A Study of Efficacy and Safety of Sacituzumab Tirumotecan (MK-2870) Plus Enfortumab Vedotin (EV) With and Without Pembrolizumab in Advanced Urothelial Carcinoma (MK-3475-04C/KEYMAKER-U04)

A Phase 1/2 Randomized, Umbrella Study to Evaluate the Efficacy and Safety of MK-2870 Plus Enfortumab Vedotin (EV) With and Without Pembrolizumab, as Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04C

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 safety and preliminary efficacy of sacituzumab tirumotecan plus enfortumab vedotin (EV). Part 2 will be based on Part 1 results and will evaluate the efficacy, pharmacokinetics, and safety of sacituzumab tirumotecan plus EV in combination with pembrolizumab in participants with advanced urothelial carcinoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Sacituzumab tirumotecan; Biological: Enfortumab Vedotin; Drug: Supportive care measures

Detailed Description

The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.

As of Amendment 5, Part 2 will not be conducted. No participants will be enrolled in Part 2, and no data for Part 2 will be collected.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus ( Site 4105)
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre ( Site 4106)
• France
  • Auvergne-Rhône-Alpes
    • Pierre-Bénite, Auvergne-Rhône-Alpes, France, 69310
      • Centre Hospitalier Lyon Sud ( Site 4606)
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus ( Site 4501)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center-Oncology ( Site 4504)
  • Ramat Gan, Israel, 5265601
    • Sheba Medical Center-ONCOLOGY ( Site 4503)
• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 4405)
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 4406)
  • Lombardy
    • Milan, Lombardy, Italy, 20132
      • Ospedale San Raffaele-Oncologia Medica ( Site 4403)
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1066 CX
      • Nederlands Kanker Instituut - Antoni van Leeuwenhoek - NKI-AVL ( Site 4302)
• South Korea
  • Seoul, South Korea, 03722
    • Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4903)
  • Seoul, South Korea, 05505
    • Asan Medical Center-Department of Oncology ( Site 4901)
  • Seoul, South Korea, 06351
    • Samsung Medical Center ( Site 4902)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron-Oncology ( Site 4767)
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos ( Site 4765)
• Taiwan
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital-Clinical Trial Center ( Site 4803)
• United Kingdom
  • London, City of
    • London, London, City of, United Kingdom, EC1A 7BE
      • St Bartholomew s Hospital ( Site 4206)
• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California San Francisco HDFCCC ( Site 4044)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center ( Site 4037)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center ( Site 4011)
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute ( Site 4047)
  • Missouri
    • St Louis, Missouri, United States, 63108
      • Siteman Cancer Center ( Site 4038)
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai ( Site 4018)
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic-Taussig Cancer Center ( Site 4036)
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 4041)

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:

• Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
• 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 are eligible.
• PART 1 ONLY: Participants must have received platinum-based chemotherapy for treatment of la/mUC.
• PART 1 ONLY: Participants must not have received >2 lines of therapy for la/mUC. Platinum-based chemotherapy followed by avelumab maintenance is considered 2 lines of therapy.
• PART 2 ONLY: Participants must not have received prior systemic therapy for la/mUC.

Exclusion Criteria:

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

• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Known active central nervous system metastases and/or carcinomatous meningitis.
• Has Grade ≥2 peripheral neuropathy.
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• 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 and/or serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.
• 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 a history of uncontrolled diabetes.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
• PART 2 ONLY: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before 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.
• PART 2 ONLY: Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
• Is human immunodeficiency virus (HIV)-infected and has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has active Hepatitis B or Hepatitis C virus infection.
• 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.
• PART 2 ONLY: History of allogeneic tissue/solid organ transplant.
• Has not adequately recovered from major surgery or has ongoing surgical complications.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacituzumab tirumotecan plus EV; Participants will receive sacituzumab tirumotecan as an intravenous (IV) infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.	Biological: Sacituzumab tirumotecan; IV infusion at different dose levels; Other Names: SKB264; MK-2870; Biological: Enfortumab Vedotin; IV infusion at different dose levels; Other Names: PADCEV™; Drug: Supportive care measures; Participants are allowed to take supportive care measures at the discretion of the investigator. Prophylactic supportive care measures may include but are not limited to antiemetic agents, antidiarrheal agents, granulocyte and erythroid growth factors, and blood transfusions.
Experimental: Sacituzumab tirumotecan plus EV and pembrolizumab; Participants will receive sacituzumab tirumotecan as an IV infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Participants will also receive pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles).	Biological: Pembrolizumab; 200 mg IV infusion; Other Names: KEYTRUDA; MK-3475; Biological: Sacituzumab tirumotecan; IV infusion at different dose levels; Other Names: SKB264; MK-2870; Biological: Enfortumab Vedotin; IV infusion at different dose levels; Other Names: PADCEV™; Drug: Supportive care measures; Participants are allowed to take supportive care measures at the discretion of the investigator. Prophylactic supportive care measures may include but are not limited to antiemetic agents, antidiarrheal agents, granulocyte and erythroid growth factors, and blood transfusions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 1: Percentage of Participants Who Experienced At Least One 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 ~3 years
Part 1: Percentage of Participants Who Discontinued Study Treatment 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 treatment due to an AE in Part 1 will be reported.	Up to ~2 years
Part 2: Percentage of Participants with 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 NCI CTCAE 5.0. The number of participants who experience a DLT in Part 2 will be reported.	Up to 21 days
Part 2: Percentage of Participants Who Experienced At Least One 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 2 will be reported.	Up to ~3 years
Part 2: Percentage of Participants Who Discontinued Study Treatment 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 treatment due to an AE in Part 2 will be reported.	Up to ~2 years
Part 2: Objective Response Rate (ORR)	ORR is defined as the percentage of participants who achieve a confirmed 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 (RECIST) 1.1 as assessed by investigator. ORR will be reported for participants in Part 2.	Up to ~3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: ORR	ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by investigator. ORR will be reported for participants in Part 1.	Up to ~3 years
Part 2: Duration of Response (DOR)	For participants who demonstrate confirmed CR or PR 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 investigator will be presented.	Up to ~3 years
Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC)	Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC	Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan	Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan	Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 1: Cmax of Enfortumab Vedotin-ADC	Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 1.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8
Part 1: Ctrough of Enfortumab Vedotin-ADC	Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 1.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8
Part 1: Cmax of Free Payload for Enfortumab Vedotin	Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8
Part 1: Ctrough of Free Payload for Enfortumab Vedotin	Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 1.	Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8
Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan	Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 1 will be presented.	Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 1: Incidence of ADA to Enfortumab Vedotin	Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 1 will be presented.	Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8
Part 2: Cmax of Sacituzumab Tirumotecan-ADC	Blood samples collected at designated time points will be used to determine the Cmax of sacituzumab tirumotecan-ADC in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Ctrough of Sacituzumab Tirumotecan-ADC	Blood samples collected at designated time points will be used to determine the Ctrough of sacituzumab tirumotecan-ADC in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan	Blood samples collected at designated time points will be used to determine the Cmax of free payload for sacituzumab tirumotecan in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan	Blood samples collected at designated time points will be used to determine the Ctrough of free payload for sacituzumab tirumotecan in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Cmax of Enfortumab Vedotin-ADC	Blood samples collected at designated time points will be used to determine the Cmax of enfortumab vedotin-ADC in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
Part 2: Ctrough of Enfortumab Vedotin-ADC	Blood samples collected at designated time points will be used to determine the Ctrough of enfortumab vedotin-ADC in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
Part 2: Cmax of Free Payload for Enfortumab Vedotin	Blood samples collected at designated time points will be used to determine the Cmax of free payload for EV in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
Part 2: Ctrough of Free Payload for Enfortumab Vedotin	Blood samples collected at designated time points will be used to determine the Ctrough of free payload for EV in Part 2.	Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8
Part 2: Cmax of Pembrolizumab-ADC	Blood samples collected at designated time points will be used to determine the Cmax of pembrolizumab-ADC.	Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Ctrough of Pembrolizumab-ADC	Blood samples collected at designated time points will be used to determine the Ctrough of pembrolizumab-ADC.	Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Cmax of Free Payload for Pembrolizumab	Blood samples collected at designated time points will be used to determine the Cmax of free payload for pembrolizumab.	Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Ctrough of Free Payload for Pembrolizumab	Blood samples collected at designated time points will be used to determine the Ctrough of free payload for pembrolizumab.	Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Incidence of ADA to Sacituzumab Tirumotecan	Blood samples collected at designated timepoints will be used to determine the ADA response to sacituzumab tirumotecan. The incidence of ADAs over time in Part 2 will be presented.	Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose
Part 2: Incidence of ADA to Enfortumab Vedotin	Blood samples collected at designated timepoints will be used to determine the ADA response to EV. The incidence of ADAs over time in Part 2 will be presented.	Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8
Part 2: Incidence of ADA to Pembrolizumab	Blood samples collected at designated timepoints will be used to determine the ADA response to pembrolizumab. The incidence of ADAs over time be presented.	Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose

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): July 17, 2024
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2028

Study Registration Dates

• First Submitted: June 21, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): July 3, 2024

Study Record Updates

• Last Update Posted (Actual): February 18, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2); Programmed Cell Death 1 Ligand 1(PDL1, PD-L1)
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Parkinson Disease 4, Autosomal Dominant Lewy Body; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab; enfortumab vedotin
• Other Study ID Numbers: 3475-04C; MK-3475-04C (Other Identifier: MSD); U1111-1293-7631 (Registry Identifier: UTN); 2023-506387-14-00 (Registry Identifier: EU CT)

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