-476-4616
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Completed
        • Anschutz Cancer Pavilion ( Site 1017)
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University of Chicago Medical Center ( Site 1037)
        • Contact:
          • Study Coordinator
          • Phone Number: 855-702-8222
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Indiana University Melvin and Bren Simon Cancer Center ( Site 1011)
        • Contact:
          • Study Coordinator
          • Phone Number: 888-600-4822
    • Missouri
      • St Louis, Missouri, United States, 63108
        • Recruiting
        • Siteman Cancer Center ( Site 1038)
        • Contact:
          • Study Coordinator
          • Phone Number: 800-600-3606
    • New York
      • New York, New York, United States, 10065
        • Recruiting
        • Memorial Sloan Kettering Cancer Center ( Site 1031)
        • Contact:
          • Study Coordinator
          • Phone Number: 646-888-4770
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic-Taussig Cancer Center ( Site 1036)
        • Contact:
          • Study Coordinator
          • Phone Number: 216-445-7728
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • UPMC Hillman Cancer Center ( Site 1014)
        • Contact:
          • Study Coordinator
          • Phone Number: 412-623-4759
    • Utah
      • Salt Lake City, Utah, United States, 84112-5500
        • Recruiting
        • Huntsman Cancer Institute ( Site 1041)
        • Contact:
          • Study Coordinator
          • Phone Number: 801-585-0155

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

The main inclusion and exclusion criteria include but are not limited to the following:

  • Histologically or cytologically confirmed diagnosis of locally advanced/unresectable or mUC of the renal pelvis, ureter (upper urinary tract), bladder, or urethra.
  • Arm A: PD-1/L1 refractory locally advanced or mUC as evidenced by: EITHER disease progression while on treatment or after treatment with an anti-PD-1/L1 monoclonal antibody (mAb) for locally advanced/unresectable or mUC administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies OR disease recurrence while on treatment or after treatment with an anti-PD-1/L1 mAb for muscle-invasive urothelial carcinoma (MIUC) administered as monotherapy.
  • Arm A: Participants 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.
  • Arm B: PD-1/L1 refractory locally advanced or mUC as evidenced by: EITHER disease progression after treatment with an anti-PD-1/L1 mAb for locally advanced/unresectable or mUC administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies; OR disease recurrence after treatment with an anti-PD-1/L1 mAb for MIUC administered as monotherapy or in combination with other checkpoint therapies >12 months after last dose of treatment with an anti-PD-1/L1 mAb.
  • Arm B: Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion from a metastatic site or from a primary tumor that has become locally advanced and not previously irradiated.

Exclusion Criteria:

  • Known additional nonurothelial malignancy that is progressing or has required active treatment within 3 years prior to study randomization/allocation.
  • Received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization/allocation.
  • Active infection requiring systemic therapy.
  • Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
  • Known history of human immunodeficiency virus (HIV).
  • Known history of hepatitis B or known hepatitis C virus infection.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A: Zilovertamab vedotin
Participants will receive zilovertamab vedotin 2mg/kg administered on Day 1 and Day 8 of each 3 week cycle (Q3W) until documented disease progression or any other discontinuation criterion is met.
Biological: Zilovertamab vedotin
Administered via intravenous (IV) infusion on day 1 and day 8 of Q3W cycles
Other Names:
  • MK-2140
  • VLS-101
Experimental: Arm B: Pembrolizumab and MK-3120
Participants will receive MK-3120 up to 5mg/kg administered on Day 1, Day 15 and Day 29 of each 6 week cycle until documented disease progression or any other discontinuation criterion is met and 400mg pembrolizumab on Day 1 of each 6 week cycle for up to 17 cycles (up to ~2 years).
Biological: Pembrolizumab
Administered via IV infusion on Day 1 of each 6 week cycle.
Other Names:
  • MK-3475
  • KEYTRUDA®
Biological: MK-3120
Administered as an IV infusion on Day 1, Day 15, and Day 29 of each 6 week cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Who Experienced At Least One Adverse Event (AE)
Time Frame: Up to approximately 5 years
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
Up to approximately 5 years
Percentage of Participants Who Discontinued Study Treatment Due to an AE
Time Frame: Up to approximately 5 years
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment
Up to approximately 5 years
Arm A: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)
Time Frame: Up to approximately 2 years
ORR is defined as the percentage of participants who achieve a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.
Up to approximately 2 years
Arm B: ORR as Assessed by Investigator
Time Frame: Up to approximately 2 years
ORR is defined as the percentage of participants who achieve a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by the investigator will be presented.
Up to approximately 2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Arm A: Duration of Response (DOR) as Assessed by BICR
Time Frame: Up to approximately 2 years
For participants who demonstrate confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by Blinded Independent Central Review (BICR) will be presented.
Up to approximately 2 years
Arm B: DOR as Assessed by Investigator
Time Frame: Up to approximately 2 years
For participants who demonstrate confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until PD or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by the investigator will be presented.
Up to approximately 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck Sharp & Dohme LLC

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 16, 2022

Primary Completion (Estimated)

February 26, 2029

Study Completion (Estimated)

February 26, 2029

Study Registration Dates

First Submitted

September 28, 2022

First Submitted That Met QC Criteria

September 28, 2022

First Posted (Actual)

October 3, 2022

Study Record Updates

Last Update Posted (Actual)

May 27, 2026

Last Update Submitted That Met QC Criteria

May 26, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3475-04A
  • MK-3475-04A (Other Identifier: MSD)
  • 2020-004544-28 (EudraCT Number)
  • 2023-506384-34-00 (Registry Identifier: EU CT)
  • U1111-1293-7548 (Registry Identifier: UTN)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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