Clinical trial NCT03062358: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Keywords: Programmed Cell Death Receptor 1 (PD-1)
Programmed Cell Death Receptor Ligand 1 (PD-L1)
Programmed Cell Death Receptor Ligand 2 (PD-L2)
PD1
PD-1
PDL1
PD-L1
PDL2
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-02-23
Enrollment: 453
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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) 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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 4 years
Secondary outcomes:
measure: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 4 years
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 4 years
measure: Duration Of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 4 years
measure: Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 4 years
measure: Time To Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 4 years
measure: Number of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: Up to approximately 30 months.
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 27 months.
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital ( Site 0032)
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University ( Site 0005)
state: Anhui
city: Fuzhou
country: China
facility: Fuzhou General Hospital of Nanjing Military Command ( Site 0019)
state: Fujian
city: Foshan
country: China
facility: The First People s Hospital of Foshan ( Site 0033)
state: Guangdong
city: Guangzhou
country: China
facility: Guangdong General Hospital ( Site 0015)
state: Guangdong
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital ( Site 0007)
state: Heilongjiang
city: Wuhan
country: China
facility: Wuhan Tongji Hospital ( Site 0021)
state: Hubei
city: Wuhan
country: China
facility: Hubei Cancer Hospital ( Site 0035)
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital ( Site 0027)
state: Hunan
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University ( Site 0026)
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital ( Site 0003)
state: Jiangsu
city: Nanjing
country: China
facility: The 81st Hospital of PLA ( Site 0016)
state: Jiangsu
city: Nantong
country: China
facility: Nantong Tumor Hospital ( Site 0028)
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University ( Site 0025)
state: Jiangsu
city: Yangzhou
country: China
facility: Yangzhou No.1 People's Hospital ( Site 0023)
state: Jiangsu
city: Chang Chun
country: China
facility: The First Hospital Of Jilin University ( Site 0001)
state: Jilin
city: Changchun
country: China
facility: Jilin Province Cancer Hospital, Department of Chemotherapy ( Site 0002)
state: Jilin
city: Dalian
country: China
facility: The First Affiliated Hospital of Dalian Medical University ( Site 0022)
state: Liaoning
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 0024)
state: Shanghai
city: XI An
country: China
facility: The first affiliated Hospital of Xi an Jiaotong University ( Site 0014)
state: Shanxi
city: Chengdu
country: China
facility: West China Hospital of Sichuan University ( Site 0030)
state: Sichuan
city: Hangzhou
country: China
facility: The First affiliated Hospital Zhejing University ( Site 0034)
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital ( Site 0011)
state: Zhejiang
city: Beijing
country: China
facility: Beijing Cancer Hospital ( Site 0010)
city: Bengbu
country: China
facility: Bengbu Medical College First Affiliated Hospital ( Site 0020)
city: Hefei
country: China
facility: The Second Affiliated Hospital of Anhui Medical University ( Site 0008)
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University ( Site 0012)
city: Shanghai
country: China
facility: Renji Hosp,Shanghai Jiao Tong University School of Medicine ( Site 0017)
city: Hong Kong
country: Hong Kong
facility: Hong Kong Sanatorium Hospital ( Site 0053)
city: Hong Kong
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital ( Site 0052)
city: Hong Kong
country: Hong Kong
facility: Princess Margaret Hospital. ( Site 0051)
city: Seoul.
country: Korea, Republic of
facility: Asan Medical Center ( Site 0072)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 0074)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0073)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 0071)
city: Petaling Jaya
country: Malaysia
facility: Beacon Hospital Sdn Bhd ( Site 0092)
state: Selangor
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre ( Site 0091)
state: Wilayah Persekutuan
city: Cheras
country: Malaysia
facility: Hospital Universiti Kebangsaan Malaysia ( Site 0093)
city: Chiayi
country: Taiwan
facility: Chia-Yi Chang Gung Memorial Hospital ( Site 0133)
city: Taichung
country: Taiwan
facility: China Medical University Hospital ( Site 0131)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 0132)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.