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)

Phase 1

Active, not recruiting

• Conditions: Urothelial Carcinoma
• Interventions: Biological: Zilovertamab vedotin; Biological: Pembrolizumab; Biological: MK-3120

• Registration Number: NCT05562830
• Lead Sponsor: Merck Sharp & Dohme LLC

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-09-28
• Study First Submitted QC: 2022-09-28
• Study First Posted: 2022-10-03
• Study Start: 2022-11-16
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-10
• Last Update Posted: 2025-07-14
• Primary Completion: 2028-05-08
• Study Completion: 2028-05-08

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 48

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: Zilovertamab vedotin	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.
Arm B: Pembrolizumab and MK-3120	Pembrolizumab	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).
Arm B: Pembrolizumab and MK-3120	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).

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced At Least One Adverse Event (AE)	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.
Percentage of Participants Who Discontinued Study Treatment Due to an AE	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
Arm A: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)	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.
Arm B: ORR as Assessed by Investigator	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.

Secondary Outcome Measures

Name	Time	Method
Arm A: Duration of Response (DOR) as Assessed by BICR	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.
Arm B: DOR as Assessed by Investigator	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.

Trial Locations

Locations (18)

University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 1045); 🇺🇸 Orange, California, United States

Anschutz Cancer Pavilion ( Site 1017); 🇺🇸 Aurora, Colorado, United States

Indiana University Melvin and Bren Simon Cancer Center ( Site 1011); 🇺🇸 Indianapolis, Indiana, United States

Siteman Cancer Center ( Site 1038); 🇺🇸 Saint Louis, Missouri, United States

Cleveland Clinic-Taussig Cancer Center ( Site 1036); 🇺🇸 Cleveland, Ohio, United States

UPMC Hillman Cancer Center ( Site 1014); 🇺🇸 Pittsburgh, Pennsylvania, United States

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

FALP-UIDO ( Site 1151); 🇨🇱 Santiago, Region M. De Santiago, Chile

Bradfordhill-Clinical Area ( Site 1155); 🇨🇱 Santiago, Region M. De Santiago, Chile

Rigshospitalet-Dept. of Oncology ( Site 1701); 🇩🇰 Copenhagen, Hovedstaden, Denmark

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