Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination With Pembrolizumab (MK-3475) Versus Lenvatinib as First-line Therapy in Participants With Advanced Hepatocellular Carcinoma (MK-7902-002/E7080-G000-311/LEAP-002)
Condition: Carcinoma, Hepatocellular
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: lenvatinib; pembrolizumab; saline placebo
Intervention description: Administered orally once a day; Administered as an IV infusion on Day 1 Q3W; Administered as an IV infusion on Day 1 Q3W
Intervention MeSH terms: Pembrolizumab; Lenvatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 794.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: receptor tyrosine kinase inhibitor; 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 evaluate the safety and efficacy of lenvatinib
      (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination
      with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in
      adult participants.

      The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to
      lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival
      (OS).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Is male or female and ≥18 years of age at the time of signing the informed consent

          -  Has a diagnosis of hepatocellular carcinoma confirmed by radiology, histology, or
             cytology

          -  Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not
             amenable to locoregional therapy or refractory to locoregional therapy, and not
             amenable to a curative treatment approach

          -  Has a Child-Pugh class A liver score

          -  Has a predicted life expectancy of >3 months

          -  Has at least one measurable hepatocellular carcinoma (HCC) lesion based on RECIST 1.1
             as confirmed by BICR

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1

          -  Participants with hepatitis B will be eligible as long as their virus is well
             controlled

        Exclusion Criteria:

          -  Has had esophageal or gastric variceal bleeding within the last 6 months

          -  Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other
             condition that might affect the absorption of lenvatinib

          -  Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula

          -  Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks
             prior to the first dose of study intervention

          -  Has significant cardiovascular impairment within 12 months of the first dose of study
             intervention such as history of congestive heart failure greater than New York Heart
             Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular
             accident stroke, or cardiac arrhythmia associated with hemodynamic instability

          -  Has had major surgery to the liver within 4 weeks prior to the first dose of study
             intervention

          -  Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of
             study intervention

          -  Has serious non-healing wound, ulcer, or bone fracture

          -  Has received any systemic chemotherapy for HCC or chemotherapy for any malignancy in
             the past 3 years

          -  Has received prior therapy with an anti-programmed cell death 1 (ant-PD-1),
             anti-programmed cell death ligand 1 (anti-PD-L1), or anti- programmed cell death
             ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or
             co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4
             [CTLA-4], OX-40, or CD137)

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             or any other form of immunosuppressive therapy within 7 days prior the first dose of
             study intervention

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years with the exceptions of basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma,
             cervical cancer in situ) that has undergone potentially curative therapy

          -  Has a known history of, or any evidence of, central nervous system (CNS) metastases
             and/or carcinomatous meningitis as assessed by local site investigator

          -  Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their
             excipients

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has urine protein ≥1 grams/24 hours

          -  Prolongation of corrected QT (QTc) interval to >480 milliseconds (corrected by
             Fridericia Formula)

          -  Has left ventricular ejection fraction (LVEF) below the institutional normal range as
             determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO)

          -  Has an active infection requiring systemic therapy with the exceptions of hepatitis B
             virus (HBV) or hepatitis C virus (HCV)

          -  Has a known history of human immunodeficiency virus (HIV) infection

          -  Has known active tuberculosis (Bacillus tuberculosis)

          -  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 a known psychiatric or substance abuse disorder that would interfere with the
             participant's ability to cooperate with the requirements of the study

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of study intervention

          -  Has had an allogenic tissue/solid organ transplant