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)

Study Overview
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Brief Summary
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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
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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.

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 Previously Exposed to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06B

Conditions
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Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Irinotecan
* Biological: Pembrolizumab
* Biological: MK-4830
* Drug: Lenvatinib
* Biological: MK-2870
* Drug: Antihistamine
* Drug: H2 Receptor Antagonist
* Drug: Acetaminophen (or equivalent)
* Drug: Dexamethasone (or equivalent)


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, 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)

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 |
| --- | --- |
| Active Comparator: Paclitaxel or irinotecan<br>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<br>* 80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.<br>Drug: Irinotecan<br>* 180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.<br>|
| Experimental: Pembrolizumab + MK-4830 + paclitaxel or irinotecan<br>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<br>* 80-100 mg/m2 IV infusion, administered on days 1, 8, and 15 of every 28-day cycle.<br>Drug: Irinotecan<br>* 180 mg/m2 IV infusion, administered on day 1 of every 14-day cycle.<br>Biological: Pembrolizumab<br>* 200 mg IV infusion, administered every Q3W.<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* 800 mg IV infusion, administered Q3W up to 35 infusions.<br>* Other names: anti-immunoglobulin-like transcript 4 (anti-ILT4);|
| Experimental: Pembrolizumab + MK-4830 + lenvatinib<br>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<br>* 200 mg IV infusion, administered every Q3W.<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* 800 mg IV infusion, administered Q3W up to 35 infusions.<br>* Other names: anti-immunoglobulin-like transcript 4 (anti-ILT4);Drug: Lenvatinib<br>* 20 mg oral administration every day.<br>* Other names: LENVIMA®;|
| Experimental: MK-2870<br>Participants will receive 4 mg/kg of MK-2870 via IV infusion on Days 1, 15, and 29 of each 42-day cycle until discontinuation. | Biological: MK-2870<br>* 4 mg/kg IV infusion on Days 1, 15, and 29 of each 42-day cycle.<br>* Other names: SKB264;Drug: Antihistamine<br>* Administered per product label.<br>Drug: H2 Receptor Antagonist<br>* Administered per product label.<br>Drug: Acetaminophen (or equivalent)<br>* Administered per product label.<br>Drug: Dexamethasone (or equivalent)<br>* Administered per product label.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) During Safety Lead-in Phase | 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. | Up to approximately 3 weeks | 
| Number of Participants Experiencing Adverse Events (AEs) 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. | Up to approximately 3 weeks | 
| Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase | 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. | 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 92 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 189 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 189 weeks | 
| Overall Survival (OS) | OS is defined as the time from the date of allocation to death from any cause. | Up to approximately 189 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 189 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 189 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)