Clinical trial NCT04102098: A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation
Official title: A Phase III, Multicenter, Randomized, Open-Label Study of Atezolizumab (Anti-PD-L1 Antibody) Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-09-25
Enrollment: 668
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 study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab compared with active surveillance in participants with completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence.


Eligibility criteria: Inclusion Criteria:

* Participants with a first diagnosis of HCC who have undergone either a curative resection or ablation (radiofrequency ablation \[RFA\] or microwave ablation \[MVA\] only) within 4-12 weeks prior to randomization
* Documented diagnosis of HCC that has been completely resected or ablated (RFA or MVA only)
* Absence of major macrovascular invasion (except Vp1/Vp2) and extrahepatic spread
* Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following curative procedure
* Full recovery from surgical resection or ablation within 4 weeks prior to randomization
* High risk for HCC recurrence after resection or ablation
* For patients who received post-operative transarterial chemoembolization: full recovery from the procedure within 4 weeks prior to randomization
* For patients with resected HCC, availability of a representative baseline tumor tissue sample
* ECOG Performance Status of 0 or 1
* Child-Pugh Class A status
* Adequate hematologic and end-organ function
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm

Exclusion Criteria:

* Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
* Evidence of residual, recurrent, or metastatic disease at randomization
* Clinically significant ascites
* History of hepatic encephalopathy
* Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization
* Have received more than 1 cycle of adjuvant TACE following surgical resection
* Active or history of autoimmune disease or immune deficiency
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Significant cardiovascular disease within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina
* History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
* Active tuberculosis
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
* Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to Day 1 of Cycle 1.
* Co-infection with HBV and HCV
* Co-infection with HBV and hepatitis D viral infection
* Clinical significant uncontrolled or symptomatic hypercalcemia
* Any treatment for HCC prior to resection or ablation, including systemic therapy and locoregional therapy such as TACE
* Treatment with systemic immunostimulatory or immunosuppressive agents
* Inadequately controlled arterial hypertension
* History of hypertensive crisis or hypertensive encephalopathy
* Significant vascular disease
* Evidence of bleeding diathesis or significant coagulopathy
* Current or recent use of aspirin or full-dose oral or parenteral anticoagulants
* Core biopsy within 3 days of Day 1 of Cycle 1
* History of GI fistula, GI perforation, or intra-abdominal abscess
* Serious non-healing or dehiscing wound
* Major surgical procedure within four weeks
* Chronic daily treatment with a non-steroidal anti-inflammatory drug

Primary outcomes:
measure: Recurrence-Free Survival (RFS), as Determined by IRF
timeFrame: Baseline up to approximately 33 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Baseline up to approximately 91 months
measure: RFS as Determined by the Investigator
timeFrame: Baseline up to approximately 91 months
measure: Time to Recurrence (TTR)
timeFrame: Baseline up to approximately 91 months
measure: RFS Rate at 24 and 36 Months, as Assessed by the IRF
timeFrame: Randomization up to 24 months and up to 36 months
measure: RFS Rate at 24 and 36 Months, as Assessed by the Investigator
timeFrame: Randomization up to 24 months and up to 36 months
measure: OS Rate at 24 and 36 Months
timeFrame: Baseline to 24 and 36 months
measure: Time to Extrahepatic Spread (EHS) or Macrovascular Invasion
timeFrame: Baseline up to approximately 91 months
measure: RFS in Pd-L1-High Subgroup
timeFrame: Baseline up to approximately 91 months
measure: Percentage of Participants With Adverse Events
timeFrame: Baseline up to approximately 91 months
measure: Serum Concentration of Atezolizumab
timeFrame: Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and 30 minutes after end of atezolizumab infusion on Day 1 of Cycle 1 (each cycle is 21 days)
measure: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: Prior to any drug administration up to approximately 33 month
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles
state: California
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Inst.
state: Washington
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Graz
country: Austria
facility: Lkh-Univ. Klinikum Graz
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt am Wörtersee
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Bonheiden
country: Belgium
facility: Imeldaziekenhuis
city: Roeselare
country: Belgium
facility: AZ Delta (Campus Rumbeke)
city: Salvador
country: Brazil
facility: Hospital Sao Rafael - HSR
state: Bahia
city: Brasilia
country: Brazil
facility: Sociedade beneficente de senhoras Hospital Sirio Libanes
state: Distrito Federal
city: Cascavel
country: Brazil
facility: Hospital do Cancer UOPECCAN
state: Paraná
city: Sao Paulo
country: Brazil
facility: Hospital Alemao Oswaldo Cruz
state: São Paulo
city: Vancouver
country: Canada
facility: Gordon & Leslie Diamond Health Care Centre
state: British Columbia
city: Montreal
country: Canada
facility: McGill University Health Centre - Glen Site
state: Quebec
city: Anhui
country: China
facility: Anhui Provincial Hospital
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Bengbu
country: China
facility: Affiliated Hospital of Bengbu Medical College
city: Changchun City
country: China
facility: The First Hospital of Jilin University
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
city: Chongqing
country: China
facility: Daping Hospital of Third Military Medical University
city: Dalian
country: China
facility: The Second Affiliated Hospital of Dalian Medical University
city: Fuzhou City
country: China
facility: Mengchao Hepatobiliary Hospital Of Fujian Medical University
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
city: Guangzhou
country: China
facility: Cancer Center of Guangzhou Medical University
city: Guangzhou
country: China
facility: Sun Yet-sen University Cancer Center
city: Guangzhou
country: China
facility: Zhujiang Hospital, Southern Medical University
city: Guangzhou
country: China
facility: Nanfang Hospital, Southern Medical University
city: Hangzhou City
country: China
facility: Zhejiang Cancer Hospital
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
city: Hefei
country: China
facility: Anhui Province Cancer Hospital
city: Hefei
country: China
facility: The Second Affiliated Hospital of Anhui Medical University
city: Jinan
country: China
facility: Shandong Cancer Hospital
city: Nanjing City
country: China
facility: The 81st Hospital of P.L.A.
city: Nanjing
country: China
facility: Zhongda Hospital Affiliated to Southeast University
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
city: Nanning
country: China
facility: Guangxi Cancer Hospital of Guangxi Medical University
city: Nanning
country: China
facility: The First Affiliate Hospital of Guangxi Medical University
city: Shanghai City
country: China
facility: Huashan Hospital Affiliated to Fudan University
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
city: Shanghai
country: China
facility: Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan Unvierstiy
city: Shenyang City
country: China
facility: The First Affiliated Hospital of China Medical University
city: ShenYang
country: China
facility: Shengjing Hospital of China Medical University
city: Tianjin
country: China
facility: Tianjin Cancer Hospital
city: Urumqi
country: China
facility: The Tumor Hospital of Xinjiang Medical University
city: Wuhan City
country: China
facility: Wuhan Union Hospital Tongji Medical College, Huazhong University of Science and Technology
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
city: Yangzhou
country: China
facility: Northern Jangsu People's Hospital
city: San José
country: Costa Rica
facility: Clinica CIMCA
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Praha
country: Czechia
facility: Fakultni Thomayerova Nemocnice
city: Besancon
country: France
facility: Hopital Jean Minoz
city: Bobigny Cedex
country: France
facility: Hôpital Avicenne - Groupement Hospitalier Universitaire Paris Seine St Denis
city: La Tronche
country: France
facility: Hôpital Albert Michallon
city: Marseille
country: France
facility: Fondation Hopital Saint Joseph
city: Pessac
country: France
facility: CHU Bordeaux - Hôpital Haut-Lévêque
city: Reims
country: France
facility: Hopital Robert Debre
city: Rennes
country: France
facility: Hopital de Pontchaillou
city: Toulouse Cedex 09
country: France
facility: CHU de Toulouse - Hôpital Rangueil
city: Vandoeuvre-les-nancy
country: France
facility: Hopitaux de Brabois - Gastro-Entereologie
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I.
city: Frankfurt Am Main
country: Germany
facility: Klinik Johann Wolfgang von Goethe Uni
city: Regensburg
country: Germany
facility: Klinikum der Uni Regensburg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Parma
country: Italy
facility: Ospedale Regionale Di Parma
state: Emilia-Romagna
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico
state: Lombardia
city: Milano
country: Italy
facility: Asst Santi Paolo E Carlo
state: Lombardia
city: Pisa
country: Italy
facility: Azlenda Ospendaliero-Universitaria Pisana
state: Toscana
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Ehime
country: Japan
facility: Ehime Prefectural Central Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hokkaido
country: Japan
facility: Sapporo Kosei General Hospital
city: Hyogo
country: Japan
facility: Hyogo Medical University Hospital
city: Hyogo
country: Japan
facility: Japanese Red Cross Society Himeji Hospital
city: Ishikawa
country: Japan
facility: Kanazawa University Hospital
city: Kanagawa
country: Japan
facility: Yokohama City University Medical Center
city: Kanagawa
country: Japan
facility: Kanagawa Cancer Center
city: Kanagawa
country: Japan
facility: Kitasato University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Osaka
country: Japan
facility: Osaka Red Cross Hospital
city: Osaka
country: Japan
facility: Kindai University Hospital
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Tokyo
country: Japan
facility: The University of Tokyo Hospital
city: Tokyo
country: Japan
facility: Japanese Red Cross Musashino Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: CHA Bundang Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Ajou University Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul St Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hosiptal
city: Monterrey
country: Mexico
facility: Filios Alta Medicina
state: Nuevo LEON
city: Oaxaca
country: Mexico
facility: Oaxaca Site Management Organization
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Lima
country: Peru
facility: Instituto Nacional de Enfermedades Neoplasicas
city: Lima
country: Peru
facility: Clínica San Gabriel
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University n.a. I.M. Sechenov
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: Group of companies "Medci"
state: Moskovskaja Oblast
city: Nizhny Novgorod
country: Russian Federation
facility: Clinical hospital #1, FBHI Volga district medical center, Federal Medical and Biological Agency
state: Niznij Novgorod
city: Pesochny
country: Russian Federation
facility: Russian Scientific Center of Radiology and Surgical Technologies
state: Sankt Petersburg
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Badajoz
country: Spain
facility: Hospital Universitario Infanta Cristina
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Chang Hua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taipei
country: Taiwan
facility: National Taiwan Uni Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation - Linkou
city: Bangkok
country: Thailand
facility: Rajavithi Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Chiang Rai
country: Thailand
facility: Chiang Rai Prachanukroh Hospital
city: Lak Si
country: Thailand
facility: Chulabhorn Hospital
city: Adana
country: Turkey
facility: Adana Baskent University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, Lee HC, Yopp A, Chow P, Qin S. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 2020 May;16(15):975-989. doi: 10.2217/fon-2020-0162. Epub 2020 Apr 30.