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)

• ClinicalTrials.gov Identifier: NCT03776136
• Recruitment Status: Active, not recruiting
• First Posted: December 14, 2018
• Last Update Posted: July 22, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Collaborator: Eisai Inc.
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: December 13, 2018
• First Posted Date: December 14, 2018
• Last Update Posted Date: July 22, 2022
• Actual Study Start Date: January 30, 2019
• Estimated Primary Completion Date: December 26, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2018)

Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 13, 2018)

• Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Melanoma

Intervention

• 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®

Study Arms

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.

Interventions:

• Drug: lenvatinib
• Biological: pembrolizumab

• Publications *: 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. Erratum In: J Clin Oncol. 2023 Mar 20;:JCO2300439.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 13, 2018): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 26, 2024
• Estimated Primary Completion Date: December 26, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Spain, Sweden, United States

Administrative Information

• NCT Number: NCT03776136
• Other Study ID Numbers: 7902-004; MK-7902-004 ( Other Identifier: Merck Protocol Number ); E7080-G000-225 ( Other Identifier: Eisai Protocol Number ); LEAP-004 ( Other Grant/Funding Number: Merck ); 2018-002518-10 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Eisai Inc.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: July 2022