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)

Carcinoma, Hepatocellular Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03062358
• Other study ID #: 3475-394
• Secondary ID: MK-3475-394
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 27, 2017
• Est. completion date: October 31, 2024

Study information

• Verified date: July 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 453
• Est. completion date: October 31, 2024
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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) 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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Biological:
• pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)

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.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital ( Site 0010)	Beijing
China	Bengbu Medical College First Affiliated Hospital ( Site 0020)	Bengbu
China	The First Hospital Of Jilin University ( Site 0001)	Chang Chun	Jilin
China	Jilin Province Cancer Hospital, Department of Chemotherapy ( Site 0002)	Changchun	Jilin
China	Hunan Cancer Hospital ( Site 0027)	Changsha	Hunan
China	The Third Xiangya Hospital of Central South University ( Site 0026)	Changsha	Hunan
China	West China Hospital of Sichuan University ( Site 0030)	Chengdu	Sichuan
China	The First Affiliated Hospital of Dalian Medical University ( Site 0022)	Dalian	Liaoning
China	The First People s Hospital of Foshan ( Site 0033)	Foshan	Guangdong
China	Fuzhou General Hospital of Nanjing Military Command ( Site 0019)	Fuzhou	Fujian
China	Guangdong General Hospital ( Site 0015)	Guangzhou	Guangdong
China	The First affiliated Hospital Zhejing University ( Site 0034)	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital ( Site 0011)	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital ( Site 0007)	Harbin	Heilongjiang
China	Anhui Provincial Hospital ( Site 0032)	Hefei	Anhui
China	The First Affiliated Hospital of Anhui Medical University ( Site 0005)	Hefei	Anhui
China	The Second Affiliated Hospital of Anhui Medical University ( Site 0008)	Hefei
China	Jiangsu Cancer Hospital ( Site 0003)	Nanjing	Jiangsu
China	The 81st Hospital of PLA ( Site 0016)	Nanjing	Jiangsu
China	Nantong Tumor Hospital ( Site 0028)	Nantong	Jiangsu
China	Fudan University Shanghai Cancer Center ( Site 0024)	Shanghai	Shanghai
China	Renji Hosp,Shanghai Jiao Tong University School of Medicine ( Site 0017)	Shanghai
China	Zhongshan Hospital Fudan University ( Site 0012)	Shanghai
China	The First Affiliated Hospital of Soochow University ( Site 0025)	Suzhou	Jiangsu
China	Hubei Cancer Hospital ( Site 0035)	Wuhan	Hubei
China	Wuhan Tongji Hospital ( Site 0021)	Wuhan	Hubei
China	The first affiliated Hospital of Xi an Jiaotong University ( Site 0014)	XI An	Shanxi
China	Yangzhou No.1 People's Hospital ( Site 0023)	Yangzhou	Jiangsu
Hong Kong	Hong Kong Sanatorium Hospital ( Site 0053)	Hong Kong
Hong Kong	Pamela Youde Nethersole Eastern Hospital ( Site 0052)	Hong Kong
Hong Kong	Princess Margaret Hospital. ( Site 0051)	Hong Kong
Korea, Republic of	Samsung Medical Center ( Site 0071)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 0074)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0073)	Seoul
Korea, Republic of	Asan Medical Center ( Site 0072)	Seoul.
Malaysia	Hospital Universiti Kebangsaan Malaysia ( Site 0093)	Cheras
Malaysia	University Malaya Medical Centre ( Site 0091)	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Beacon Hospital Sdn Bhd ( Site 0092)	Petaling Jaya	Selangor
Taiwan	Chia-Yi Chang Gung Memorial Hospital ( Site 0133)	Chiayi
Taiwan	China Medical University Hospital ( Site 0131)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 0132)	Tainan

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

China,  Hong Kong,  Korea, Republic of,  Malaysia,  Taiwan, 

References & Publications (1)

Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, Meng Z, Bai Y, Chen X, Liu X, Xiao J, Ho GF, Mao Y, Wang X, Ying J, Li J, Zhong W, Zhou Y, Siegel AB, Hao C. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023 Mar 1;41(7):1434-1443. doi: 10.1200/JCO.22.00620. Epub 2022 Dec 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS is the time from randomization to death due to any cause, based on the Kaplan-Meier method for censored data.	Up to approximately 4 years
Secondary	Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	PFS is the time from randomization to first documented disease progression or death due to any cause per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) based on the Kaplan-Meier method for censored data.	Up to approximately 4 years
Secondary	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	ORR is the percentage of participants who achieve complete response (CR) or partial response (PR) with confirmation per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.	Up to approximately 4 years
Secondary	Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	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 BICR or death, based on Kaplan-Meier method for censored data. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.	Up to approximately 4 years
Secondary	Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	DCR is the percentage of participants who achieve CR, PR, or stable disease (SD) for =5 weeks prior to evidence of disease progression per RECIST 1.1 by BICR. CR is the disappearance of all target lesions; PR is at least a 30% decrease in the sum of diameters of target lesions.	Up to approximately 4 years
Secondary	Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	TTP is the time from randomization to first documented disease progression per RECIST 1.1 by BICR, based on Kaplan-Meier method for censored data.	Up to approximately 4 years
Secondary	Number of Participants Who Experienced At Least One Adverse Event (AE)	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.	Up to approximately 30 months.
Secondary	Number of Participants Who Discontinued Study Treatment Due to an AE	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.	Up to approximately 27 months.

External Links

•   Merck Clinical Trials Information