Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) for Advanced Melanoma in Anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/L1)-Exposed Participants (MK-7902-004/E7080-G000-225/LEAP-004)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of combination therapy of lenvatinib (E7080/MK-7902) and pembrolizumab following approximately 2 years of pembrolizumab therapy and approximately 2 years or more lenvatinib therapy in adult participants with unresectable or advanced melanoma who have been exposed to anti-PD-1/L1 agents approved for unresectable or metastatic melanoma. No statistical hypothesis will be tested in this study.

Official Title
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A Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent (LEAP-004)

Conditions
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Advanced Melanoma

Intervention / Treatment
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* Drug: lenvatinib
* Biological: pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically or cytologically confirmed melanoma Has unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8 that is not amenable to local therapy Has the presence of ≥1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 as confirmed by BICR. Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies Has submitted pre-trial imaging Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Has provided a baseline tumor biopsy Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications from the Intervention Male participants must agree to use approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study intervention Has adequate organ function Exclusion Criteria: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment Has a known additional malignancy that is progressing or requires active treatment Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has ocular melanoma Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Has an active infection requiring systemic therapy Has known history of Human Immunodeficiency Virus (HIV) or HIV 1/2 antibodies Has known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (HCV RNA qualitative] is detected) Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease Has a history of active tuberculosis (Bacillus tuberculosis) Has presence of a gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib Has had major surgery within 4 weeks prior to first dose of study interventions (adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility) Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula Has radiographic evidence of major blood vessel invasion/infiltration Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug Has clinically significant cardiovascular disease within 12 months from first dose of study drug, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability Has received prior radiotherapy within 2 weeks of Cycle 1 Day 1 with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to Cycle 1 Day 1 Has received a live vaccine within 30 days before the first dose of study treatment Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator Has had an allogeneic tissue/solid organ transplant Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lenvatinib plus pembrolizumab<br>Participants receive lenvatinib 20 mg orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity. | Drug: lenvatinib<br>* Administered orally once a day during each 21-day cycle.<br>* Other names: LENVIMA™;Biological: pembrolizumab<br>* Administered as an IV infusion on Day 1 Q3W.<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) | ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) per RECIST 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) | PFS is defined as the time from the first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to the RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to 3 years | 
| Overall Survival (OS) | OS is defined as the time from the first day of study treatment to death due to any cause. | Up to 3 years | 
| Duration of Response (DOR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) | DOR is defined as the time from first documented evidence of CR or PR, per RECIST 1.1 as assessed by BICR, until disease progression or death due to any cause, whichever occurs first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. | Up to 3 years | 
| Percentage of Participants Who Experience At Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who experience at least one AE will be reported. | Up to 3 years | 
| Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants who discontinue study treatment due to an AE will be reported. | Up to 3 years | 
| Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) | Blood samples will be obtained on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) for pharmacokinetic (PK) analysis to determine the AUC of lenvatinib. | At designated time points on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) | 

 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), programmed cell death ligand 2 (PD-L2, PDL2)