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)
- Registration Number
- NCT03776136
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 103
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description lenvatinib plus pembrolizumab lenvatinib 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. lenvatinib plus pembrolizumab 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.
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) Up to approximately 55 months ORR was defined as the percentage of participants in the analysis population who have a confirmed Complete Response (CR: disappearance of all lesions) or a Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR). Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ).
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) Up to approximately 55 months PFS was defined as the time from first day of study intervention to the first documented progressive disease (PD) per RECIST 1.1 by BICR, or death from any cause, whichever occurred first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). PFS was calculated using the nonparametric Kaplan-Meier method; participants who did not experience a PFS event were censored at the last disease assessment, or the last assessment before new anticancer treatment if new treatment was initiated.
Overall Survival (OS) Up to approximately 55 months OS was defined as the time from the first day of study intervention to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS was calculated using the nonparametric Kaplan-Meier method.
Duration of Response (DOR) Up to approximately 55 months For participants who demonstrated a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: ≥30% decrease in the sum of target lesion diameters without progression in other lesions) per RECIST 1.1, DOR was defined as the time from first documented CR or PR until progressive disease (PD) or death from any cause, whichever occurs first. Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). DOR was calculated using the nonparametric Kaplan-Meier method for censored data.
Area Under the Concentration Time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-inf) 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) AUC0-inf was defined as the area under the concentration-time curve from time zero extrapolated to infinity. Plasma blood samples collected at specified timepoints, were used to estimate AUC0-inf following Lenvatinib and Pembrolizumab administration. Based on the lenvatinib plasma concentration data obtained on Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, a protocol specified population PK analysis was performed to characterize the steady state AUC0-inf of lenvatinib when co-administered with pembrolizumab.
Number of Participants Who Experience At Least One Adverse Event (AE) Up to approximately 55 months An AE was 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. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE is presented.
Number of Participants Who Discontinue Study Treatment Due to an AE Up to approximately 48 months An AE was 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. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented.
Trial Locations
- Locations (23)
John Wayne Cancer Institute ( Site 0301)
🇺🇸Santa Monica, California, United States
Advocate Medical Group-Park Ridge ( Site 0313)
🇺🇸Park Ridge, Illinois, United States
Southeast Nebraska Cancer Center ( Site 0316)
🇺🇸Lincoln, Nebraska, United States
Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 0317)
🇺🇸Dallas, Texas, United States
Fiona Stanley Hospital ( Site 0156)
🇦🇺Perth, Western Australia, Australia
Box Hill Hospital ( Site 0157)
🇦🇺Box Hill, Victoria, Australia
Hospital Clinic i Provincial Barcelona ( Site 0001)
🇪🇸Barcelona, Spain
Lismore Base Hospital ( Site 0153)
🇦🇺Lismore, Australia
Inova Schar Cancer Institute ( Site 0314)
🇺🇸Fairfax, Virginia, United States
Sunnybrook Research Institute ( Site 0654)
🇨🇦Toronto, Ontario, Canada
Hospital Universitario Virgen de la Macarena ( Site 0004)
🇪🇸Sevilla, Spain
Princess Margaret Cancer Centre ( Site 0655)
🇨🇦Toronto, Ontario, Canada
Princess Alexandra Hospital ( Site 0154)
🇦🇺Woolloongabba, Queensland, Australia
Hospital General Universitario de Valencia ( Site 0002)
🇪🇸Valencia, Spain
Karolinska Universitetssjukhuset ( Site 0051)
🇸🇪Solna, Sweden
Norrlands Universitetssjukhus ( Site 0056)
🇸🇪Umea, Sweden
Skanes Universitetssjukhus ( Site 0053)
🇸🇪Lund, Sweden
Hospital General Universitario Gregorio Maranon ( Site 0003)
🇪🇸Madrid, Spain
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0652)
🇨🇦Montreal, Quebec, Canada
Melanoma Institute Australia ( Site 0152)
🇦🇺Wollstonecraft, New South Wales, Australia
McGill University Health Centre ( Site 0651)
🇨🇦Montreal, Quebec, Canada
Sahlgrenska Universitetssjukhuset ( Site 0052)
🇸🇪Goteborg, Sweden
Ironwood Cancer & Research Centers ( Site 0312)
🇺🇸Chandler, Arizona, United States