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)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03776136

Collaborator

Eisai Inc. (Industry)

100

Enrollment

Locations

Arm

70.9

Anticipated Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Melanoma	Drug: lenvatinib Biological: pembrolizumab	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Jan 30, 2019

Anticipated Primary Completion Date :

Dec 26, 2024

Anticipated Study Completion Date :

Dec 26, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lenvatinib plus pembrolizumab 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 Administered orally once a day during each 21-day cycle. Other Names: MK-7902 E7080 LENVIMA™ Biological: pembrolizumab Administered as an IV infusion on Day 1 Q3W. Other Names: MK-3475 Keytruda®

Arm

Intervention/Treatment

Experimental: lenvatinib plus pembrolizumab

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

Administered orally once a day during each 21-day cycle.

Other Names:

MK-7902

E7080

LENVIMA™

Biological: pembrolizumab

Administered as an IV infusion on Day 1 Q3W.

Other Names:

MK-3475

Keytruda®

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [Up to 3 years]
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.

Secondary Outcome Measures

Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [Up to 3 years]
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.
Overall Survival (OS) [Up to 3 years]
OS is defined as the time from the first day of study treatment to death due to any cause.
Duration of Response (DOR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [Up to 3 years]
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.
Percentage of Participants Who Experience At Least One Adverse Event (AE) [Up to 3 years]
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.
Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [Up to 3 years]
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.
Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) [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)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ironwood Cancer & Research Centers ( Site 0312)	Chandler	Arizona	United States	85224
2	John Wayne Cancer Institute ( Site 0301)	Santa Monica	California	United States	90404
3	Advocate Medical Group-Park Ridge ( Site 0313)	Park Ridge	Illinois	United States	60068
4	Southeast Nebraska Cancer Center ( Site 0316)	Lincoln	Nebraska	United States	68510
5	Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)	Dallas	Texas	United States	75246
6	Inova Schar Cancer Institute ( Site 0314)	Fairfax	Virginia	United States	22031-4867
7	Melanoma Institute Australia ( Site 0152)	Wollstonecraft	New South Wales	Australia	2065
8	Princess Alexandra Hospital ( Site 0154)	Woolloongabba	Queensland	Australia	4102
9	Box Hill Hospital ( Site 0157)	Box Hill	Victoria	Australia	3128
10	Fiona Stanley Hospital ( Site 0156)	Perth	Western Australia	Australia	6150
11	Lismore Base Hospital ( Site 0153)	Lismore		Australia	2480
12	Sunnybrook Research Institute ( Site 0654)	Toronto	Ontario	Canada	M4N 3M5
13	Princess Margaret Cancer Centre ( Site 0655)	Toronto	Ontario	Canada	M5G 2M9
14	Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)	Montreal	Quebec	Canada	H2X 3E4
15	McGill University Health Centre ( Site 0651)	Montreal	Quebec	Canada	H4A 3J1
16	Hospital Clinic i Provincial Barcelona ( Site 0001)	Barcelona		Spain	08036
17	Hospital General Universitario Gregorio Maranon ( Site 0003)	Madrid		Spain	28007
18	Hospital Universitario Virgen de la Macarena ( Site 0004)	Sevilla		Spain	41009
19	Hospital General Universitario de Valencia ( Site 0002)	Valencia		Spain	46014
20	Sahlgrenska Universitetssjukhuset ( Site 0052)	Goteborg		Sweden	413 45
21	Skanes Universitetssjukhus ( Site 0053)	Lund		Sweden	221 85
22	Karolinska Universitetssjukhuset ( Site 0051)	Solna		Sweden	171 64
23	Norrlands Universitetssjukhus ( Site 0056)	Umea		Sweden	901 85