Clinical trial NCT03412773: Phase 3 Study of Tislelizumab Versus Sorafenib in Participants With Unresectable HCC
Official title: RATIONALE-301: A Randomized, Open-label, Multicenter Phase 3 Study to Compare the Efficacy and Safety of BGB-A317 Versus Sorafenib as First-Line Treatment in Patients With Unresectable Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatocellular Carcinoma (HCC)
Keywords: Advanced liver cancer
RATIONALE-301
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2018-01-26
Enrollment: 674
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: This is a Phase 3, randomized, open-label, multicenter, global study designed to compare the efficacy and safety of tislelizumab versus sorafenib as a first-line systemic treatment in participants with unresectable hepatocellular carcinoma. This study also includes a substudy investigating the safety, tolerability, PK, and preliminary efficacy in HCC in Japanese participants. In Japan, preliminary safety and tolerability will be evaluated (Safety Run-In Substudy) before Japanese participants are recruited in this Phase 3 study.


Eligibility criteria: Key Inclusion Criteria:

1. Histologically confirmed diagnosis of HCC
2. Barcelona Clinic Liver Cancer (BCLC) Stage B or C disease not amenable to or progressing after loco-regional therapy and not amenable to a curative treatment approach
3. No prior systemic therapy for HCC (with the exception of HCC participants enrolled in the safety run-in substudy \[Japan only\])
4. Measurable disease
5. Child-Pugh score A
6. Easter Cooperative Oncology Group (ECOG) Performance Status ≤ 1
7. Adequate organ function

Key Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC histology
2. Tumor thrombus involving main trunk of portal vein or inferior vena cava
3. Loco-regional therapy to the liver within 28 days before randomization
4. Clinical evidence of portal hypertension with bleeding esophageal or gastric varices at Screening, or within 6 months before randomization
5. Bleeding or thrombotic disorder or any prescribed anticoagulant requiring therapeutic international normalized ratio monitoring (eg, warfarin or similar agents) at Screening, or within 6 months before randomization/enrollment
6. Presence at Screening of active immune deficiency or autoimmune disease and/or prior history of any immune deficiency or autoimmune disease that may relapse
7. Participant with any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 14 days before randomization
8. History of interstitial lung disease or non-infectious pneumonitis, unless induced by radiation therapy
9. QT interval corrected for heart rate (QTc) (corrected by Fridericia's method) \> 450 msec at Screening

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization up to 4 years, approximately
measure: Safety Run-In Substudy[Japan only]: Percentage of participants with adverse events
timeFrame: From date of enrollment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Percentage of participants with dose-limiting toxicities (DLT) [Determination of the pivotal Phase 3 dose of tislelizumab in Japanese participants]
timeFrame: From the date of enrollment up to 28 days [DLT period].
measure: Safety Run-In Substudy[Japan only]: Maximum Concentration (Cmax) of Tislelizumab
timeFrame: From first dose of study treatment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Trough Serum Concentration (Cmin) of tislelizumab
timeFrame: From first dose of study treatment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Area Under the Curve (AUC) of tislelizumab
timeFrame: From first dose of study treatment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]:Anti-Drug Antibodies (ADA) against tislelizumab at Cmin
timeFrame: From first dose of study treatment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Percentage of Participants With Clinically Significant Changes in Vital Signs Findings
timeFrame: From date of enrollment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Percentage of Participants With Clinically Significant Changes in Physical Examination Findings
timeFrame: From date of enrollment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Percentage of Participants With Clinically Significant Changes in Clinical Laboratory Results Findings
timeFrame: From date of enrollment up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Percentage of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings
timeFrame: From date of enrollment up to 4 years, approximately.
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From date of randomization up to 4 years, approximately
measure: Progression-free survival (PFS)
timeFrame: From date of randomization up to 4 years, approximately
measure: Duration of Response (DOR)
timeFrame: From first determination of an objective response up to 4 years, approximately
measure: Time to Progression (TTP)
timeFrame: From date of randomization up to 4 years, approximately.
measure: Health-Related Quality of Life (HRQoL)
timeFrame: From date of enrollment up to 4 years, approximately.
measure: Disease Control Rate (DCR)
timeFrame: From first dose of study treatment up to 4 years, approximately
measure: Clinical Benefit Rate (CBR)
timeFrame: From first dose of study treatment up to 4 years, approximately
measure: Percentage of participants with adverse events
timeFrame: From date of screening up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Objective Response Rate (ORR)
timeFrame: From date of randomization up to 4 years, approximately.
measure: Safety Run-In Substudy[Japan only]: Progression-free survival (PFS)
timeFrame: From date of randomization up 4 years, approximately
measure: Safety Run-In Substudy[Japan only]: Duration of Response (DOR)
timeFrame: From date of randomization up 4 years, approximately
measure: Safety Run-In Substudy[Japan only]: Overall Survival (OS)
timeFrame: From date of randomization up 4 years, approximately
measure: Safety Run-In Substudy[Japan only]: Anti-tislelizumab antibody
timeFrame: From first dose of study treatment up 4 years, approximately
measure: Percentage of Participants With Clinically Significant Changes in Vital Signs Findings
timeFrame: From date of enrollment up to 4 years, approximately
measure: Percentage of Participants With Clinically Significant Changes in Physical Examination Findings
timeFrame: From date of enrollment up to 4 years, approximately
measure: Percentage of Participants With Clinically Significant Changes in Clinical Laboratory Results Findings
timeFrame: From date of enrollment up to 4 years, approximately
measure: Percentage of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings
timeFrame: From date of enrollment up to 4 years, approximately
Other outcomes:
Locations:
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: University of California - Hematology and Oncology
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Tinley Park
country: United States
facility: Healthcare Research Network III, LLC
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Medical Center (OMC) - New Orleans ACCRU Network Sit
state: Louisiana
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Newark
country: United States
facility: Umdnj-Njms
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health/Monter Cancer Center
state: New York
city: White Plains
country: United States
facility: White Plains Hospital Center for Cancer Care - Oncology
state: New York
city: Kettering
country: United States
facility: Precision Cancer Research / Dayton Physicians Network
state: Ohio
city: Philadelphia
country: United States
facility: Hahnemann University Hospital - Gastroenterology Hepatology
state: Pennsylvania
city: Philadelphia
country: United States
facility: Cancer Treatment Centers of America - Oncology
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center (VUMC)
state: Tennessee
city: San Antonio
country: United States
facility: The Mays Cancer Center
state: Texas
city: Bengbu
country: China
facility: The First Affiliated Hospital of Bengbu Medical College
state: Anhui
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital Of Anhui Medical University
state: Anhui
city: Hefei
country: China
facility: Anhui Medical University - The Second Hospital
state: Anhui
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Chinese PLA General Hospital
state: Beijing
city: Beijing
country: China
facility: 302 Military Hospital of China
state: Beijing
city: Beijing
country: China
facility: Beijing YouAn Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Cancer Hopital Chinese Academy of Medical Sciences
state: Beijing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Fuzhou
country: China
facility: Fujian Provincial Cancer Hospital
state: Fujian
city: Guangzhou
country: China
facility: Guangdong General Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital , Sun Yat-sen University
state: Guangdong
city: Guangzhou
country: China
facility: The First Affiliated Hospital, Sun Yat-sen University
state: Guangdong
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
state: Guangxi
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Wuhan
country: China
facility: Wuhan Union Hospital
state: Hubei
city: Nanjing
country: China
facility: Nanjing Bayi Hospital
state: Jiangsu
city: Nanjing
country: China
facility: Jiangsu Cancer Hospital
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Qingdao
country: China
facility: The Affiliated Hospital Of Qingdao University
state: Shandong
city: Weifang
country: China
facility: Weifang People's Hospital
state: Shandong
city: Shanghai
country: China
facility: Shanghai Cancer Hospital of Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
state: Shanghai
city: Xian
country: China
facility: The First Affiliated Hospital Of XI'AN Jiaotong University
state: Shanxi
city: Sichuan
country: China
facility: Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital
state: Sichuan
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
state: Wuhan
city: HangZhou
country: China
facility: The First Affiliated Hospital of Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Chongqing
country: China
facility: The First Affiliated Hospital of Chongqing Medical University
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
state: Brno-Mesto
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Somme
country: France
facility: CHU Amiens-Hopital Nord - Hépato-Gastroentérologie
state: Amiens
city: Caen, Cedex 05
country: France
facility: CHU Cote De Nacre - Hepato-Gastro-Enterologie Et N
state: Basse-Normandie
city: Plérin
country: France
facility: Hôpital Privé des Côtes d'Armor - Service oncologie
state: Bretagne
city: Reims
country: France
facility: Hopital Robert DEBRE, CHU Reims
state: Champagne-Ardenne
city: Besançon
country: France
facility: Hospitalier Jean Minjoz
state: Franche-Comté
city: La Tronche
country: France
facility: CHU de Grenoble Alpes
state: Isere
city: Clichy Cedex
country: France
facility: Bichat-Beaujon Service Inter Hospitalier De Cancerologie
state: Lie-de-France
city: Villejuif
country: France
facility: Hopital Paul Brousse- Aphp Hopitaux Universitairees Paris Su
state: Lie-de-France
city: Nantes
country: France
facility: CHU Nantes -hopital hotel Dieu
state: Loire-Atlantique
city: Rahon
country: France
facility: CHU Saint Etienne
state: Lyon
city: Lille
country: France
facility: CHRU De Lille - Hôpital Claude Huriez
state: Nord
city: Nice
country: France
facility: CHU de Nice - Hôpital de l'Archet II
state: Provence-Alpes-Côte-d'Azur
city: Bretagne
country: France
facility: CHU Saint Eloi - Pôle Digestif
state: Rennes Cedex
city: Villejuif
country: France
facility: Gustave Roussy - Medical Oncology
state: Val-de-Marne
city: Poitiers
country: France
facility: Hospital of Poitiers
state: Vienne
city: Frankfurt/Main
country: Germany
facility: Krankenhaus Nordwest gGmbH
state: Hessen
city: Bonn
country: Germany
facility: Maria Gonzalez-Carmona
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Stefan Pluntke
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Castellana Grotte
country: Italy
facility: IRCCS Saverio De Bellis, AO Gastroenterologia
state: Bari
city: Feltre
country: Italy
facility: Medical Oncology
state: Belluno
city: Catania
country: Italy
facility: PO G.Rodolico, AOU Policlinico-Vittorio Emanuele di Catania
state: Catani
city: Vicenza
country: Italy
facility: Ospedale S.Bortolo, AULSS n.6 Vicenza
state: Veneto
city: Bologna
country: Italy
facility: Policlinico S.Orsola Malpighi, AOU di Bologna - SSD Malattie
city: Cremona
country: Italy
facility: PO di Cremona, ASST di Cremona - Oncologia - Cremona - Radiology
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi, ASL Lecce
city: Modena
country: Italy
facility: AOU Policlinico di Modena
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Pavia
country: Italy
facility: Ist. Clinici Scientifici Maugeri - Unità Operativa di Oncologia
city: Roma
country: Italy
facility: Regina Elena, Istituto Nazionale dei Tumori, IFO, IRCCS
city: Torino
country: Italy
facility: PO Umberto I, AO Ordine Mauriziano
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
state: Aiti [Aichi]
city: Matsuyama
country: Japan
facility: Ehime Prefectural Central Hospital - Gastroenterology
state: Ehime
city: Ogaki
country: Japan
facility: Ogaki Municipal Hospital
state: Gihu [Gifu]
city: Sapporo
country: Japan
facility: Hokkaido University Hospital - Gastroenterology
state: Hokkaidô [Hokkaido]
city: Kanazawa-shi
country: Japan
facility: Kanazawa University Hospital
state: Isikawa [Ishikawa]
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
state: Kanagawa
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Kyoto-shi
country: Japan
facility: University Hospital, Kyoto Prefectural Univ of Medicine
state: Kyôto [Kyoto]
city: Omura
country: Japan
facility: Nagasaki Medical Center
state: Nagasaki
city: Osaka-sayama
country: Japan
facility: Kinki University Hospital, Faculty of Medicine - Hematology & Clinical Oncology
state: Osaka
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Chiba
country: Japan
facility: Chiba University Hospital
state: Tiba [Chiba]
city: Chiyoda-Ku
country: Japan
facility: Sasaki Foundation Kyoundo Hospital
state: Tokyo
city: Itabashi-ku
country: Japan
facility: Nihon University Itabashi Hospital - Gastroenterological surgery
state: Tôkyô [Tokyo]
city: Shibuya-ku
country: Japan
facility: JRC Medical Center
state: Tôkyô [Tokyo]
city: Shinjuku-ku
country: Japan
facility: National Center for Global Health and Medicine
state: Tôkyô [Tokyo]
city: Fukuoka
country: Japan
facility: Kyushu Medical Center
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Morioka
country: Japan
facility: Iwate Medical University Hospital
city: Nishinomiya-shi
country: Japan
facility: Hyogo College of Medicine Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Tottori
country: Japan
facility: Tottori University Hospital
city: Wakayama-shi
country: Japan
facility: Wakayama Medical University
city: Osaka
country: Japan
facility: Osaka City General Hospital
state: Ôsaka [Osaka]
city: Osaka
country: Japan
facility: Osaka National Hospital
state: Ôsaka [Osaka]
city: Osaka
country: Japan
facility: Osaka City University Hospital
state: Ôsaka [Osaka]
city: Warszawa
country: Poland
facility: Centrum Onkologii Instytut im. M. Sklodowskiej-Curie
state: Mazowieckie
city: Poznan
country: Poland
facility: Clinical Research Center Sp. z o.o., Medic-R Sp. K.
state: Wielkopolskie
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Gromkowskiego we Wroclawiu
city: Hospitalet de Llobregat
country: Spain
facility: Institut Catalá d´Oncología (I.C.O.)
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital Universitario Madrid Sanchinarro Centro integral Oncologico Clara Campal (CIOCC)
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Kaohsiung
country: Taiwan
facility: Chang Gung Medical Foundation - Kaohsiung Chang Gung Memorial Hospital - Gastroenterology
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University - Chung-Ho Memorial Hospital
city: New Taipei
country: Taiwan
facility: Tri-Service General Hospital - Neihu Branch
city: Taichung
country: Taiwan
facility: China Medical University Hospital - Transplantology - Taichung
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tainan
country: Taiwan
facility: Chi Mei Medical Center - YongKang
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Chang Gung Medical Foundation - LinKou Chang Gung Memorial Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital - Clinical Reasearch
city: London
country: United Kingdom
facility: Royal Free Hospital London NHS Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: Withington
country: United Kingdom
facility: The Christie NHS Foundation Trust - Oak Road Treatment Centre
Study officials:
affiliation: BeiGene
name: Yaxi Chen, MD
role: STUDY_DIRECTOR
References:
citation: Qin S, Finn RS, Kudo M, Meyer T, Vogel A, Ducreux M, Macarulla TM, Tomasello G, Boisserie F, Hou J, Li X, Song J, Zhu AX. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 2019 Jun;15(16):1811-1822. doi: 10.2217/fon-2019-0097. Epub 2019 Apr 10.