Clinical trial NCT05845814: A Study of Efficacy and Safety of Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)
Official title: A Phase 1/2 Randomized, Umbrella Study to Evaluate the Safety and Efficacy of Pembrolizumab Plus Enfortumab Vedotin (EV) in Combination With Investigational Agents Versus Pembrolizumab Plus EV, as First-Line Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04B
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Urothelial Carcinoma
Urothelial Neoplasms
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2023-05-06
Enrollment: 390
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Part 1, participants will be randomized in a 1:1:1 ratio to receive either Arm A (coformulated favezelimab/pembrolizumab plus EV), Arm B (coformulated vibostolimab/pembrolizumab plus EV), or Arm C (pembrolizumab plus EV). If Part 2 is conducted, participants will be randomized in a 1:1:1 ratio to Arms A, B, and C or in a 1:1 ratio to Arms A and C or B and C, depending on the treatment arm(s) that are expanded in Part 2.
Primary purpose: TREATMENT

Brief summary: This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the efficacy and safety of coformulated favezelimab/pembrolizumab plus EV and coformulated vibostolimab/pembrolizumab plus EV relative to pembrolizumab plus EV. There will be no comparison of coformulated favezelimab/pembrolizumab plus EV versus coformulated vibostolimab/pembrolizumab plus EV. If ORR and/or DRR are substantially better on coformulated favezelimab/pembrolizumab plus EV and/or coformulated vibostolimab/pembrolizumab plus EV compared with pembrolizumab plus EV, after evaluation of the totality of data, the sponsor might consider Part 2 (expansion) to further characterize the efficacy and safety of the treatment arms under study.

Detailed description: The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.

With Amendment 2, participants will discontinue treatment with coformulated vibostolimab/pembrolizumab (Arm B) and be transitioned to pembrolizumab only. Per protocol, no analysis of Part 2 primary or secondary outcome measures (including efficacy or safety) will occur since Part 2 of the study will no longer take place.

Eligibility criteria: Inclusion Criteria:

* Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).

  * Participants with mixed histology are eligible provided the urothelial component is ≥50% (and \<10% plasmacytoid component)
  * Participants whose tumors contain any neuroendocrine component are not eligible (variant histology to be confirmed locally)
* Must not have received prior systemic therapy for la/mUC. The following therapies in earlier disease setting (eg, muscle-invasive urothelial carcinoma (MIUC)) are permitted:

  * Participants that received neoadjuvant or adjuvant chemotherapy are permitted.
  * Participants who received anti- programmed cell death 1 protein (PD-1) or programmed cell death ligand 1 (PD-L1) therapy for an earlier disease stage (eg, NMIBC, MIUC) with progression/recurrence \>12 months from completion of therapy are permitted.
* 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. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
* Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement or with \<Grade 2 neuropathy are eligible.

Exclusion Criteria:

* Has a known additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
* Central nervous system (CNS) metastases are permitted on-study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) participant does not have leptomeningeal disease.
* Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
* Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
* Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
* Has a history of uncontrolled diabetes.
* Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
* Has an active infection (viral, bacterial, or fungal) requiring systemic therapy.
* Has a known history of human immunodeficiency virus (HIV) infection.
* Has hepatitis B or hepatitis C virus infection.
* Has had major surgery within 4 weeks prior to first dose of study intervention.
* Has had an allogenic tissue/solid organ transplant

Primary outcomes:
measure: Part 1: Objective Response Rate (ORR)
timeFrame: Up to ~4 years
measure: Part 1: Percentage of Participants experiencing an Adverse Event (AE)
timeFrame: Up to ~4 years
measure: Part 1: Percentage of Participants who Discontinue study interventions due to an AE
timeFrame: Up to ~4 years
measure: Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
timeFrame: Up to 21 days
measure: Part 2: Progression Free Survival (PFS)
timeFrame: Up to ~4 years
Secondary outcomes:
measure: Part 1: PFS
timeFrame: Up to ~4 years
measure: Part 1: Duration of Response (DOR)
timeFrame: Up to ~4 years
measure: Part 2: Overall Survival (OS)
timeFrame: Up to ~4 years
measure: Part 2: ORR
timeFrame: Up to ~4 years
measure: Part 2: DOR
timeFrame: Up to ~4 years
measure: Part 2: Percentage of Participants experiencing an Adverse Event (AE)
timeFrame: Up to ~4 years
measure: Part 2: Percentage of Participants who Discontinue study interventions due to an AE
timeFrame: Up to ~4 years
measure: Part 2: Percentage of Participants with Dose-limiting toxicities (DLT)
timeFrame: Up to 21 days
measure: Part 1: Mean Change from baseline in the global health status/quality of life of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLC-C30) (Items 29 and 30)
timeFrame: Baseline and up to ~4 years
measure: Part 1: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
timeFrame: Baseline and up to ~4 years
measure: Part 1: Mean Change from Baseline in the European Quality of Life 5 Dimensions, 5-level Questionnaire (EQ-5D-5L) visual analog score (VAS)
timeFrame: Baseline and up to ~4 years
measure: Part 2: Mean Change from baseline in the global health status/quality of life of the EORTC QLC-C30 (Items 29 and 30)
timeFrame: Baseline and up to ~4 years
measure: Part 2: Mean Change from baseline in the physical functioning scale of the EORTC QLQ-C30
timeFrame: Baseline and up to ~4 years
measure: Part 2: Mean Change from Baseline in the EQ-5D-5L visual analog score (VAS)
timeFrame: Baseline and up to ~4 years
measure: Part 1: Time-to-Deterioration (TTD) for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
timeFrame: Up to ~4 years
measure: Part 1: TTD for the physical functioning scale of the EORTC QLQ-C30
timeFrame: Up to ~4 years
measure: Part 1: TTD for the EQ-5D-5L VAS
timeFrame: Up to ~4 years
measure: Part 2: TTD for the global health status/quality of life of the EORTC QLQ-C30 (Items 29 and 30)
timeFrame: Up to ~4 years
measure: Part 2: TTD for the physical functioning scale of the EORTC QLQ-C30
timeFrame: Up to ~4 years
measure: Part 2: TTD for the EQ-5D-5L VAS
timeFrame: Up to ~4 years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Moores Cancer Center ( Site 3028)
state: California
city: Orange
country: United States
facility: University of California, Irvine (UCI) Health - UC Irvine Medical Center ( Site 3045)
state: California
city: Aurora
country: United States
facility: Anschutz Cancer Pavilion ( Site 3017)
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine ( Site 3043)
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center ( Site 3011)
state: Indiana
city: Saint Louis
country: United States
facility: Washington University School of Medicine ( Site 3038)
state: Missouri
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai ( Site 3018)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 3031)
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic-Taussig Cancer Center ( Site 3036)
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center ( Site 3014)
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute-HCI Clinical Trials Office ( Site 3041)
state: Utah
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Si
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Health-Cancer Clinical Trials Centre ( Site 3950)
state: Victoria
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus-The Ottawa Hospital Cancer Centre ( Site 3105)
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute - Odette Cancer Centre ( Site 3108)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 3106)
state: Ontario
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 3151)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 3155)
state: Region M. De Santiago
city: Viña del Mar
country: Chile
facility: ONCOCENTRO APYS-ACEREY ( Site 3158)
state: Valparaiso
city: Antofagasta
country: Chile
facility: Bradford Hill Norte ( Site 3152)
city: Bordeaux
country: France
facility: CHU de Bordeaux Hop St ANDRE ( Site 3607)
state: Aquitaine
city: Dijon
country: France
facility: Centre Georges François Leclerc-Centre de recherche clinique ( Site 3608)
state: Cote-d Or
city: Toulouse
country: France
facility: Oncopole Claudius Regaud ( Site 3610)
state: Haute-Garonne
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou ( Site 3605)
state: Ile-de-France
city: Pierre-Bénite
country: France
facility: centre hospitalier lyon sud ( Site 3606)
state: Rhone
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology Division ( Site 3501)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center-Oncology ( Site 3504)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center-ONCOLOGY ( Site 3503)
city: Milano
country: Italy
facility: Ospedale San Raffaele-Oncologia Medica ( Site 3403)
state: Lombardia
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Site 3405)
state: Lombardia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 3406)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System-Medical oncology ( Site 3903)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center-Department of Oncology ( Site 3901)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 3902)
city: Maastricht
country: Netherlands
facility: Maastricht UMC+ ( Site 3304)
state: Limburg
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 3302)
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum-Medical Oncology ( Site 3303)
state: Zuid-Holland
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron ( Site 3767)
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos ( Site 3765)
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital at Kaohsiung-Oncology and Hematology ( Site 3802)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital-Clinical Trial Center ( Site 3803)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital-Oncology ( Site 3801)
city: London
country: United Kingdom
facility: St Bartholomew's Hospital-Centre for Experimental Cancer Medicine ( Site 3206)
state: London, City Of
city: London
country: United Kingdom
facility: ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 3201)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: