Safety and Efficacy Study of Pembrolizumab (MK-3475) Combined With Lenvatinib (MK-7902/E7080) as First-line Intervention in Adults With Advance Melanoma (MK-7902-003/E7080-G000-312/LEAP-003)
Condition: Malignant Melanoma
MeSH terms: Melanoma
Intervention: Pembrolizumab; Lenvatinib; Placebo for lenvatinib
Intervention description: IV infusion; Oral capsule; Oral capsule
Intervention MeSH terms: Pembrolizumab; Lenvatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 674.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: programmed cell death 1 (PD-1, PD1); programmed cell death-ligand 1 (PD-L1, PDL1); programmed cell death-ligand 2 (PD-L2, PDL2)

Summary:

      The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475)
      combined with lenvatinib (MK-7902/E7080) compared to pembrolizumab alone (with placebo for
      lenvatinib) as first-line treatment in adults with no prior systemic therapy for their
      advanced melanoma.

      The primary study hypotheses are that: 1) The combination of pembrolizumab and lenvatinib is
      superior to pembrolizumab and placebo as assessed by Progression-free Survival (PFS) per
      Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and 2) The combination
      of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by
      Overall Survival (OS). For this study, RECIST 1.1 has been modified to follow a maximum of 10
      target lesions and a maximum of 5 target lesions per organ.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has histologically or cytologically confirmed melanoma.

          -  Has unresectable Stage III or Stage IV melanoma, as per American Joint Committee on
             Cancer guidelines, not amenable to local therapy.

          -  Has been untreated for advanced or metastatic disease except as follows:

               1. Proto-oncogene B-Raf (BRAF) V600 mutation-positive melanoma may have received
                  standard of care targeted therapy as first-line therapy for advanced or
                  metastatic disease. Participants that do not have a BRAF V600 mutation but did
                  receive BRAF or BRAF/MEKi therapy are eligible to participate in this study after
                  discussion with the medical monitor.

               2. Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy
                  (such as anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4],
                  anti-programmed cell death 1 [anti-PD-1] therapy or interferon) will only be
                  permitted if relapse did not occur during active treatment or within 6 months of
                  treatment discontinuation.

          -  Have documentation of BRAF V600-activating mutation status or consent to BRAF V600
             mutation testing during the Screening period (participants with BRAF mutation-positive
             melanoma as well as BRAF wild-type or unknown are eligible).

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

          -  Has the presence of ≥1 measurable lesion by computed tomography (CT) or magnetic
             resonance imaging (MRI) per RECIST 1.1.

          -  Provides a tumor biopsy. Participants must submit tumor sample during Screening for
             confirmation of adequacy of tumor tissue at a central pathology laboratory.
             Participants who do not submit a tumor tissue sample will not be randomized. The tumor
             biopsy may not be obtained from a lone target lesion. Confirmation of presence of
             tumor tissue is not required prior to randomization.

          -  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 contraception during the treatment period and for
             at least 7 days after the last dose of study treatment and refrain from donating sperm
             during this period. Please note that 7 days after lenvatinib/placebo is stopped, if
             the participant is on pembrolizumab only, no male contraception measures are needed.
             Contraception use by men should be consistent with local regulations regarding the
             methods of contraception for those participating in clinical studies. If the
             contraception requirements in the local label for any of the study interventions is
             more stringent than the requirements above, the local label requirements are to be
             followed.

          -  Female participants must not be pregnant, not breastfeeding, and ≥1 of the following
             conditions applies:

               1. Not a woman of childbearing potential (WOCBP). OR

               2. A WOCBP who agrees to use study-approved contraception during the treatment
                  period and for at least 120 days after the last dose of study treatment.

          -  The participant (or legally acceptable representative) has provided documented
             informed consent for the study.

          -  Has adequately controlled blood pressure (BP) with or without antihypertensive
             medications, defined as BP ≤150/90 mmHg at screening and no change in antihypertensive
             medications within 1 week before Cycle 1 Day 1.

          -  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.
             Exceptions include early stage cancers (carcinoma in situ or Stage 1, non-ulcerated
             primary melanoma <1 mm in depth with no nodal involvement) treated with curative
             intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ
             cervical cancer, or in situ breast cancer that has undergone potentially curative
             therapy.

          -  Has known active central nervous system 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
             (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has an active infection requiring systemic therapy.

          -  Has known history of human immunodeficiency virus (HIV) infection

          -  Has known history of or is positive for hepatitis B virus or hepatitis C virus
             infection.

          -  Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease.

          -  Has a history of active tuberculosis (Bacillus tuberculosis).

          -  Gastrointestinal malabsorption or any other condition that might affect the absorption
             of lenvatinib.

          -  Has had a major surgery within 3 weeks prior to first dose of study intervention.
             Note: Adequate wound healing after major surgery must be assessed clinically
             independent of time elapsed for eligibility.

          -  Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula.

          -  Has radiographic evidence of encasement or invasion of major blood vessel, or of
             intratumoral cavitation.

          -  Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior
             to the first dose of study treatment.

          -  Has clinically significant cardiovascular disease from 12 months of the first dose of
             study treatment 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 urine protein ≥1 g/24-hour. Note: Participants with ≥2+ (≥100 mg/dL) proteinuria
             on urine dipstick testing (or urinalysis) will undergo 24-hour urine collection for
             quantitative assessment of proteinuria.

          -  Prolongation of QTcF interval to >480 ms. Note: If the QTcF is prolonged to >480 ms in
             the presence of a pacemaker, contact the Sponsor to determine eligibility.

          -  Has left ventricular ejection fraction (LVEF) below the institutional (or local
             laboratory) normal range, as determined by multigated acquisition scan (MUGA) or
             echocardiogram.

          -  Has received prior therapy in the adjuvant setting. Note: Targeted therapy,
             anti-CTLA-4, or anti-PD-1 may be allowed.

          -  Has received prior systemic treatment for unresectable or metastatic melanoma other
             than targeted therapy as noted in Inclusion Criteria above

          -  Has received prior therapy with a monoclonal antibody, chemotherapy, or an
             investigational agent or device within 4 weeks or 5 half-lives (whichever is longer)
             before administration of study treatment or not recovered (≤Grade 1 or at Baseline)
             from adverse events due to previously administered agents.

        Exception to this rule would be use of denosumab, which is not excluded. Note: Participants
        with alopecia and ≤Grade 2 neuropathy are an exception and may enroll.

          -  Has received prior radiotherapy within 2 weeks of first dose of study treatment (Cycle
             1 Day 1). Participants must have recovered from all radiation-related toxicities, not
             require corticosteroids, and not have had radiation pneumonitis.

          -  Has received 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 current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the participant's
             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.