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Investigational drug combinations for PD-1/L1‑resistant advanced urothelial cancer

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Study of Investigational Agents With or Without Pembrolizumab in Participants With PD-1/L1 Refractory Locally Advanced or Metastatic Urothelial Carcinoma (KEYMAKER-U04): Substudy 04A

Phase1; Phase2 Interventional Merck Sharp & Dohme LLC · NCT05562830

This program will test investigational drugs, with or without pembrolizumab, in people with locally advanced or metastatic urothelial carcinoma that has stopped responding to PD‑1/L1 inhibitors.

Quick facts

PhasePhase1; Phase2
Study typeInterventional
Enrollment48 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC Industry-sponsored
Drugs / interventionspembrolizumab
Locations28 sites (Orange, California and 27 other locations)
Trial IDNCT05562830 on ClinicalTrials.gov

What this trial studies

This substudy is part of an umbrella platform that assigns investigational treatments on a rolling basis to people with locally advanced or metastatic urothelial carcinoma refractory to PD‑1/L1 inhibitors. It enrolls adults into Phase 1/2 arms testing agents such as zilovertamab vedotin and MK‑3120, alone or combined with pembrolizumab, to define safety, tolerability, and early signs of benefit. Participants must have histologically confirmed disease and, for certain arms, provide tumor tissue for biomarker evaluation. The protocol is designed to adapt treatment assignments as new investigational agents are added.

Who should consider this trial

Good fit: Ideal candidates are adults with histologically confirmed locally advanced or metastatic urothelial carcinoma whose disease progressed on or after PD‑1/L1 inhibitor therapy and who can provide an archival or new tumor biopsy suitable for biomarker testing.

Not a fit: Patients who cannot safely undergo biopsy, have uncontrolled serious comorbidities, or have previously received the specific investigational agents being tested are unlikely to benefit from this substudy.

Why it matters

Potential benefit: If successful, these treatments could provide new active therapy options for people with PD‑1/L1‑refractory advanced urothelial carcinoma.

How similar studies have performed: Some antibody–drug conjugates and novel immunotherapy combinations have shown activity in urothelial cancer, but applying these particular investigational agents in PD‑1/L1‑refractory disease is relatively novel.

Eligibility criteria

Show full inclusion / exclusion criteria 
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.

Where this trial is running

Orange, California and 27 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Urothelial Carcinoma
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.