Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Advanced Hepatocellular Carcinoma (KEYNOTE-224)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib<br>Participants with previously systemically treated HCC received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment. | Biological: Pembrolizumab<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Cohort 2: HCC-Systemic Therapy Naïve<br>Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment. | Biological: Pembrolizumab<br>* Intravenous (IV) infusion<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target and non-target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered non-responders. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target and non-target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed, started a new anti-cancer therapy, been lost to follow-up, or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants who had a CR (disappearance of all target and non-target lesions), PR (at least a 30% decrease in the sum of diameters of target and non-target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions.]). CR, PR, and SD were evaluated per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Time to Progression (TTP) | TTP was defined as the time from the first dose to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored data. TTP per RECIST 1.1 is presented. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Progression-Free Survival (PFS) | PFS was defined as the time from the first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. PFS is presented. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Overall Survival (OS) | OS was determined for all participants and was defined as the time from the first dose to death due to any cause. Participants were censored at the last known alive date. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS is presented. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only. | Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death 1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)