Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) Plus Chemotherapy in Participants With Metastatic Esophageal Carcinoma (MK-7902-014/E7080-G000-320/LEAP-014)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of pembrolizumab plus lenvatinib plus chemotherapy compared with pembrolizumab plus chemotherapy as first-line intervention in participants with metastatic esophageal carcinoma The primary hypotheses are that pembrolizumab plus lenvatinib plus chemotherapy is superior to pembrolizumab plus chemotherapy with respect to overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).

Detailed Description
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There will be 2 parts to the study: the cisplatin and 5-fluorouracil (5-FU) (FP) and paclitaxel and cisplatin (TP) Safety Run-in (Part 1) and the Main Study (Part 2). In Part 1 (FP and TP Safety Run-in), participants will be treated with pembrolizumab plus lenvatinib plus FP or TP. Dose-limiting toxicities, safety, and tolerability will be assessed. In Part 2 (Main Study), participants (not including those participating in Part 1) will be treated with pembrolizumab plus lenvatinib plus chemotherapy or pembrolizumab plus chemotherapy. Efficacy, safety, and tolerability will be assessed.

Official Title
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A Phase 3, Randomized Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) + Lenvatinib (E7080/MK-7902) + Chemotherapy Compared With Standard of Care as First-line Intervention in Participants With Metastatic Esophageal Carcinoma

Conditions
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Metastatic Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Lenvatinib
* Drug: Cisplatin
* Drug: 5-FU
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Levoleucovorin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus Male participants are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last; 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only and is greater than 90 days post chemotherapy, no male contraception is needed Female participant is not pregnant or breastfeeding and is not a woman of childbearing potential (WOCBP) or is a WOCBP using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 120 days after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever occurs last, and agrees not to donate eggs during this period Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP≤150/90 millimeters of mercury (mm Hg) with no change in antihypertensive medications within 1 week prior to randomization Has adequate organ function Exclusion Criteria: Has had previous therapy for locally advanced unresectable or metastatic esophageal cancer Has locally advanced esophageal carcinoma Has metastatic adenocarcinoma of the esophagus Has direct invasion into adjacent organs such as the aorta or trachea Has radiographic evidence of encasement of a major blood vessel, or of intratumoral cavitation Has perforation risks or significant gastrointestinal (GI) bleeding Has had clinically significant hemoptysis within 3 weeks prior to the first dose of study drug or tumor bleeding within 2 weeks prior to the first dose of study intervention Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention Has GI obstruction, poor oral intake, difficulty in taking oral medication, or existing esophageal stent Has had major surgery, open biopsy, or significant traumatic injury within 3 weeks prior to first dose of study interventions Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention; administration of killed vaccines is allowed Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any form of immunosuppressive therapy within 7 days prior to the first dose of study intervention, or has a history of organ transplant, including allogeneic stem cell transplant Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has an active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease Has poorly controlled diarrhea Has clinically significant cardiovascular disease within 12 months from first dose of study intervention Has peripheral neuropathy ≥Grade 2 Has a known history of human immunodeficiency virus (HIV) infection Has a known history of Hepatitis B or know active Hepatitis C virus infection Has a weight loss of >20% within the last 3 months

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 + Lenvatinib + Chemotherapy<br>Participants receive pembrolizumab intravenously (IV) plus lenvatinib orally in combination with FP or TP in Part 1, or in combination with investigator's choice of chemotherapy with FP IV or TP IV or oxaliplatin, 5-FU and leucovorin (mFOLFOX6) IV in Part 2. Induction consists of pembrolizumab 400 mg once every 6-weeks (Q6W) for up to  12 weeks plus lenvatinib 8 mg once daily (QD) for up to  12 weeks plus chemotherapy with FP (cisplatin 80 mg/m^2 and 5-FU 4000 mg/m^2) or TP (paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2) once every 3 weeks (Q3W) for up to  12 weeks or mFOLFOX6 (oxaliplatin 85 mg/m^2, 5-FU 400 mg/m^2 followed by 2400 mg/m^2, and leucovorin 400 mg/m^2 [or levoleucovorin 200 mg/m^2] once every 2 weeks [Q2W] for up to  12 weeks). This is followed by consolidation with pembrolizumab 400 mg Q6W for up to 16 cycles (each cycle = 6 weeks; total pembrolizumab treatment duration is  2 years) plus lenvatinib 20 mg QD until progressive disease or discontinuation. | Drug: Pembrolizumab<br>* 400 mg once every 6-week-cycle, via IV infusion.<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* 8 mg QD (induction) or 20 mg QD (consolidation) via oral capsule.<br>* Other names: LENVIMA®;Drug: Cisplatin<br>* 80 mg/m^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 75 mg/m^2 Q3W via infusion, as part of investigator's choice TP chemotherapy.<br>* Other names: PLATINOL®;Drug: 5-FU<br>* 4000 mg/m^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 400 mg/m^2 Q2W via bolus IV infusion followed by 2400 mg/m^2 Q2W via continuous IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: ADRUCIL®;Drug: Oxaliplatin<br>* 85 mg/m^2 Q2W via IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: ELOXATIN®;Drug: Leucovorin<br>* 400 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: WELLCOVORIN®;Drug: Levoleucovorin<br>* 200 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: FUSILEV®;Drug: Paclitaxel<br>* 175 mg/m^2 Q3W via IV infusion, as part of investigator's choice TP chemotherapy.<br>* Other names: ONXAL®;|
| Active Comparator: Pembrolizumab + Chemotherapy<br>Participants receive pembrolizumab 400 mg IV Q6W for up to 18 cycles (each cycle = 6 weeks; total pembrolizumab treatment duration is  2 years) in combination with investigator's choice of chemotherapy with FP (cisplatin 80 mg/m^2 IV Q3W for up to 6 administrations [up to  18 weeks] and 5-FU 4000 mg/m^2 IV Q3W for up to 35 administrations [up to  2 years]) or TP (paclitaxel 175 mg/m^2 and cisplatin 75 mg/m^2 Q3W for up 6 administrations [up to  18 weeks]) or in combination with mFOLFOX6 (oxaliplatin 85 mg/m^2, 5-FU 400 mg/m^2 followed by 2400 mg/m^2 and leucovorin 400 mg/m^2 [or levoleucovorin 200 mg/m^2] IV Q2W for up to 52 administrations [approximately 2 years]), during Part 2. | Drug: Pembrolizumab<br>* 400 mg once every 6-week-cycle, via IV infusion.<br>* Other names: KEYTRUDA®;Drug: Cisplatin<br>* 80 mg/m^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 75 mg/m^2 Q3W via infusion, as part of investigator's choice TP chemotherapy.<br>* Other names: PLATINOL®;Drug: 5-FU<br>* 4000 mg/m^2 Q3W via IV infusion, as part of investigator's choice FP chemotherapy or 400 mg/m^2 Q2W via bolus IV infusion followed by 2400 mg/m^2 Q2W via continuous IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: ADRUCIL®;Drug: Oxaliplatin<br>* 85 mg/m^2 Q2W via IV infusion, as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: ELOXATIN®;Drug: Leucovorin<br>* 400 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: WELLCOVORIN®;Drug: Levoleucovorin<br>* 200 mg/m^2 Q2W as part of investigator's choice mFOLFOX6 chemotherapy.<br>* Other names: FUSILEV®;Drug: Paclitaxel<br>* 175 mg/m^2 Q3W via IV infusion, as part of investigator's choice TP chemotherapy.<br>* Other names: ONXAL®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 (FP and TP Safety Run-in): Number of Participants With Dose Limiting Toxicities (DLTs) | Hematologic DLTs are defined as Grade 4 neutropenia lasting for ≥7 days, Grade 3 or Grade 4 febrile neutropenia, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 anemia. Other nonhematologic toxicities considered a DLT include any other Grade 4 or Grade 5 toxicity, Grade 3 toxicities lasting >3 days (excluding nausea, vomiting, and diarrhea controlled by medical intervention within 72 hours, and Grade 3 rash in the absence of desquamation with no mucosal involvement), Grade 3 hypertension not able to be controlled by medication, ≥Grade 3 gastrointestinal perforation, ≥Grade 3 wound dehiscence requiring medical or surgical intervention, any grade thromboembolic event or any Grade 3 nonhematologic laboratory value requiring medical intervention or hospitalization. The number of participants in Part 1 with DLTs will be presented. | Up to  21 days | 
| Part 1 (FP and TP Safety Run-in): Number of Participants With Adverse Events (AEs) | 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. The number of participants in Part 1 with AEs will be presented. | Up to  51 months | 
| Part 1 (FP and TP Safety Run-in): Number of Participants who Discontinued Study Treatment Due to an AE | 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. The number of participants in Part 1 who discontinue study treatment due to an AE will be presented. | Up to  51 months | 
| Part 2 (Main Study): Overall Survival (OS) in all Participants | OS is defined as the time from randomization to death due to any cause. OS in Part 2 for all randomized participants will be presented. | Up to  49 months | 
| Part 2 (Main Study): Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in all Participants | PFS is defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS in Part 2 for all randomized participants will be presented. | Up to  41 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 (Main Study): Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR in all Participants | 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 RECIST 1.1 adjusted to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. ORR in Part 2 for all randomized participants will be presented. | Up to  34 months | 
| Part 2 (Main Study): Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR in all Participants | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 by BICR, DOR is defined as the time from first documented evidence of CR or PR until 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR in Part 2 for all randomized participants will be presented. | Up to  34 months | 
| Part 2 (Main Study): OS in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | OS is defined as the time from randomization to death due to any cause. OS in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. | Up to  49 months | 
| Part 2 (Main Study): PFS per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. | Up to  41 months | 
| Part 2 (Main Study): ORR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | ORR is defined as the percentage of participants with CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 adjusted to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. ORR in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. | Up to  34 months | 
| Part 2 (Main Study): DOR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10 | For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), per RECIST 1.1 by BICR, DOR is defined as the time from first documented evidence of CR or PR until 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. RECIST 1.1 has been adjusted to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. DOR in Part 2 for randomized participants with PD-L1 CPS ≥10 will be presented. | Up to  34 months | 
| Part 2 (Main Study): Number of Participants With AEs | 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. The number of participants in Part 2 with AEs will be presented. | Up to  49 months | 
| Part 2 (Main Study): Number of Participants who Discontinued Study Treatment Due to an AE | 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. The number of participants in Part 2 who discontinue study treatment due to an AE will be presented. | Up to  49 months | 
| Part 2 (Main Study): Change From Baseline in Health-related Quality of life (HRQoL) Score Using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) | The EORTC QLQ-C30 is a questionnaire to assess the overall HRQoL. Participant responses to the question  How would you rate your overall quality of life (QoL) during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall QoL. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL EORTC QLQ-C30 score in participants in Part 2 will be presented. | Baseline and  24 months | 
| Part 2 (Main Study): Change From Baseline in HRQoL Score Using EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18) | The EORTC QLQ-OES18 is a disease-specific questionnaire to assess measurements specific to esophageal cancer. It contains 18 items and is based on four subscales-dysphagia, eating, reflux and pain. All items are scored using a four-point scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. A higher score indicates worse level of symptoms. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL QLQ-OES18 score in participants in Part 2 will be presented. | Baseline and  24 months | 
| Part 2 (Main Study): Time to Deterioration (TTD) in HRQoL Score Using EORTC QLQ-C30 | TTD is defined as the time from baseline to the first onset of a ≥10-point change from baseline in the HRQoL EORTC QLQ-C30 score. The EORTC QLQ-C30 is a questionnaire to assess the overall HRQoL. Participant responses to the question  How would you rate your overall QoL during the past week? are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall QoL. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A longer TTD indicates a better outcome. The TTD in HRQoL EORTC QLQ-C30 score in participants in Part 2 will be presented. | Up to   24 months | 
| Part 2 (Main Study): TTD in HRQoL Score Using EORTC QLQ-OES18 | TTD is defined as the time from baseline to the first onset of a ≥10-point change from baseline in the HRQoL EORTC QLQ-OES18 score. The EORTC QLQ-OES18 is a disease-specific questionnaire to assess measurements specific to esophageal cancer. It contains 18 items and is based on four subscales-dysphagia, eating, reflux and pain. All items are scored using a four-point scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. A higher score indicates worse level of symptoms. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A longer TTD indicates a better outcome. The TTD in HRQoL QLQ-OES18 score in participants in Part 2 will be presented. | Up to   24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)