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

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Gastroesophageal Adenocarcinoma; Esophageal Cancer; Esophageal Neoplasms; Gastroesophageal Junction

Treatments: Biological: Ramucirumab; Drug: Paclitaxel; Biological: MK-2870

Study type: Interventional

Funder types: Industry

Identifiers

NCT06445972

Keymaker-U06 (Other Identifier)

MK-3475-06D (Other Identifier)

3475-06D

U1111-1299-8160 (Other Identifier)

2023-509306-29 (Other Identifier)

Details and patient eligibility

About

This is a phase 1/2 multicenter, open-label umbrella platform study that will evaluate the safety and efficacy of MK-2870 plus paclitaxel 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.

Full description

The master protocol is MK-3475-U06.

Enrollment: 90 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

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

• Has histologically and/or cytologically confirmed diagnosis of previously treated, 2L (received first line (1L) treatment) gastric adenocarcinoma, GEJ 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
• Has gastroesophageal adenocarcinoma that is not human epidermal growth factor receptor 2 (HER2)/neu positive
• Can provide an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion
• 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

Exclusion criteria

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

• Has squamous cell or undifferentiated esophageal gastric 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 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 randomization
• Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or 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 randomization
• Has uncontrolled arterial hypertension ≥150/≥90 mm 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 randomization, or central venous access device placement within 7 days prior to 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 (NSAIDs) or other antiplatelet agents
• Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to 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 randomization
• Has a history of human immunodeficiency virus (HIV) infection
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study drug 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 a 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 (CNS) metastases and/or carcinomatous meningitis
• Has an active infection requiring systemic therapy
• Has a concurrent active Hepatitis B (defined as hepatitis B surface antigen (HBsAg) positive and/or detectable hepatitis B virus deoxyribonucleic acid (HBV DNA)) and Hepatitis C virus (defined as anti-hepatitis C virus antibody (HCV Ab) positive and detectable HCV ribonucleic acid (RNA)) infection
• Has severe hypersensitivity (Grade ≥3) to MK-2870, any of its excipients and/or to another biologic therapy
• Has not adequately recovered from major surgery or have ongoing surgical complications

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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90 participants in 2 patient groups

Ramucirumab + Paclitaxel

Active Comparator group

Description:

Participants will receive ramucirumab at 8mg/kg via intravenous (IV) infusion on days 1 and 15 of each 4-week cycle for up to \~60 weeks plus paclitaxel at 80 mg/M\^2 via IV infusion on Days 1, 8, and 15 of each 4-week cycle (3 weeks on and 1 week off) for up to \~60 weeks.

Treatment:

Drug: Paclitaxel

Biological: Ramucirumab

MK-2870 + Paclitaxel

Experimental group

Description:

Following a 28-day run-in with MK-2870 at 3 mg/kg and 4 mg/kg IV infusion on Days 1 and 15 of a 6-week cycle plus paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8 and 15 of a 4-week cycle, participants will receive paclitaxel at 80 mg/M\^2 IV infusion on days 1, 8, 15 of each 4-week cycle (3 weeks on and 1 week off) up to \~60 weeks plus MK-2870 at selected dose IV infusion on days 1, 15, 29 of every 6-week cycle until discontinuation.

Treatment:

Biological: MK-2870

Drug: Paclitaxel