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

2023-505189-26 (Registry Identifier)

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.
Participants with human immunodeficiency virus (HIV) with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
Concurrent active hepatitis B and 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)

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