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)

Merck Sharp & Dohme (MSD)

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Urothelial Carcinoma

Treatments: Biological: Zilovertamab vedotin; Biological: Pembrolizumab; Biological: MK-3120

Study type: Interventional

Funder types: Industry

Identifiers

NCT05562830

U1111-1293-7548 (Registry Identifier)

3475-04A

2020-004544-28 (EudraCT Number)

MK-3475-04A (Other Identifier)

2023-506384-34-00 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 48 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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48 participants in 2 patient groups

Arm A: Zilovertamab vedotin

Experimental group

Description:

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.

Treatment:

Biological: Zilovertamab vedotin

Arm B: Pembrolizumab and MK-3120

Experimental group

Description:

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).

Treatment:

Biological: MK-3120

Biological: Pembrolizumab