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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

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.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
48

Phase

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.
  • 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 Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Merck Sharp & Dohme LLC

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 16, 2022

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 26, 2029

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 26, 2029

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 28, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 28, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 3, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 27, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 26, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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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