Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Esophageal Squamous Cell Carcinoma

Treatments: Biological: Sacituzumab tirumotecan; Drug: Oxaliplatin; Drug: Rescue Medication; Biological: I-DXd; Drug: Levoleucovorin; Drug: 5-Fluorouracil (5-FU); Biological: Pembrolizumab; Drug: Leucovorin

Study type: Interventional

Funder types: Industry

Identifiers

NCT06780111

2024-514273-22-00 (Registry Identifier)

U1111-1307-6484 (Other Identifier)

3475-06E

jRCT2041240166 (Registry Identifier)

MK-3475-06E (Other Identifier)

Details and patient eligibility

About

Researchers are looking for new ways to treat esophageal squamous cell carcinoma (ESCC). ESCC is a type of cancer that starts in certain cells that line the esophagus. The esophagus is the tube that connects the throat to the stomach. This study will look at ESCC that is either locally advanced unresectable, which means it has spread into tissue near where it started and cannot be completely removed by surgery, or metastatic, which means it has spread to other body parts.

Available treatments for these types of ESCC include pembrolizumab and chemotherapy. Pembrolizumab is an immunotherapy, which is a treatment that helps the immune system fight cancer. Chemotherapy is medicine that destroys cancer cells or stops them from growing.

Researchers want to learn about giving pembrolizumab and investigational agents, with or without chemotherapy to treat ESCC. Ifinatamab deruxtecan (I-DXd), is an antibody-drug conjugate (ADC). An ADC attaches to a protein on cancer cells and delivers treatment to destroy those cells.

The main goal of this study is to learn about the safety of investigational agents and pembrolizumab with or without chemotherapy and if people tolerate them. Researchers also want to learn how cancer responds (gets smaller or goes away) to the study treatments.

Full description

The master protocol is MK-3475-U06

Enrollment: 298 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

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

• Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic squamous cell carcinoma of the esophagus in first-line (1L) setting.
• Has measurable disease per RECIST 1.1 as assessed by the local site. investigator or designee/radiology assessment and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
• Has AEs due to previous anticancer therapies of ≤Grade 1 or baseline (except alopecia and vitiligo). Endocrine-related AEs adequately treated with hormone replacement are acceptable.
• Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Has adequate organ function.

Exclusion Criteria

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

• Has had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.
• Has tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) at an increased risk of fistula.
• Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention.
• Has clinically significant corneal disease, history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2) agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor.
• Has received prior systemic anticancer therapy including investigational agents 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 inadequate cardiac function assessed as: - corrected QT interval by Fredericia (QTcF) value >470 msec.
• Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
• Has peripheral neuropathy ≥ Grade 2.
• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) 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 active autoimmune disease that has required systemic treatment in the past 2 years.
• Has had (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease, and/or suspected interstitial lung disease (ILD)/pneumonitis that cannot be ruled out by imaging at Screening.
• Has active infection requiring systemic therapy.
• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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298 participants in 5 patient groups

Pembrolizumab + Chemotherapy

Active Comparator group

Description:

Participants will receive 400 mg of pembrolizumab via intravenous (IV) infusion every six weeks (Q6W) on Day 1 of each 42 day cycle up to 18 cycles (up to approximately 2 years), and mFOLFOX6 chemotherapy: oxaliplatin 85 mg/m\^2 via IV infusion every 2 weeks (Q2W) until progressive disease (PD) or toxicity; leucovorin 400 mg/m2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity; 5-fluorouracil (5-FU) 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity.

Treatment:

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Biological: Pembrolizumab

Drug: Levoleucovorin

Drug: Oxaliplatin

Pembrolizumab + I-DXd

Experimental group

Description:

Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle for up to 35 cycles (up to approximately 2 years). Participants will also receive up to 12 mg/kg I-XDd Q3W via IV infusion until PD or toxicity.

Treatment:

Biological: Pembrolizumab

Drug: Rescue Medication

Biological: I-DXd

Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin

Experimental group

Description:

Participants will receive 200 mg pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles (up to approximately 2 years). Participants will also receive I-DXd up to 12 mg/kg via IV infusion Q3W until PD or toxicity, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Treatment:

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Biological: Pembrolizumab

Drug: Levoleucovorin

Drug: Rescue Medication

Biological: I-DXd

Pembrolizumab + I-DXd + 5-FU IV + Leucovorin or Levoleucovorin + Oxaliplatin

Experimental group

Description:

Participants will receive 200 mg of pembrolizumab via IV infusion Q3W on Day 1 of each 21 day cycle up to 35 cycles (up to approximately 2 years). Participants will also receive up to 12 mg/kg I-DXd via IV infusion q3w until PD or toxicity, 5-FU 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, 60mg/m\^2 oxaliplatin via IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Treatment:

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Biological: Pembrolizumab

Drug: Levoleucovorin

Drug: Rescue Medication

Biological: I-DXd

Drug: Oxaliplatin

Pembrolizumab + Sacituzumab tirumotecan + 5-FU IV + Leucovorin or Levoleucovorin

Experimental group

Description:

Participants will receive 400 mg pembrolizumab via IV infusion Q6W on Day 1 of each 42 day cycle up to 18 cycles (up to approximately 2 years). Participants will also receive sacituzumab tirumotecan 4 mg/kg via IV infusion Days 1, 15, and 29 every 42 day cycle until PD or toxicity, 5-FU 400 mg/m\^2 bolus IV infusion followed by 2400 mg/m\^2 continuous 46-48 hour IV infusion Q2W until PD or toxicity, and leucovorin 400 mg/m\^2 OR levoleucovorin 200 mg/m\^2 via IV infusion Q2W until PD or toxicity.

Treatment:

Drug: Leucovorin

Drug: 5-Fluorouracil (5-FU)

Biological: Pembrolizumab

Drug: Levoleucovorin

Drug: Rescue Medication

Biological: Sacituzumab tirumotecan