Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Pembrolizumab
Intervention description: Intravenous (IV) infusion
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 156.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death 1 (PD1, PD-1); Programmed Cell Death Ligand 1 (PDL1, PD-L1); Programmed Cell Death Ligand 2 (PDL2, PD-L2)

Summary:

      This is a efficacy and safety study of pembrolizumab (MK-3475, KEYTRUDA®) as monotherapy in
      participants with hepatocellular carcinoma (HCC) in two cohorts: participants with advanced
      HCC and with no curative option after disease progression on sorafenib or intolerance of
      sorafenib (Cohort 1) or who had not received treatment for systemic disease (Cohort 2). Study
      participants may receive pembrolizumab once every 3 weeks for up to 35 initial cycles (up to
      approximately 2 years) and a potential additional 17 cycles in a re-treatment phase
      (approximately an additional 1 year of treatment) .

      The primary objective of this study is to determine the Objective Response Rate (ORR) of
      pembrolizumab given as monotherapy in participants with HCC.

      Effective with Amendment 7: Upon study completion, participants are discontinued and may be
      enrolled in a pembrolizumab extension study, if available.
    

Eligibility criteria:

        Inclusion Criteria:

          -  For Cohort 1: has histologically or cytologically confirmed diagnosis of HCC
             (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
             based on pathology report

          -  For Cohort 2: has an HCC diagnosis confirmed by radiology, histology, or cytology
             (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)

          -  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 within 7 days of first dose of study drug

          -  Has a predicted life expectancy >3 months

          -  Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1 as confirmed by the blinded central imaging vendor

          -  Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale within 7 days of first dose of study drug

          -  For Cohort 1: has documented objective radiographic progression after stopping
             treatment with sorafenib or else intolerance to sorafenib

          -  Is willing to use an adequate method of contraception for the course of the study
             through 120 days after the last dose of study drug (male and female participants of
             childbearing potential)

          -  Demonstrates adequate organ function

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy, herbal/complementary oral or
             IV medicine, or used an investigational device within 4 weeks of the first dose of
             study drug. Participant must also have recovered from associated therapy (i.e., to
             Grade ≤1 or baseline) and from adverse events due to any prior therapy

          -  For Cohort 1: has received sorafenib within 14 days of first dose of study drug

          -  Has had esophageal or gastric variceal bleeding within the last 6 months

          -  Has clinically apparent ascites on physical examination

          -  Has portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac
             involvement of HCC based on imaging

          -  Has had encephalopathy in the last 6 months. Participants on rifaximin or lactulose to
             control their encephalopathy are not allowed

          -  Had a solid organ or hematologic transplant

          -  For Cohort 1: had prior systemic therapy for HCC other than sorafenib, or intercurrent
             local therapy to the liver tumor between sorafenib and study drug

          -  For Cohort 2: had prior systemic therapy in the advanced disease setting

          -  Has active autoimmune disease that has required systemic treatment in past 2 years
             (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive
             drugs)

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of study
             drug

          -  Has a diagnosed additional malignancy within 5 years for Cohort 1 and 3 years for
             Cohort 2 prior to first dose of study treatment with the exception of curatively
             treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or
             curatively resected in situ cervical and/or breast cancers

          -  Has radiographically detectable central nervous system (CNS) metastases and/or
             carcinomatous meningitis

          -  Has evidence or history of interstitial lung disease or active noninfectious
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known severe hypersensitivity to pembrolizumab, its active substance and/or any
             of its excipients

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the study

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 120 days
             after the last dose of trial treatment

          -  Has received prior immunotherapy including anti-programmed death-1 (anti-PD-1),
             anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has
             previously participated in clinical studies with pembrolizumab (MK-3475)

          -  Has a known history of human immunodeficiency virus (HIV)

          -  Has untreated active Hepatitis B virus (HBV)

          -  For Cohort 1: has dual infection with HBV/Hepatitis C virus (HCV) or other hepatitis
             combinations at study entry

          -  For Cohort 2: has dual active HBV infection (Hepatitis B surface antigen positive
             and/or detectable HBV deoxyribonucleic acid [DNA]) and HCV infection (detectable HCV
             ribonucleic acid [RNA]) at study entry

          -  Has received a live vaccine within 30 days of planned start of study drug (Cycle 1,
             Day 1)