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

Primary Purpose

Hepatocellular Carcinoma

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Pembrolizumab

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Programmed Cell Death 1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib

Cohort 2: HCC-Systemic Therapy Naïve

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02702414

First Posted

March 3, 2016

Last Updated

October 11, 2023

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT02702414

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Completed

Study Start Date

May 31, 2016 (Actual)

Primary Completion Date

January 19, 2021 (Actual)

Study Completion Date

September 29, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatocellular Carcinoma

Keywords

Programmed Cell Death 1 (PD1, PD-1), Programmed Cell Death Ligand 1 (PDL1, PD-L1), Programmed Cell Death Ligand 2 (PDL2, PD-L2)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

156 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2: HCC-Systemic Therapy Naïve

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

Pembrolizumab

Other Intervention Name(s)

MK-3475, KEYTRUDA®

Intervention Description

Intravenous (IV) infusion

Primary Outcome Measure Information:

Title

Objective Response Rate (ORR)

Description

Time Frame