A Study of Combination Therapies With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer (MK-3475-06A)

Study Overview
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Brief Summary
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This is a phase I/II multicenter, open-label umbrella platform study that will evaluate the safety and efficacy of investigational agents with pembrolizumab, plus chemotherapy or lenvatinib, for the treatment of participants with advanced esophageal cancer who have failed 1 prior line of therapy and have not been previously exposed to programmed cell death 1 protein (PD-1)/ programmed cell death ligand 1 (PD-L1) based treatment. With protocol amendment 5 (effective: 17-November-2023), enrollment in study arms Pembrolizumab plus MK-4830 plus Chemotherapy and Pembrolizumab plus MK-4830 plus lenvatinib is discontinued.

Detailed Description
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The master protocol is MK-3475-U06.

Official Title
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A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer naïve to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06A.

Conditions
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Esophageal Squamous Cell Carcinoma (ESCC)

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Coformulation favezelimab/pembrolizumab
* Biological: MK-4830
* Drug: Lenvatinib
* Drug: Irinotecan
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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. 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 received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration 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 Participants with known gastrointestinal (GI) malabsorption or any other condition that may affect the absorption of lenvatinib Has risk for significant GI bleeding, such as: Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization Has significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab plus chemotherapy<br>Participants will receive pembrolizumab intravenously plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years. | Biological: Pembrolizumab<br>* 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: KEYTRUDA®;Drug: Irinotecan<br>* 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.<br>Drug: Paclitaxel<br>* 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle<br>|
| Experimental: Coformulation Favezelimab/Pembrolizumab plus Chemotherapy<br>Participants will receive coformulation of favezelimab/pembrolizumab administered intravenously plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years. | Biological: Coformulation favezelimab/pembrolizumab<br>* 800 mg favezelimab + 200 mg pembrolizumab administered via IV infusion on day 1 and then Q3W<br>* Other names: MK-4280A;Drug: Irinotecan<br>* 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.<br>Drug: Paclitaxel<br>* 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle<br>|
| Experimental: Pembrolizumab plus MK-4830 plus Chemotherapy<br>Participants will receive pembrolizumab intravenously plus MK-4830 plus chemotherapy (investigator's choice of irinotecan or paclitaxel) at specified doses on specified days for a total treatment duration of up to approximately 2 years. | Biological: Pembrolizumab<br>* 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* 800 mg administered via IV infusion Q3W<br>* Other names: anti-immunoglobulin-like transcript 4 (ILT4);Drug: Irinotecan<br>* 180 mg/m^2 administered via IV infusion on day 1 of every 14-day cycle.<br>Drug: Paclitaxel<br>* 80-100 mg/m^2 administered via IV infusion on Days 1, 8 and 15 of every 28 day cycle<br>|
| Experimental: Pembrolizumab plus MK-4830 plus lenvatinib<br>Participants will receive pembrolizumab intravenously plus MK-4830 plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years. | Biological: Pembrolizumab<br>* 200 mg administered via intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* 800 mg administered via IV infusion Q3W<br>* Other names: anti-immunoglobulin-like transcript 4 (ILT4);Drug: Lenvatinib<br>* 20 mg administered via oral capsules each day<br>* Other names: LENVIMA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose-limiting Toxicity (DLT) During Safety Lead-in Phase | A DLT is defined as any drug-related adverse event (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. | Up to approximately 3 weeks | 
| Number of Participants Experiencing an Adverse Event (AE) During Safety Lead-in Phase | 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. | Up to approximately 3 Weeks | 
| Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase | 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. | Up to approximately 3 weeks | 
| Objective Response Rate (ORR) | 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. | Up to approximately 119 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | Up to approximately 216 weeks | 
| Duration of Response (DOR) | 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. | Up to approximately 216 weeks | 
| Overall Survival (OS) | OS is defined as the time from the date of allocation to death from any cause. | Up to approximately 216 weeks | 
| Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase | 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. | Up to approximately 216 weeks | 
| Number of Participants Who Discontinue Study Treatment Due to An AE During the Efficacy Phase | 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. | Up to approximately 104 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal cancer, Programmed Cell Death 1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL-1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL-2, PD-L2)