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)

NCT06483334 | Active Not Recruiting Phase 1 FDA Drug

• 4 other identifiers: 3475-04CMK-3475-04C2023-506387-14-00U1111-1293-7631
• Study Type: interventional
• Target: 38
• Locations: 10 countries
• Sites: 25

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 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.

Conditions

Metastatic Urothelial Carcinoma; Locally Advanced Urothelial Carcinoma

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1(PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (27)

• Part 1: ORR

  Up to ~3 years

• Part 2: Duration of Response (DOR)

  Up to ~3 years

• Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC)

  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

  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

  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

Study Arms (2)

Sacituzumab tirumotecan plus EV

EXPERIMENTAL

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; Biological: Enfortumab Vedotin; Drug: Supportive care measures

Sacituzumab tirumotecan plus EV and pembrolizumab

EXPERIMENTAL

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: Sacituzumab tirumotecan; Biological: Enfortumab Vedotin; Biological: Pembrolizumab; Drug: Supportive care measures

Interventions

Supportive care measures DRUG

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.

Sacituzumab tirumotecan plus EV; Sacituzumab tirumotecan plus EV and pembrolizumab

Sacituzumab tirumotecan BIOLOGICAL

IV infusion at different dose levels

Also known as: MK-2870, SKB264

Sacituzumab tirumotecan plus EV; Sacituzumab tirumotecan plus EV and pembrolizumab

Enfortumab Vedotin BIOLOGICAL

IV infusion at different dose levels

Also known as: PADCEV™

Sacituzumab tirumotecan plus EV; Sacituzumab tirumotecan plus EV and pembrolizumab

Pembrolizumab BIOLOGICAL

200 mg IV infusion

Also known as: MK-3475, KEYTRUDA

Sacituzumab tirumotecan plus EV and pembrolizumab

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).
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (25)

University of California San Francisco HDFCCC ( Site 4044)

San Francisco, California, 94158, United States

Location

University of Chicago Medical Center ( Site 4037)

Chicago, Illinois, 60637, United States

Location

Indiana University Melvin and Bren Simon Cancer Center ( Site 4011)

Indianapolis, Indiana, 46202, United States

Location

Dana-Farber Cancer Institute ( Site 4047)

Boston, Massachusetts, 02115, United States

Location

Siteman Cancer Center ( Site 4038)

St Louis, Missouri, 63108, United States

Location

Icahn School of Medicine at Mount Sinai ( Site 4018)

New York, New York, 10029, United States

Location

Cleveland Clinic-Taussig Cancer Center ( Site 4036)

Cleveland, Ohio, 44195, United States

Location

Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 4041)

Salt Lake City, Utah, 84112, United States

Location

The Ottawa Hospital - General Campus ( Site 4105)

Ottawa, Ontario, K1H 8L6, Canada

Location

Princess Margaret Cancer Centre ( Site 4106)

Toronto, Ontario, M5G 2M9, Canada

Location

Centre Hospitalier Lyon Sud ( Site 4606)

Pierre-Bénite, Auvergne-Rhône-Alpes, 69310, France

Location

Rambam Health Care Campus ( Site 4501)

Haifa, 3109601, Israel

Location

Rabin Medical Center-Oncology ( Site 4504)

Petah Tikva, 4941492, Israel

Location

Sheba Medical Center-ONCOLOGY ( Site 4503)

Ramat Gan, 5265601, Israel

Location

Ospedale San Raffaele-Oncologia Medica ( Site 4403)

Milan, Lombardy, 20132, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori ( Site 4405)

Milan, 20133, Italy

Location

Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 4406)

Naples, 80131, Italy

Location

Nederlands Kanker Instituut - Antoni van Leeuwenhoek - NKI-AVL ( Site 4302)

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Severance Hospital, Yonsei University Health System-Medical oncology ( Site 4903)

Seoul, 03722, South Korea

Location

Asan Medical Center-Department of Oncology ( Site 4901)

Seoul, 05505, South Korea

Location

Samsung Medical Center ( Site 4902)

Seoul, 06351, South Korea

Location

Hospital Universitari Vall d'Hebron-Oncology ( Site 4767)

Barcelona, 08035, Spain

Location

Hospital Clinico San Carlos ( Site 4765)

Madrid, 28040, Spain

Location

National Cheng Kung University Hospital-Clinical Trial Center ( Site 4803)

Tainan, 704, Taiwan

Location

St Bartholomew s Hospital ( Site 4206)

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

Location

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

enfortumab vedotin; 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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 is non-randomized open-label. Part 2 is randomized open-label (as of Amendment 5, Part 2 will not be conducted).

Study Record Dates

• First Submitted: June 21, 2024
• First Posted: July 3, 2024
• Study Start: July 17, 2024
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2028
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

ES (2); GB (1); FR (1); US (8); CA (2); IL (3); IT (3); KR (3); NL (1); TW (1)