Clinical trial NCT03776136: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Melanoma
Keywords: programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
programmed cell death ligand 2 (PD-L2, PDL2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Eisai Inc.
First posted: 2018-12-14
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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-programmed cell death ligand 1 (PD-1/L1) agents approved for unresectable or metastatic melanoma. No statistical hypothesis will be tested in this study.


Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 55 months
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 55 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 55 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 55 months
measure: Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf)
timeFrame: Cycle 1 Day 1: 0.5 to 4 hours and 6 to 10 hours postdose; Cycle 1 Day 15: Predose and 2 to 12 hours postdose; Cycle 2 Day 1: Predose, 0.5 to 4 hours, and 6 to 10 hours post-dose (each cycle =21 days)
measure: Number of Participants Who Experience At Least One Adverse Event (AE)
timeFrame: Up to approximately 55 months
measure: Number of Participants Who Discontinue Study Treatment Due to an AE
timeFrame: Up to approximately 48 months
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Ironwood Cancer & Research Centers ( Site 0312)
state: Arizona
city: Santa Monica
country: United States
facility: John Wayne Cancer Institute ( Site 0301)
state: California
city: Park Ridge
country: United States
facility: Advocate Medical Group-Park Ridge ( Site 0313)
state: Illinois
city: Lincoln
country: United States
facility: Southeast Nebraska Cancer Center ( Site 0316)
state: Nebraska
city: Dallas
country: United States
facility: Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 0314)
state: Virginia
city: Wollstonecraft
country: Australia
facility: Melanoma Institute Australia ( Site 0152)
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital ( Site 0154)
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital ( Site 0157)
state: Victoria
city: Perth
country: Australia
facility: Fiona Stanley Hospital ( Site 0156)
state: Western Australia
city: Lismore
country: Australia
facility: Lismore Base Hospital ( Site 0153)
city: Toronto
country: Canada
facility: Sunnybrook Research Institute ( Site 0654)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0655)
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre ( Site 0651)
state: Quebec
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial Barcelona ( Site 0001)
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon ( Site 0003)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena ( Site 0004)
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia ( Site 0002)
city: Goteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset ( Site 0052)
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus ( Site 0053)
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset ( Site 0051)
city: Umea
country: Sweden
facility: Norrlands Universitetssjukhus ( Site 0056)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Arance A, de la Cruz-Merino L, Petrella TM, Jamal R, Ny L, Carneiro A, Berrocal A, Marquez-Rodas I, Spreafico A, Atkinson V, Costa Svedman F, Mant A, Khattak MA, Mihalcioiu C, Jang S, Cowey CL, Smith AD, Hawk N, Chen K, Diede SJ, Krepler C, Long GV. Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. J Clin Oncol. 2023 Jan 1;41(1):75-85. doi: 10.1200/JCO.22.00221. Epub 2022 Jul 22.