A Study to Evaluate 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

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05319730

Collaborator

(none)

300

Enrollment

Arms

48.8

Anticipated Duration (Months)

Study Details

Study Description

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 pembrolizumab, with or without 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.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Squamous Cell Carcinoma	Drug: Paclitaxel Drug: Irinotecan Biological: Pembrolizumab Biological: MK-4830 Drug: Lenvatinib	Phase 1/Phase 2

Detailed Description

The master screening protocol is MK-3475-U06.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With Pembrolizumab (MK-3475) in Participants With Advanced Esophageal Cancer Previously Exposed to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06B

Anticipated Study Start Date :

Feb 27, 2023

Anticipated Primary Completion Date :

May 25, 2025

Anticipated Study Completion Date :

Mar 24, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Paclitaxel or 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.	Drug: Paclitaxel 80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle. Drug: Irinotecan 180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.
Experimental: Pembrolizumab + MK-4830 + paclitaxel or 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.	Drug: Paclitaxel 80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle. Drug: Irinotecan 180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle. Biological: Pembrolizumab 200 mg IV infusion, administered every Q3W. Other Names: MK-3475 KEYTRUDA® Biological: MK-4830 800 mg IV infusion, administered Q3W up to 35 infusions. Other Names: anti- immunoglobulin-like transcript 4 (anti-ILT4)
Experimental: Pembrolizumab + MK-4830 + 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.	Biological: Pembrolizumab 200 mg IV infusion, administered every Q3W. Other Names: MK-3475 KEYTRUDA® Biological: MK-4830 800 mg IV infusion, administered Q3W up to 35 infusions. Other Names: anti- immunoglobulin-like transcript 4 (anti-ILT4) Drug: Lenvatinib 20 mg oral administration every day. Other Names: MK-7902 LENVIMA®

Arm

Intervention/Treatment

Active Comparator: Paclitaxel or 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.

Drug: Paclitaxel

80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.

Drug: Irinotecan

180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.

Experimental: Pembrolizumab + MK-4830 + paclitaxel or 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.

Drug: Paclitaxel

80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.

Drug: Irinotecan

180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.

Biological: Pembrolizumab

200 mg IV infusion, administered every Q3W.

Other Names:

MK-3475

KEYTRUDA®

Biological: MK-4830

800 mg IV infusion, administered Q3W up to 35 infusions.

Other Names:

anti- immunoglobulin-like transcript 4 (anti-ILT4)

Experimental: Pembrolizumab + MK-4830 + 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.

Biological: Pembrolizumab

200 mg IV infusion, administered every Q3W.

Other Names:

MK-3475

KEYTRUDA®

Biological: MK-4830

800 mg IV infusion, administered Q3W up to 35 infusions.

Other Names:

anti- immunoglobulin-like transcript 4 (anti-ILT4)

Drug: Lenvatinib

20 mg oral administration every day.

Other Names:

MK-7902

LENVIMA®

Outcome Measures

Primary Outcome Measures

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.
Objective Response (OR) [Up to approximately 110 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.

Secondary Outcome Measures

Progression-Free Survival (PFS) [Up to approximately 212 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 212 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.
Overall Survival (OS) [Up to approximately 212 weeks]
OS is defined as the time from the date of allocation to death from any cause.
Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase [Up to approximately 212 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 140 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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 experienced documented radiographic or clinical disease. progression on one prior line of standard therapy.
Has an evaluable baseline tumor sample (newly obtained or archival) for analysis.
Has adequately controlled blood pressure (BP) with or without antihypertensive medications.

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.
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.
Gastrointestinal (GI) obstruction, poor oral intake, or difficulty in taking oral medication.