Substudy 06C: A Study of Investigational Agents With Pembrolizumab (MK-3475) and Chemotherapy in Participants With First-Line Locally Advanced Unresectable/Metastatic Gastroesophageal Adenocarcinoma (MK-3475-06C/KEYMAKER-U06)

Official title

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With Pembrolizumab (MK-3475) and Chemotherapy in Participants With 1L Locally Advanced Unresectable/Metastatic Gastroesophageal Adenocarcinoma (Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, and Esophageal Adenocarcinoma): Substudy 06C

Overview

This is a phase 1/2, multicenter, open-label umbrella platform study that will evaluate the safety and tolerability of investigational agents with pembrolizumab and fluoropyrimidine chemotherapy for the first-line (1L) treatment of participants with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric, gastroesophageal junction, or esophageal adenocarcinoma. This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to evaluate the safety and tolerability, and to establish a recommended Phase 2 dose (RP2D) for investigational agents in combination with chemotherapy and immunotherapy. There is no formal hypothesis in this study.

Detailed description

The master protocol is MK-3475-U06.

Interventions

• Biological Pembrolizumab
  Administered via intravenous (IV) infusion.
• Biological Sacituzumab Tirumotecan (sac-TMT)
  Administered via IV infusion.
• Drug Capecitabine
  Administered via oral tablet.
• Drug Leucovorin
  Administered via IV infusion.
• Drug Levoleucovorin
  Administered via IV infusion.
• Drug 5-Fluorouracil (5-FU)
  Administered via IV infusion
• Drug Oxaliplatin
  Administered via IV infusion
• Biological Patritumab Deruxtecan
  Administered via IV infusion

Primary outcome measures

• Safety Lead-in Phase: Number of Participants Who Experience One or More Dose-Limiting Toxicities (DLTs) [Time frame: Up to approximately 28 days]
• Safety Lead-in Phase: Number of Participants Who Experienced an Adverse Event (AE) [Time frame: Up to approximately 28 days]
• Safety Lead-in Phase: Number of Participants Who Discontinued Study Intervention Due to an AE [Time frame: Up to approximately 28 days]
• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) [Time frame: Up to approximately 28 months]

Secondary outcome measures (6)

• Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR [Time frame: Up to approximately 55 months]
• Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [Time frame: Up to approximately 55 months]
• Overall Survival (OS) [Time frame: Up to approximately 55 months]
• Number of Participants Who Experience an Adverse Event (AE) [Time frame: Up to approximately 55 months]
• Number of Participants Who Discontinue Study Treatment Due to an AE [Time frame: Up to approximately 55 months]
• Incidence of Antidrug Antibodies (ADA) to investigational agents - (sacituzumab tirumotecan (sac-TMT, MK-2870) and patritumab deruxtecan (HER3-DXd)) [Time frame: At designated timepoints up to approximately 55 months]

Eligibility criteria

Inclusion criteria

The main inclusion criteria include but are not limited to the following:

• Has histologically and/or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic first-line (1L) gastroesophageal adenocarcinoma
• Is not expected to require tumor resection during the treatment course
• Tumor tissue must be confirmed as negative for human epidermal growth factor receptor 2 (HER2) expression as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines
• Core/excisional biopsy of a tumor lesion not previously irradiated has been provided
• Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline
• Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible
• Has adequate organ function
• Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by the local site investigator/radiology assessment and verified by blinded independent central review (BICR)
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the first dose of study intervention
• Has a life expectancy of at least 6 months
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to allocation/randomization
• Participants with history of Hepatitis C Virus (HCV) infection are eligible if HCV viral load is undetectable at screening
• Human Immunodeficiency Virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy

Exclusion criteria

The main exclusion criteria include but are not limited to the following:

• Has squamous cell or undifferentiated gastroesophageal cancer.
• Has had previous therapy for locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ)/esophageal adenocarcinoma
• Has experienced weight loss >20% over 3 months before the first dose of study intervention
• Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
• Has Grade ≥2 peripheral neuropathy
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease within 6 months preceding study intervention
• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
• Has history of human immunodeficiency virus (HIV) infection with Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has received prior treatment with a trophoblast antigen 2 (TROP2)-targeted or anti-human epidermal growth factor receptor 3 (HER3) targeted agents
• Has received prior treatment with a topoisomerase I inhibitor-based antibody-drug conjugate (ADC) and/or a topoisomerase I inhibitor-based chemotherapy
• Has received prior systemic anticancer therapy within 4 weeks before the first dose of study intervention
• Has received prior therapy with an anti-Programmed Cell Death Protein 1 (PD-1), anti-Programmed Cell Death-Ligand 1 (PD-L1), anti-Programmed Cell Death-Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR)
• Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities, requiring corticosteroids
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has received a strong inducer/inhibitor of CYP3A4 that cannot be discontinued
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has Severe hypersensitivity (≥Grade 3) to pembrolizumab, sacituzumab tirumotecan, patritumab deruxtecan, or other biologic therapy, chemotherapy (ie, oxaliplatin, fluorouracil, capecitabine), leucovorin, levoleucovorin, or any of their excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years
• Has history of interstitial lung disease (ILD)/pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at Screening
• Has an active infection requiring systemic therapy
• Has concurrent active hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] positive and/or detectable HBV DNA) and hepatitis C virus (defined as anti-hepatitis C virus \[HCV\] Ab positive and detectable HCV ribonucleic acid \[RNA\] infection or a known history of hepatitis B and/or C infection
• Has history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study
• Has gastrointestinal (GI) obstruction, poor oral intake, or difficulty in taking oral medication
• Has poorly controlled diarrhea
• Has had a major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention
• Has history of allogeneic tissue/solid organ transplant
• Has not adequately recovered from major surgery or has ongoing surgical complications

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 6927) — Tucson
• UCLA Hematology/Oncology - Santa Monica ( Site 6905) — Los Angeles
• Norton Hospital-Norton Cancer Institute - Downtown ( Site 6900) — Louisville
• The Cancer and Hematology Centers ( Site 6912) — Grand Rapids
• Hematology-Oncology Associates of Central NY, P.C. ( Site 6925) — East Syracuse
• Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center — New York
• UPMC Hillman Cancer Center-UPMC ( Site 6904) — Pittsburgh
• University of Texas MD Anderson Cancer Center ( Site 6920) — Houston

China · 8 centers

• Beijing Cancer hospital-Digestive Oncology ( Site 5500) — Beijing
• The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation — Fuzhou
• The First Affiliated hospital of Xiamen University ( Site 5503) — Xiamen
• Henan Cancer Hospital ( Site 5504) — Zhengzhou
• The First Affiliated Hospital of Nanchang University ( Site 5514) — Nanchang
• Fudan University Shanghai Cancer Center ( Site 5513) — Shanghai
• Xinjiang Medical University Cancer Hospital - Urumqi ( Site 5506) — Ürümqi
• Sir Run Run Shaw Hospital of Zhejiang University School of Medicine ( Site 5510) — Hangzhou

Chile · 7 centers

• Clínica Puerto Montt ( Site 6409) — Port Montt
• Centro de Investigación del Maule ( Site 6408) — Talca
• FALP-UIDO ( Site 6400) — Santiago
• Centro de Oncología de Precisión-Oncology ( Site 6404) — Santiago
• Clínica UC San Carlos de Apoquindo ( Site 6405) — Santiago
• Bradfordhill-Clinical Area ( Site 6401) — Santiago
• Bradford Hill Norte ( Site 6407) — Antofagasta

Brazil · 4 centers

• Liga Norte Riograndense Contra o Câncer ( Site 6303) — Natal
• Hospital Nossa Senhora da Conceição ( Site 6301) — Porto Alegre
• ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 6300) — São Paulo
• IBCC - Instituto Brasileiro de Controle do Câncer ( Site 6304) — São Paulo

Germany · 4 centers

• NCT-Department of Medical Oncology ( Site 6809) — Heidelberg
• Universitaetsklinikum Duesseldorf-Gastroenterology, Hepatology and Infectiology ( Site 680 — Düsseldorf
• Universitaetsklinikum Carl Gustav Carus Dresden-Medical Dept I - Medical Oncology ( Site 6 — Dresden
• Facharztzentrum Eppendorf-Facharztzentrum Eppendorf ( Site 6807) — Hamburg

Italy · 4 centers

• IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"-Oncologia Medica — Meldola
• Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Oncologia Medica 1 ( Si — Milan
• Azienda Ospedaliero Universitaria Pisana ( Site 5206) — Pisa
• Ospedale San Raffaele-Oncologia Medica ( Site 5202) — Milan

Taiwan · 4 centers

• China Medical University Hospital ( Site 6007) — Taichung
• National Cheng Kung University Hospital ( Site 6001) — Tainan
• National Taiwan University Hospital-Oncology ( Site 6000) — Taipei
• Taipei Veterans General Hospital ( Site 6005) — Taipei

Thailand · 4 centers

• Faculty of Medicine Siriraj Hospital ( Site 6102) — Bangkoknoi
• Chulalongkorn Hospital ( Site 6104) — Pathumwan
• Ramathibodi Hospital ( Site 6103) — Ratchathewi
• Songklanagarind hospital ( Site 6101) — Hat Yai

France · 3 centers

• CHU-BREST Cavale Blanche ( Site 5104) — Brest
• CIC. ( Site 5100) — Lille
• Pitie Salpetriere University Hospital-Hepato-Gastro-Enterology ( Site 5102) — Paris

South Korea · 2 centers

• Asan Medical Center-Department of Oncology ( Site 5901) — Seoul
• Samsung Medical Center-Division of Hematology/Oncology ( Site 5900) — Seoul

Switzerland · 2 centers

• Hôpitaux Universitaires de Genève (HUG) ( Site 6701) — Geneva
• Kantonsspital Graubünden-Medizin ( Site 6700) — Chur

Norway · 1 center

• Oslo universitetssykehus, Radiumhospitalet ( Site 6501) — Oslo

Identifiers

NCT: NCT06469944 · 3475-06C · MK-3475-06C · KEYMAKER-06C · 2023-509307-33-00 · U1111-1299-8084

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗