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)

Merck Sharp & Dohme (MSD)

Status and phase

Enrolling

Phase 2

Phase 1

Conditions

Gastroesophageal Adenocarcinoma

Esophageal Cancer

Esophageal Neoplasms

Gastroesophageal Junction

Treatments

Drug: Levoleucovorin

Drug: 5-Fluorouracil (5-FU)

Drug: Oxaliplatin

Drug: Leucovorin

Biological: Pembrolizumab

Drug: Capecitabine

Biological: Patritumab Deruxtecan

Biological: Sacituzumab Tirumotecan (sac-TMT)

Study type

Interventional

Funder types

Industry

Identifiers

NCT06469944

3475-06C

2023-509307-33-00 (Registry Identifier)

MK-3475-06C (Other Identifier)

U1111-1299-8084 (Other Identifier)

KEYMAKER-06C (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 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.

Full description

The master protocol is MK-3475-U06.

Enrollment

160 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 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 (noninfectious) pneumonitis or interstitial lung disease (ILD) that required steroids or has current pneumonitis or ILD, or where suspected ILD or pneumonitis 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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

160 participants in 3 patient groups

Pembrolizumab plus Chemotherapy

Active Comparator group

Description:

Participants will receive pembrolizumab 400 mg via intravenous (IV) injection on day 1 of every 6 week cycle (Q6W) for up to 18 cycles (up to \~2 years) AND investigator's choice of CAPOX chemotherapy (capecitabine 1000 mg/m\^2 orally twice daily for 14 days every 3 weeks (Q3W) and oxaliplatin 130 mg/m\^2 via IV infusion Q3W) OR mFOLFOX6 chemotherapy (oxaliplatin 85 mg/m\^2 via IV infusion Q3W; 5-Fluorouracil (5-FU) 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once every 2 weeks (Q2W); and leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W).

Treatment:

Drug: Capecitabine

Biological: Pembrolizumab

Drug: Oxaliplatin

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Drug: Levoleucovorin

Pembrolizumab plus Sacituzumab Tirumotecan plus Chemotherapy

Experimental group

Description:

Participants will receive sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W AND leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W.

Treatment:

Biological: Sacituzumab Tirumotecan (sac-TMT)

Drug: Capecitabine

Biological: Pembrolizumab

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Drug: Levoleucovorin

Pembrolizumab plus Patritumab Deruxtecan plus Chemotherapy

Experimental group

Description:

Participants will receive patritumab deruxtecan via IV infusion on Days 1 and 22 Q6W until discontinuation, pembrolizumab 400 mg via IV injection on day 1 Q6W for up to 18 cycles (up to \~2 years) AND investigator's choice of capecitabine 1000 mg/m\^2 orally twice daily for 14 days Q3W OR 5-FU 400 mg/\^2 via bolus IV plus 2400 mg/m\^2 continuous IV once Q2W AND leucovorin 400 mg/m\^2 via IV infusion Q2W OR levoleucovorin 200 mg/m\^2 Q2W.

Treatment:

Biological: Patritumab Deruxtecan

Drug: Capecitabine

Biological: Pembrolizumab

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Drug: Levoleucovorin