A Study to Evaluate Investigational Agents With or Without Pembrolizumab (MK-3475) in Participants With Advanced Esophageal Cancer Previously Exposed to Programmed Cell Death 1 Protein (PD-1)/ Programmed Cell Death Ligand 1 (PD-L1) Treatment (MK-3475-06B)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Esophageal Squamous Cell Carcinoma

Treatments: Drug: Irinotecan; Drug: Dexamethasone (or equivalent); Biological: Pembrolizumab; Drug: Antihistamine; Drug: Paclitaxel; Biological: Sacituzumab tirumotecan; Biological: MK-4830; Drug: Lenvatinib; Drug: H2 Receptor Antagonist; Drug: Acetaminophen (or equivalent)

Study type: Interventional

Funder types: Industry

Identifiers

NCT05319730

jRCT2031220582 (Registry Identifier)

2021-005443-76 (EudraCT Number)

3475-06B

Details and patient eligibility

About

This is a Phase 1/2, multicenter, randomized, open-label umbrella platform study to evaluate the safety and efficacy of investigational agents with or without pembrolizumab and/or chemotherapy, for the treatment of participants with second line (2L) esophageal squamous cell carcinoma (ESCC) who have previously been exposed to PD-1/PD-L1 based treatment.

Full description

The master protocol is MK-3475-U06.

As of Protocol Amendment 5, the Pembrolizumab Plus MK-4830 Plus Paclitaxel/Irinotecan arm and the Pembrolizumab Plus MK-4830 Plus Lenvatinib arm are no longer actively enrolling participants.

Enrollment: 200 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable ESCC.
• Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy, that includes a platinum agent and previous exposure to an anti-PD1/PD-L1 based therapy.
• Has an evaluable baseline tumor sample (newly obtained or archival) for analysis.
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications.
• 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 or participants who have ≤Grade 2 neuropathy are eligible.

Exclusion Criteria:

• Direct invasion into adjacent organs such as the aorta or trachea.
• Has experienced weight loss >10% over approximately 2 months prior to first dose of study therapy.
• Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
• 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 medication.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Active autoimmune disease that has required systemic treatment in past 2 years.
• History of human immunodeficiency virus (HIV) infection.
• History of Hepatitis B or known active Hepatitis C virus infection.
• History of allogenic tissue/solid organ transplant.
• Clinically significant cardiovascular disease within 12 months from first dose of study intervention.
• Known GI malabsorption or any other condition that may affect the absorption of lenvatinib. (Not applicable to actively enrolling arms as of Amendment 5)
• Has risk for significant GI bleeding such as a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization, significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization. (Not applicable to actively enrolling arms as of Amendment 5)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 4 patient groups

Paclitaxel or irinotecan

Active Comparator group

Description:

Participants receive paclitaxel 80-100 mg/m\^2 intravenously (IV) on days 1, 8, and 15 every 28-day cycle until progressive disease (PD) or discontinuation, or irinotecan 180 mg/m\^2 IV on day 1 of every 14-day cycle until PD or discontinuation.

Treatment:

Drug: Paclitaxel

Drug: Irinotecan

Pembrolizumab + MK-4830 + paclitaxel or irinotecan

Experimental group

Description:

Participants receive pembrolizumab 200 mg IV once every 3 weeks (Q3W) for up to 35 cycles (cycle=21 days) or until PD or discontinuation + MK-4830 800 mg IV Q3W up to 35 infusions + paclitaxel 80-100 mg/m\^2 IV on days 1, 8, and 15 every 28-day cycle until PD or discontinuation or irinotecan 180 mg/m\^2 180 mg/m\^2 on day 1 every 14-day cycle until PD or discontinuation.

Treatment:

Biological: MK-4830

Drug: Paclitaxel

Biological: Pembrolizumab

Drug: Irinotecan

Pembrolizumab + MK-4830 + lenvatinib

Experimental group

Description:

Participants receive pembrolizumab 200 mg IV Q3W up to 35 cycles (cycle=21 days) until PD or discontinuation + MK-4830 800 mg IV Q3W up to 35 infusions + lenvatinib 20 mg oral administration every day until PD or discontinuation.

Treatment:

Drug: Lenvatinib

Biological: MK-4830

Biological: Pembrolizumab

Sacituzumab tirumotecan

Experimental group

Description:

Participants will receive 4 mg/kg of sacituzumab tirumotecan via IV infusion on Days 1, 15, and 29 of each 42-day cycle until discontinuation.

Treatment:

Drug: Acetaminophen (or equivalent)

Drug: H2 Receptor Antagonist

Biological: Sacituzumab tirumotecan

Drug: Antihistamine

Drug: Dexamethasone (or equivalent)