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)

Phase 1

Recruiting

• Conditions: Esophageal Squamous Cell Carcinoma
• Interventions: Drug: Paclitaxel; Biological: Sacituzumab tirumotecan; Drug: Irinotecan; Drug: Antihistamine; Biological: Pembrolizumab; Drug: Lenvatinib; Drug: H2 Receptor Antagonist; Biological: MK-4830; Drug: Acetaminophen (or equivalent); Drug: Dexamethasone (or equivalent); Drug: Steroid Mouthwash (dexamethasone or equivalent); Drug: Supportive care measures

• Registration Number: NCT05319730
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed 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.

Study Timeline

• Study First Submitted: 2022-04-01
• Study First Submitted QC: 2022-04-01
• Study First Posted: 2022-04-08
• Study Start: 2023-05-16
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-17
• Last Update Posted: 2025-07-18
• Primary Completion: 2026-11-07
• Study Completion: 2029-04-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable esophageal squamous cell carcinoma (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-programmed cell death 1 (PD1)/programmed cell death ligand 1 (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 gastrointestinal (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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Paclitaxel or irinotecan	Paclitaxel	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.
Paclitaxel or irinotecan	Irinotecan	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.
Pembrolizumab + MK-4830 + paclitaxel or irinotecan	Paclitaxel	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.
Pembrolizumab + MK-4830 + paclitaxel or irinotecan	Irinotecan	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.
Pembrolizumab + MK-4830 + paclitaxel or irinotecan	Pembrolizumab	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.
Pembrolizumab + MK-4830 + paclitaxel or irinotecan	MK-4830	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.
Pembrolizumab + MK-4830 + lenvatinib	Pembrolizumab	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.
Pembrolizumab + MK-4830 + lenvatinib	MK-4830	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.
Pembrolizumab + MK-4830 + lenvatinib	Lenvatinib	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.
Sacituzumab tirumotecan	Sacituzumab tirumotecan	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.
Sacituzumab tirumotecan	Antihistamine	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.
Sacituzumab tirumotecan	H2 Receptor Antagonist	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.
Sacituzumab tirumotecan	Acetaminophen (or equivalent)	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.
Sacituzumab tirumotecan	Dexamethasone (or equivalent)	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.
Sacituzumab tirumotecan	Steroid Mouthwash (dexamethasone or equivalent)	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.
Sacituzumab tirumotecan	Supportive care measures	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 92 weeks	ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) During Safety Lead-in Phase	Up to approximately 3 weeks	A DLT is defined as any drug-related AE according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) Version 5.0, observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle.
Number of Participants Experiencing Adverse Events (AEs) During Safety Lead-in Phase	Up to approximately 3 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase	Up to approximately 3 weeks	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Up to approximately 189 weeks	PFS is defined as the time from allocation to the first documented progressive disease (PD) as assessed by RECIST 1.1 or death due to any cause, whichever occurs first. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.
Duration of Response (DOR)	Up to approximately 189 weeks	For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase	Up to approximately 189 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Number of Participants Who Discontinue Study Treatment Due to An AE During the Efficacy Phase	Up to approximately 189 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Overall Survival (OS)	Up to approximately 189 weeks	OS is defined as the time from the date of allocation to death from any cause.

Trial Locations

Locations (56)

UCLA Hematology/Oncology - Santa Monica ( Site 4905); 🇺🇸 Los Angeles, California, United States

University of Arizona Cancer Center-University of Arizona Cancer Center ( Site 4927); 🇺🇸 Tucson, Arizona, United States

Hematology-Oncology Associates of Central NY, P.C. ( Site 4925); 🇺🇸 East Syracuse, New York, United States

Columbia University Irving Medical Center-CUIMC Herbert Irving Comprehensive Cancer Center Clinical ( Site 4907); 🇺🇸 New York, New York, United States

UPMC Hillman Cancer Center-UPMC ( Site 4904); 🇺🇸 Pittsburgh, Pennsylvania, United States

Liga Norte Riograndense Contra o Câncer ( Site 4303); 🇧🇷 Natal., Rio Grande Do Norte, Brazil

Hospital Nossa Senhora da Conceição ( Site 4301); 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 4300); 🇧🇷 Sao Paulo, Brazil

FALP-UIDO ( Site 4400); 🇨🇱 Santiago, Region M. De Santiago, Chile

Centro de Oncología de Precisión-Oncology ( Site 4404); 🇨🇱 Santiago, Region M. De Santiago, Chile

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