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)

Official title

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

Overview

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.

Interventions

• Biological Zilovertamab vedotin
  Administered via intravenous (IV) infusion on day 1 and day 8 of Q3W cycles
• Biological Pembrolizumab
  Administered via IV infusion on Day 1 of each 6 week cycle.
• Biological MK-3120
  Administered as an IV infusion on Day 1, Day 15, and Day 29 of each 6 week cycle.

Primary outcome measures

• Percentage of Participants Who Experienced At Least One Adverse Event (AE) [Time frame: Up to approximately 5 years]
• Percentage of Participants Who Discontinued Study Treatment Due to an AE [Time frame: Up to approximately 5 years]
• Arm A: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) [Time frame: Up to approximately 2 years]
• Arm B: ORR as Assessed by Investigator [Time frame: Up to approximately 2 years]

Secondary outcome measures (2)

• Arm A: Duration of Response (DOR) as Assessed by BICR [Time frame: Up to approximately 2 years]
• Arm B: DOR as Assessed by Investigator [Time frame: Up to approximately 2 years]

Eligibility 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 1045) — Orange
• University of California San Francisco ( Site 1044) — San Francisco
• Anschutz Cancer Pavilion ( Site 1017) — Aurora
• University of Chicago Medical Center ( Site 1037) — Chicago
• Indiana University Melvin and Bren Simon Cancer Center ( Site 1011) — Indianapolis
• Siteman Cancer Center ( Site 1038) — St Louis
• Memorial Sloan Kettering Cancer Center ( Site 1031) — New York
• Cleveland Clinic-Taussig Cancer Center ( Site 1036) — Cleveland
• … and 2 more centers

Israel · 3 centers

• Rambam Health Care Campus-Oncology ( Site 1501) — Haifa
• Rabin Medical Center-Oncology ( Site 1504) — Petah Tikva
• Sheba Medical Center-ONCOLOGY ( Site 1503) — Ramat Gan

South Korea · 3 centers

• Severance Hospital, Yonsei University Health System ( Site 1903) — Seoul
• Asan Medical Center ( Site 1901) — Seoul
• Samsung Medical Center ( Site 1902) — Seoul

Chile · 2 centers

• FALP-UIDO ( Site 1151) — Santiago
• Bradford Hill ( Site 1155) — Santiago

Italy · 2 centers

• Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Si — Milan
• Istituto Nazionale Tumori IRCCS Fondazione Pascale-S.C. Sperimentazioni Cliniche ( Site 14 — Naples

Spain · 2 centers

• Hospital Universitari Vall d'Hebron ( Site 1767) — Barcelona
• Hospital Clinico San Carlos ( Site 1765) — Madrid

United Kingdom · 2 centers

• St Bartholomew's Hospital ( Site 1206) — London
• ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 1201) — London

Australia · 1 center

• Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Ser — Brisbane

Canada · 1 center

• Princess Margaret Cancer Centre ( Site 1106) — Toronto

Denmark · 1 center

• Rigshospitalet-Dept. of Oncology ( Site 1701) — Copenhagen

Netherlands · 1 center

• Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 130 — Amsterdam

Identifiers

NCT: NCT05562830 · 3475-04A · MK-3475-04A · 2023-506384-34-00 · U1111-1293-7548 · 2020-004544-28

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗