Substudy 06D: Combination Therapies in Second Line (2L) Gastroesophageal Adenocarcinoma (MK-3475-06D/Keymaker-U06)

Official title

A Phase 1/2 Open-Label, Umbrella Platform Design Study to Evaluate the Safety and Efficacy of Investigational Agents in Combination With Standard of Care Treatments as the Second-Line Treatment of Participants With Advanced/Metastatic Gastroesophageal Adenocarcinoma: Substudy 06D

Overview

This is a phase 1/2 multicenter, open-label umbrella platform study that will evaluate the safety and efficacy of sacituzumab tirumotecan (MK-2870) plus paclitaxel versus ramucirumab plus paclitaxel, and HER3-DXD plus ramucirumab versus ramucirumab plus paclitaxel for the treatment of participants with advanced or metastatic gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, or esophageal adenocarcinoma who have failed 1 prior line of therapy. This is an estimation study, and no formal hypothesis testing will be performed.

Detailed description

This is a substudy of the master protocol MK-3475-U06 (KEYMAKER-U06).

Interventions

• Biological Ramucirumab
  8 mg/kg IV Infusion
• Drug Paclitaxel
  80 mg/M\^2 IV infusion
• Biological Sacituzumab Tirumotecan
  3 mg/kg or 4 mg/kg IV Infusion
• Drug Rescue Medications
  Participants receive rescue medications according to each approved drug's product label. Recommended rescue medications for the Sacituzumab Tirumotecan + Paclitaxel arm include antihistamines (histamine-1 and histamine-2 receptor antagonists), acetaminophen or equivalent, dexamethasone or equivalent infusion, and steroid mouth wash (dexamethasone or equivalent) and rescue medications for the HER3-DXd + ramucirumab arm include 5-HT3-receptor antagonist, NK-1 receptor antagonist, and corticosteroi
• Biological HER3-DXd
  IV Infusion

Primary outcome measures

• Percentage of Participants who Experience Dose Limiting Toxicities (DLTs) During the Safety Lead-In Phase [Time frame: Up to ~28 days]
• Percentage of Particiapants who Experience an Adverse Event (AE) During the Safety Lead-In Phase [Time frame: Up to ~60 days]
• Percentage of Participants who Discontinue Study Intervention Due to an AE During the Safety Lead-In Phase [Time frame: Up to ~28 days]
• Objective Response Rate (ORR) [Time frame: Up to ~28 months]

Secondary outcome measures (7)

• Progression Free Survival (PFS) [Time frame: Up to ~50 months]
• Duration of Response (DOR) [Time frame: Up to ~50 months]
• Overall Survival (OS) [Time frame: Up to ~50 months]
• Percentage of Particiapants who Experience an AE During the Efficacy Phase [Time frame: Up to ~50 months]
• Percentage of Participants who Discontinue Study Intervention Due to an AE During the Efficacy Phase [Time frame: Up to ~50 months]
• Incidence of sacituzumab tirumotecan anti-drug antibody (ADA) [Time frame: Up to ~50 months]
• Incidence of HER3-DXd ADA [Time frame: Up to ~50 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 treated, second line (2L) (received first line (1L) treatment) gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma
• Has metastatic disease or locally advanced, unresectable disease
• Has experienced documented objective radiographic or clinical disease progression during or after 1L therapy containing any platinum/fluoropyrimidine doublet with or without immunotherapy
• Tumor tissue must be confirmed as negative for HER2 expression (IHC 0/1+ or IHC2+/in situ hybridization negative) as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines
• Can provide a core/excisional biopsy of a tumor lesion not previously irradiated (collected from a biopsy performed after the most recent systemic anticancer therapy regimen)
• AEs due to previous anticancer therapies must be ≤Grade 1 or baseline (except alopecia and vitiligo). Endocrine-related AEs adequately treated with hormone replacement are acceptable
• Has Eastern Cooperative Oncology Group performance status of 0 or 1
• Has a life expectancy of at least 3 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 experienced weight loss >20% over 3 months before the first dose of study intervention
• Has 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 a serious or nonhealing wound or peptic ulcer or bone fracture within 28 days prior to allocation/randomization
• Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea)
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
• Has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to allocation/randomization
• Has uncontrolled arterial hypertension ≥150/≥90 mm mercury (Hg)
• Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment
• Has undergone major surgery within 28 days prior to allocation/randomization, or central venous access device placement within 7 days prior to allocation/randomization or planned major surgery following initiation of study treatment
• Is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents
• Is receiving chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet agents
• Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism during the 3 months prior to allocation/randomization
• Has significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal (GI) tract within 3 months prior to study entry
• Has history of GI perforation and/or fistulae within 6 months prior to allocation/randomization
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
• Has received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)- or HER3-targeted agent, topoisomerase 1 inhibitor-based ADC and/or a topoisomerase 1 inhibitor-based chemotherapy, or any previous systemic therapy targeting vascular endothelial growth factor (VEGF) or the vascular endothelial growth factor receptor (VEGFR) signaling pathways
• Has received prior systemic anticancer therapy within 4 weeks before the first dose of study intervention
• 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. Administration of killed vaccines is allowed
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• Has known additional malignancy that is progressing or has required active treatment within the past 3 years. Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded
• Has known active central nervous system metastases and/or carcinomatous meningitis
• Has an active infection requiring systemic therapy
• Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV deoxyribonucleic acid) and Hepatitis C virus (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid) infection
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease, or where suspected ILD or pneumonitis cannot be ruled out by imaging at screening
• Has severe hypersensitivity (Grade ≥3) to MK-2870, or HER3-DXd, any of their excipients, and/or to another biologic therapy
• Has not adequately recovered from major surgery or have 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

Single blind

Primary purpose

Treatment

Study locations

United States · 8 centers

• University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 8927) — Tucson
• UCLA Hematology/Oncology - Santa Monica ( Site 8905) — Los Angeles
• Norton Cancer Institute - Downtown ( Site 8900) — Louisville
• The Cancer and Hematology Centers ( Site 8912) — Grand Rapids
• Hematology-Oncology Associates of Central NY, P.C. ( Site 8925) — East Syracuse
• Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center — New York
• UPMC Hillman Cancer Center-UPMC ( Site 8904) — Pittsburgh
• University of Texas MD Anderson Cancer Center ( Site 8920) — Houston

China · 8 centers

• Beijing Cancer hospital-Digestive Oncology ( Site 7500) — 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 7503) — Xiamen
• Henan Cancer Hospital ( Site 7504) — Zhengzhou
• The First Affiliated Hospital of Nanchang University ( Site 7514) — Nanchang
• Fudan University Shanghai Cancer Center ( Site 7513) — Shanghai
• Xinjiang Medical University Cancer Hospital - Urumqi ( Site 7506) — Ürümqi
• Sir Run Run Shaw Hospital of Zhejiang University School of Medicine ( Site 7510) — Hangzhou

Chile · 7 centers

• Clínica Puerto Montt ( Site 8409) — Port Montt
• Centro de Investigación del Maule ( Site 8408) — Talca
• FALP-UIDO ( Site 8400) — Santiago
• Centro de Oncología de Precisión-Oncology ( Site 8404) — Santiago
• Clínica UC San Carlos de Apoquindo ( Site 8405) — Santiago
• Bradfordhill-Clinical Area ( Site 8401) — Santiago
• Bradford Hill Norte ( Site 8407) — Antofagasta

Brazil · 4 centers

• Liga Norte Riograndense Contra o Câncer ( Site 8303) — Natal
• Hospital Nossa Senhora da Conceição ( Site 8301) — Porto Alegre
• IBCC - Instituto Brasileiro de Controle do Câncer ( Site 8304) — São Paulo
• ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 8300) — São Paulo

Germany · 4 centers

• NCT-Department of Medical Oncology ( Site 8809) — Heidelberg
• Universitaetsklinikum Duesseldorf-Gastroenterology, Hepatology and Infectiology ( Site 880 — Düsseldorf
• Universitaetsklinikum Carl Gustav Carus Dresden-Medical Dept I - Medical Oncology ( Site 8 — Dresden
• Facharztzentrum Eppendorf-Facharztzentrum Eppendorf ( Site 8807) — 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 7206) — Pisa
• Ospedale San Raffaele-Oncologia Medica ( Site 7202) — Milan

Taiwan · 4 centers

• China Medical University Hospital ( Site 8007) — Taichung
• National Cheng Kung University Hospital ( Site 8001) — Tainan
• National Taiwan University Hospital-Oncology ( Site 8000) — Taipei
• Taipei Veterans General Hospital ( Site 8005) — Taipei

France · 3 centers

• Centre Hospitalier Régional Universitaire de Brest - Hôpital-Institut de cancérologie et h — Brest
• CIC. ( Site 7100) — Lille
• Pitie Salpetriere University Hospital-Hepato-Gastro-Enterology ( Site 7102) — Paris

South Korea · 2 centers

• Asan Medical Center-Department of Oncology ( Site 7901) — Seoul
• Samsung Medical Center-Division of Hematology/Oncology ( Site 7900) — Seoul

Switzerland · 2 centers

• Hôpitaux Universitaires de Genève (HUG) ( Site 8701) — Geneva
• Kantonsspital Graubünden-Medizin ( Site 8700) — Chur

Norway · 1 center

• Oslo universitetssykehus, Radiumhospitalet ( Site 8501) — Oslo

Identifiers

NCT: NCT06445972 · 3475-06D · 2023-509306-29-00 · U1111-1299-8160 · MK-3475-06D

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗