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)

NCT05562830 | Recruiting Phase 1 FDA Drug

• 5 other identifiers: 3475-04AMK-3475-04A2023-506384-34-00U1111-1293-75482020-004544-28
• Study Type: interventional
• Target: 48
• Locations: 11 countries
• Sites: 28

Brief Summary

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.

Conditions

Urothelial Carcinoma

Outcome Measures

Primary Outcomes (4)

• Percentage of Participants Who Experienced At Least One Adverse Event (AE)

  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

  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)

  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

  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 Outcomes (2)

• Arm A: Duration of Response (DOR) as Assessed by BICR

  Up to approximately 2 years

• Arm B: DOR as Assessed by Investigator

  Up to approximately 2 years

Study Arms (2)

Arm A: Zilovertamab vedotin

EXPERIMENTAL

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

Arm B: Pembrolizumab and MK-3120

EXPERIMENTAL

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; Biological: MK-3120

Interventions

MK-3120 BIOLOGICAL

Administered as an IV infusion on Day 1, Day 15, and Day 29 of each 6 week cycle.

Arm B: Pembrolizumab and MK-3120

Zilovertamab vedotin BIOLOGICAL

Administered via intravenous (IV) infusion on day 1 and day 8 of Q3W cycles

Also known as: MK-2140, VLS-101

Arm A: Zilovertamab vedotin

Pembrolizumab BIOLOGICAL

Administered via IV infusion on Day 1 of each 6 week cycle.

Also known as: MK-3475, KEYTRUDA®

Arm B: Pembrolizumab and MK-3120

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (28)

University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 1045)

Orange, California, 92868, United States

RECRUITING

University of California San Francisco ( Site 1044)

San Francisco, California, 94158, United States

RECRUITING

Anschutz Cancer Pavilion ( Site 1017)

Aurora, Colorado, 80045, United States

COMPLETED

University of Chicago Medical Center ( Site 1037)

Chicago, Illinois, 60637, United States

RECRUITING

Indiana University Melvin and Bren Simon Cancer Center ( Site 1011)

Indianapolis, Indiana, 46202, United States

RECRUITING

Siteman Cancer Center ( Site 1038)

St Louis, Missouri, 63108, United States

RECRUITING

Memorial Sloan Kettering Cancer Center ( Site 1031)

New York, New York, 10065, United States

RECRUITING

Cleveland Clinic-Taussig Cancer Center ( Site 1036)

Cleveland, Ohio, 44195, United States

RECRUITING

UPMC Hillman Cancer Center ( Site 1014)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Huntsman Cancer Institute ( Site 1041)

Salt Lake City, Utah, 84112-5500, United States

RECRUITING

Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Site 1952)

Brisbane, Queensland, 4029, Australia

COMPLETED

Princess Margaret Cancer Centre ( Site 1106)

Toronto, Ontario, M5G 2M9, Canada

RECRUITING

FALP-UIDO ( Site 1151)

Santiago, Region M. de Santiago, 7500921, Chile

RECRUITING

Bradford Hill ( Site 1155)

Santiago, Region M. de Santiago, 8420383, Chile

RECRUITING

Rigshospitalet-Dept. of Oncology ( Site 1701)

Copenhagen, Capital Region, 2100, Denmark

RECRUITING

Rambam Health Care Campus-Oncology ( Site 1501)

Haifa, 3109601, Israel

RECRUITING

Rabin Medical Center-Oncology ( Site 1504)

Petah Tikva, 4941492, Israel

RECRUITING

Sheba Medical Center-ONCOLOGY ( Site 1503)

Ramat Gan, 5265601, Israel

RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 1408)

Milan, Lombardy, 20133, Italy

RECRUITING

Istituto Nazionale Tumori IRCCS Fondazione Pascale-S.C. Sperimentazioni Cliniche ( Site 1406)

Naples, 80131, Italy

RECRUITING

Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 1302)

Amsterdam, North Holland, 1066 CX, Netherlands

RECRUITING

Severance Hospital, Yonsei University Health System ( Site 1903)

Seoul, 03722, South Korea

RECRUITING

Asan Medical Center ( Site 1901)

Seoul, 05505, South Korea

RECRUITING

Samsung Medical Center ( Site 1902)

Seoul, 06351, South Korea

RECRUITING

Hospital Universitari Vall d'Hebron ( Site 1767)

Barcelona, Catalonia, 08035, Spain

RECRUITING

Hospital Clinico San Carlos ( Site 1765)

Madrid, 28040, Spain

RECRUITING

St Bartholomew's Hospital ( Site 1206)

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

RECRUITING

ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 1201)

London, London, City of, SW3 6JJ, United Kingdom

RECRUITING

Related Links

• Merck Oncology Clinical Trials Information
• Protocol Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Central Study Contacts

Toll Free Number

CONTACT

1-888-577-8839; Trialsites@msd.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2022
• First Posted: October 3, 2022
• Study Start: November 16, 2022
• Primary Completion (Estimated): June 28, 2030
• Study Completion (Estimated): June 28, 2030
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

DK (1); NL (1); KR (3); CL (2); AU (1); CA (1); IL (3); GB (2); ES (2); US (10); IT (2)