KEYMAKER-U04 Substudy 04D: A Clinical Study of New Treatments Given With Enfortumab Vedotin and Pembrolizumab in People With Urothelial Cancer (MK-3475-04D/KEYMAKER-U04)

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Study of Investigational Agents in Combination With Enfortumab Vedotin Plus Pembrolizumab as First-Line Treatment in Participants With Locally Advanced or Metastatic Urothelial Carcinoma: KEYMAKER-U04-Substudy 04D

Researchers are looking for new ways to treat people with urothelial cancer (UC) that is locally advanced or metastatic. The standard treatment for locally advanced or metastatic UC is enfortumab vedotin (EV) given with pembrolizumab.

The goals of this study are to learn about:

• The safety of the study treatment when given with standard treatment and if people tolerate it
• The number of people who have the cancer respond (cancer gets smaller or goes away) with the new study treatment when given with standard treatment.

Study Overview

• Status: Recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: MK-3120; Drug: EV; Biological: Pembrolizumab; Drug: Rescue Medication

Detailed Description

This is a substudy of the master protocol MK-3475-U04 (KEYMAKER-U04)

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@msd.com

Study Locations

• Chile
  • Region M. de Santiago
    • Santiago, Region M. de Santiago, Chile, 7500921
      • Recruiting
      • FALP ( Site 5151)
      • Contact: Study Coordinator; Phone Number: 56224205098
• France
  • Gironde
    • Bordeaux, Gironde, France, 33075
      • Recruiting
      • CHU de Bordeaux Hop St ANDRE ( Site 5607)
      • Contact: Study Coordinator; Phone Number: +33556794708
• Israel
  • Haifa, Israel, 3109601
    • Recruiting
    • Rambam Health Care Campus ( Site 5501)
    • Contact: Study Coordinator; Phone Number: +97247772688
  • Petah Tikva, Israel, 4941492
    • Recruiting
    • Rabin Medical Center ( Site 5504)
    • Contact: Study Coordinator; Phone Number: +97239377377
• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Recruiting
      • Erasmus MC ( Site 5303)
      • Contact: Study Coordinator; Phone Number: +31107040704
• South Korea
  • Seoul, South Korea, 03722
    • Recruiting
    • Severance Hospital, Yonsei University Health System ( Site 5903)
    • Contact: Study Coordinator; Phone Number: +8215887757
  • Seoul, South Korea, 05505
    • Recruiting
    • Asan Medical Center ( Site 5901)
    • Contact: Study Coordinator; Phone Number: +8216887575
  • Seoul, South Korea, 06351
    • Recruiting
    • Samsung Medical Center ( Site 5902)
    • Contact: Study Coordinator; Phone Number: +8215993114
• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall de Hebron ( Site 5767)
    • Contact: Study Coordinator; Phone Number: +34932543450
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Clinico San Carlos ( Site 5765)
    • Contact: Study Coordinator; Phone Number: +34913303546
• United Kingdom
  • London, City of
    • London, London, City of, United Kingdom, EC1A 7BE
      • Recruiting
      • St Bartholomew s Hospital ( Site 5206)
      • Contact: Study Coordinator; Phone Number: +442078228498
• United States
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF Medical Center at Mission Bay ( Site 5044)
      • Contact: Study Coordinator; Phone Number: 415-699-7286
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Taussig Cancer ( Site 5036)
      • Contact: Study Coordinator; Phone Number: 216-444-8311
  • Utah
    • Salt Lake City, Utah, United States, 84112-5550
      • Recruiting
      • Huntsman Cancer Institute ( Site 5041)
      • Contact: Study Coordinator; Phone Number: 801-585-0155

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

• Has histologically documented urothelial carcinoma (UC) that is locally advanced and unresectable or metastatic
• Must provide a newly obtained or archival tumor tissue sample (core or excisional biopsy)
• Must not have received prior systemic therapy for locally advanced or metastatic UC
• If infected with Human Immunodeficiency Virus (HIV), has well controlled HIV on antiretroviral therapy
• If positive for hepatitis B surface antigen, has received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load before randomization
• If participant has a history of hepatitis C virus (HCV), has undetectable HCV viral load before randomization

Exclusion Criteria:

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

• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing
• Has active keratitis or corneal ulcerations
• Has active inflammatory bowel disease requiring immunosuppressive medication, or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within the 6 months preceding study intervention
• Has a history of uncontrolled diabetes
• Has pleural effusion, ascites, and/or pericardial effusion that are symptomatic or require repeated drainage
• Has active autoimmune disease that has required systemic treatment in the past 2 years
• Has known additional malignancy that is progressing or has required active treatment within the past 2 years
• Has known active central nervous system metastases and/or carcinomatous meningitis
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• If infected with HIV, has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has concurrent active HBV and HCV infection
• Has a history of stem cell/solid organ transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm A: MK-3120 + Enfortumab Vedotin (EV) + Pembrolizumab; Participants will receive MK-3120 administered intravenously on Day 1 and Day 8 of each 3-week cycle and EV administered intravenously on Day 1 and Day 8 of each 3-week cycle until documented disease progression or any other discontinuation criterion is met and Pembrolizumab 200 mg administered intravenously on Day 1 of each 3-week cycle for up to 35 cycles (~2 years).

Drug: MK-3120; Administered via intravenous (IV) infusion on day 1 and day 8 of each 3-week cycle; Drug: EV; Administered via IV infusion on day 1 and day 8 of each 3-week cycle; Other Names: AGS 22M6E; AGS-22CE; Biological: Pembrolizumab; Administered via IV infusion on day 1 of each 3-week cycle; Other Names: MK-3475; KEYTRUDA®; Drug: Rescue Medication; Participants receive rescue medication at the investigator's discretion, per approved product label. Recommended rescue medication is Granulocyte Colony-Stimulating Factor (G-CSF).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experience an Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants that experience AEs will be reported.	Up to approximately 27 months
Number of Participants Who Experience a Dose Limiting Toxicity (DLT)	DLT will be defined as any drug-related AE observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next treatment. The number of participants who experience a DLT as Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be presented.	Up to approximately 21 days
Number of Participants Who Discontinue Study Treatment Due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants that discontinue study intervention due to an AE will be reported.	Up to approximately 24 months
Objective Response Rate (ORR) as Assessed by Investigator	ORR is defined as the percentage of participants with 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 Investigator will be presented.	Up to approximately 58 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR) as Assessed by Investigator	For participants who demonstrate a confirmed CR (disappearance of all target lesions) or 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), DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. 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 investigator will be presented.	Up to approximately 58 months
Serum Maximum Concentration (Cmax) of MK-3120 Antibody-Drug Conjugate (ADC)	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of MK-3120 ADC.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Trough Concentration (Ctrough) of MK-3120 ADC	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of MK-3120 ADC.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Cmax of MK-3120 Total Antibodies (TAb)	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of MK-3120 TAb.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Ctrough of MK-3120 TAb	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of MK-3120 TAb.	Predose and at designated time points post-dose (up to approximately 24 months)
Plasma Cmax of MK-3120 Free Payload	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of MK-3120 Free Payload.	Predose and at designated time points post-dose (up to approximately 24 months)
Plasma Ctrough of MK-3120 Free Payload	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of MK-3120 Free Payload.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Cmax of EV ADC	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of EV ADC.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Ctrough of EV ADC	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of EV ADC.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Cmax of EV TAb	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of Enfortumab Vedotin (EV) TAb.	Predose and at designated time points post-dose (up to approximately 24 months)
Serum Ctrough of EV TAb	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of EV TAb.	Predose and at designated time points post-dose (up to approximately 24 months)
Plasma Cmax of EV Free Payload	Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of Enfortumab Vedotin (EV) Free Payload.	Predose and at designated time points post-dose (up to approximately 24 months)
Plasma Ctrough of EV Free Payload	Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough of EV Free Payload.	Predose and at designated time points post-dose (up to approximately 24 months)

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2026
• Primary Completion (Estimated): July 8, 2031
• Study Completion (Estimated): July 8, 2031

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Actual): November 18, 2025

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; pembrolizumab; enfortumab vedotin
• Other Study ID Numbers: 3475-04D; U1111-1322-3713 (Registry Identifier: UTN); 2025-522253-19-00 (Registry Identifier: EU CT); MK-3475-04D (Other Identifier: MSD)

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