Study of Pembrolizumab (MK-3475) or Placebo Given With Best Supportive Care in Asian Participants With Previously Treated Advanced Hepatocellular Carcinoma (MK-3475-394/KEYNOTE-394)

• ClinicalTrials.gov Identifier: NCT03062358
• Recruitment Status: Active, not recruiting
• First Posted: February 23, 2017
• Last Update Posted: March 4, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: February 21, 2017
• First Posted Date: February 23, 2017
• Last Update Posted Date: March 4, 2022
• Actual Study Start Date: April 27, 2017
• Actual Primary Completion Date: June 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 15, 2018)

Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]

OS is the time from randomization to death due to any cause.

• Original Primary Outcome Measures (submitted: February 21, 2017): Overall Survival (OS) [ Time Frame: Up to 2 years ]

Current Secondary Outcome Measures (submitted: November 15, 2018)

• Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
  PFS is the time from randomization to first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR).
• Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
  ORR is the proportion of the participants who achieve complete response (CR) or partial response (PR) per RECIST 1.1 by Blinded Independent Central Review (BICR).
• Duration Of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
  DOR is the time from first documented evidence of CR or PR per RECIST 1.1 by BICR until disease progression per RECIST 1.1 by Blinded Independent Central Review (BICR) or death.
• Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
  DCR is the percentage of participants who achieve CR, PR, or stable disease (SD) for ≥6 weeks prior to evidence of disease progression per RECIST 1.1 by Blinded Independent Central Review (BICR).
• Time To Progression (TTP) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 2 years ]
  TTP is the time from randomization to first documented disease progression per RECIST 1.1 by Blinded Independent Central Review (BICR).
• Number of Participants Who Experienced At Least One Adverse Event (AE) [ Time Frame: From time of signing the informed consent form (ICF) until the end of follow-up (up to approximately 118 weeks) ]
  An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy.
• Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: From time of signing the ICF until the end of study medication (up to approximately 105 weeks) ]
  The number of participants discontinuing study drug due to an AE will be presented.

Original Secondary Outcome Measures (submitted: February 21, 2017)

• Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 2 years ]
• Objective Response Rate (ORR) per RECIST 1.1 by BICR [ Time Frame: Up to approximately 2 years ]
• Duration Of Response (DOR) per RECIST 1.1 by BICR [ Time Frame: Up to approximately 2 years ]
• Disease Control Rate (DCR) per RECIST 1.1 by BICR [ Time Frame: Up to approximately 2 years ]
• Time To Progression (TTP) per RECIST 1.1 by BICR [ Time Frame: Up to approximately 2 years ]
• Number of Participants with Adverse Events (AEs) [ Time Frame: From time of signing the informed consent form (ICF) until the end of follow-up (up to approximately 118 Weeks) ]
• Number of Participants Discontinuing Study Treatment Due to AEs [ Time Frame: From time of signing the ICF until the end of study medication (up to approximately 105 Weeks) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Pembrolizumab (MK-3475) or Placebo Given With Best Supportive Care in Asian Participants With Previously Treated Advanced Hepatocellular Carcinoma (MK-3475-394/KEYNOTE-394)
• Official Title: A Phase III Randomized Double-blind Study of Pembrolizumab Plus Best Supportive Care vs. Placebo Plus Best Supportive Care as Second-Line Therapy in Asian Subjects With Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-394)
• Brief Summary: The purpose of this study is to determine the efficacy and safety of pembrolizumab or placebo given with best supportive care (BSC) in Asian participants with previously systemically treated advanced hepatocellular carcinoma (HCC). The primary hypothesis of this study is that overall survival is prolonged in participants who receive pembrolizumab compared to those who receive placebo.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular

Intervention

• Biological: pembrolizumab
  Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
  Other Name: KEYTRUDA®
• Drug: placebo
  Normal saline solution administered as an IV infusion Q3W
• Other: best supportive care (BSC)
  BSC will include pain management and management of other potential complications including ascites per local standards of care.

Study Arms

• Experimental: pembrolizumab + BSC
  Participants receive pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC.
  Interventions:

  • Biological: pembrolizumab
  • Other: best supportive care (BSC)
• Placebo Comparator: placebo + BSC
  Participants receive placebo by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC.
  Interventions:

  • Drug: placebo
  • Other: best supportive care (BSC)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 27, 2021): 454
• Original Estimated Enrollment (submitted: February 21, 2017): 330
• Estimated Study Completion Date: June 30, 2023
• Actual Primary Completion Date: June 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Has a 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 A liver score within 7 days prior to first dose of study medication
• Has a life expectancy of >3 months
• Has at least one measurable lesion based on RECIST version 1.1 as determined by investigator
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 7 days prior to receiving the first dose of study medication
• Has documented objective radiographic progression during or after treatment with sorafenib or oxaliplatin-based chemotherapy, or else intolerance to sorafenib or oxaliplatin-based chemotherapy
• Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy
• Female and male participants of reproductive potential must agree to use adequate contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication

Exclusion Criteria:

• Is currently participating or has participated in a study with an investigational agent or using an investigational device within 4 weeks of the first dose of study medication
• Has received sorafenib or oxaliplatin-based chemotherapy within 14 days of first dose of study medication
• 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 branch (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging
• Has had clinically diagnosed hepatic encephalopathy in the last 6 months
• Has had a solid organ or hematologic transplant
• Has had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib or oxaliplatin-based chemotherapy, prior to start of study medication
• Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
• 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 medication
• Has received locoregional therapy to liver (transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation, radioembolization, or ablation) or other site within 4 weeks prior to the first dose of study medication
• Has had major surgery to liver or other site within 4 weeks prior to the first dose of study medication
• Has had a minor surgery ≤7 days prior to the first dose of study medication
• Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to study start
• Has a diagnosed additional malignancy within 3 years prior to first dose of study medication with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers
• Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring systemic therapy
• Is pregnant or breast feeding or expecting to conceive or father starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication
• Has received prior immunotherapy with an anti-Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (anti-PD-L1), or anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) or has previously participated in clinical studies with pembrolizumab
• Has a known history of human immunodeficiency virus (HIV)
• Has untreated active Hepatitis B
• Has Hepatitis C in which participants received therapy for HCV <4 weeks prior to receiving pembrolizumab
• Has received a live vaccine within 30 days prior to the first dose of study therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, Hong Kong, Korea, Republic of, Malaysia, Taiwan
• Removed Location Countries: Philippines

Administrative Information

• NCT Number: NCT03062358
• Other Study ID Numbers: 3475-394; MK-3475-394 ( Other Identifier: Merck Registration Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: March 2022