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

Carcinoma, Hepatocellular Clinical Trial

— IMbrave050  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04102098
• Other study ID #: WO41535
• Secondary ID: 2019-002491-14
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 31, 2019
• Est. completion date: July 16, 2027

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 668
• Est. completion date: July 16, 2027
• Est. primary completion date: October 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Recurrence

Intervention

Drug:
• Atezolizumab
Atezolizumab 1200 mg will be administered by IV infusion on Day 1 of each 21-day cycle.
• Bevacizumab
Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.

Locations

Country	Name	City	State
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Riverina Cancer Care Centre	Wagga Wagga	New South Wales
Austria	Lkh-Univ. Klinikum Graz	Graz
Austria	Klinikum Klagenfurt am Wörtersee; Abt.Gastroenterologie&Hepatologie,Endokrinologie	Klagenfurt
Austria	Medizinische Universität Wien; Univ.Klinik für Innere Medizin III - Gastroenterologie & Hepatologie	Wien
Belgium	Imeldaziekenhuis	Bonheiden
Belgium	AZ Delta (Campus Rumbeke)	Roeselare
Brazil	Sociedade beneficente de senhoras Hospital Sirio Libanes	Brasilia	DF
Brazil	Hospital do Cancer UOPECCAN; Pesquisa Clínica	Cascavel	PR
Brazil	Hospital das Clinicas - UFRGS	Porto Alegre	RS
Brazil	Hospital Sao Rafael - HSR	Salvador	BA
Brazil	Hospital Alemao Oswaldo Cruz; Oncologia	Sao Paulo	SP
Canada	McGill University Health Centre - Glen Site	Montreal	Quebec
Canada	Gordon & Leslie Diamond Health Care Centre	Vancouver	British Columbia
China	Beijing Cancer Hospital	Beijing
China	Peking Union Medical College Hospital	Beijing City
China	Affiliated Hospital of Bengbu Medical College	Bengbu
China	The First Hospital of Jilin University	Changchun City
China	West China Hospital, Sichuan University	Chengdu
China	Daping Hospital of Third Military Medical University	Chongqing
China	The Second Affiliated Hospital of Dalian Medical University	Dalian
China	Fujian Cancer Hospital	Fuzhou
China	Mengchao Hepatobiliary Hospital Of Fujian Medical University	Fuzhou City
China	Cancer Center of Guangzhou Medical University	Guangzhou
China	Nanfang Hospital, Southern Medical University	Guangzhou
China	Zhujiang Hospital, Southern Medical University	Guangzhou
China	Sun Yet-sen University Cancer Center	Guangzhou City
China	Zhejiang Cancer Hospital; Zhejiang Cancer Hospital cancer department	Hangzhou City
China	Harbin Medical University Cancer Hospital	Harbin
China	Anhui Provincial Hospital	Hefei
China	The Second Affiliated Hospital of Anhui Medical University	Hefei
China	Anhui Province Cancer Hospital	Hefei City
China	Shandong Cancer Hospital	Jinan
China	Zhongda Hospital Affiliated to Southeast University	Nanjing
China	Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School	Nanjing City
China	The 81st Hospital of P.L.A.	Nanjing City
China	The First Affiliate Hospital of Guangxi Medical University	Nanning
China	Guangxi Cancer Hospital of Guangxi Medical University	Nanning City
China	Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai
China	Fudan University Shanghai Cancer Center	Shanghai City
China	Huashan Hospital Affiliated to Fudan University	Shanghai City
China	Zhongshan Hospital Fudan Unvierstiy	Shanghai City
China	Shengjing Hospital of China Medical University	ShenYang
China	The First Affiliated Hospital of China Medical University	Shenyang City
China	Tianjin Cancer Hospital	Tianjin
China	The Tumor Hospital of Xinjiang Medical University	Urumqi
China	Hubei Cancer Hospital	Wuhan
China	Renmin Hospital of Wuhan University	Wuhan
China	Zhongnan Hospital of Wuhan University	Wuhan
China	Wuhan Union Hospital Tongji Medical College, Huazhong University of Science and Technology	Wuhan City
China	Northern Jangsu People's Hospital	Yangzhou City
Costa Rica	Clinica CIMCA	San José
Czechia	Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika	Brno
Czechia	Fakultni Thomayerova Nemocnice; Onkologicke Oddeleni	Praha
France	Hopital Jean Minoz; Oncologie	Besancon
France	Hôpital Avicenne - Groupement Hospitalier Universitaire Paris Seine St Denis; Service d'Hépatologie	Bobigny Cedex
France	Hôpital Albert Michallon	La Tronche
France	Fondation Hopital Saint Joseph; Gastro-Enterologie	Marseille
France	CHU Bordeaux - Hôpital Haut-Lévêque; Service d?Hépato-Gastroentérologie et d Oncologie digestive	Pessac
France	Hopital Robert Debre; Gastro Enterologie	Reims
France	Hopital de Pontchaillou; Service Hepato Gastro Enterologie	Rennes
France	CHU de Toulouse - Hôpital Rangueil	Toulouse Cedex 09
France	Hopitaux de Brabois - Gastro-Entereologie	Vandoeuvre-les-nancy
Germany	Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I.; Onkologische Gastroenterologie	Bonn
Germany	Klinik Johann Wolfgang von Goethe Uni; Zentrum der Inneren Medizin; Medizinische Klinik I	Frankfurt
Germany	Klinikum der Uni Regensburg; Klinik f.Innere Medizin I Abt. Hämatologie und Internistische Onkologie	Regensburg
Germany	Universitätsklinikum Ulm; Zentrum für Innere Medizin Klinik für Innere Medizin I	Ulm
Hong Kong	Queen Mary Hospital; Dept. Of Haematology & Oncology	Hong Kong
Hong Kong	Prince of Wales Hospital; Department of Clinical Onocology	Shatin
Italy	Asst Santi Paolo E Carlo	Milano	Lombardia
Italy	Ospedale Maggiore Policlinico; U.O.C. di Oncologia Medica	Milano	Lombardia
Italy	Ospedale Regionale Di Parma; Divisione Di Oncologia Medica	Parma	Emilia-Romagna
Italy	Azlenda Ospendaliero-Universitaria Pisana; C.O. Oncologia 2	Pisa	Toscana
Japan	Chiba University Hospital	Chiba
Japan	Ehime Prefectural Central Hospital	Ehime
Japan	Hiroshima University Hospital	Hiroshima
Japan	Sapporo Kosei Genaral Hospital	Hokkaido
Japan	Hyogo Medical University Hospital	Hyogo
Japan	Japanese Red Cross Society Himeji Hospital	Hyogo
Japan	Kanazawa University Hospital	Ishikawa
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Kitasato University Hospital	Kanagawa
Japan	Yokohama City University Medical Center	Kanagawa
Japan	Kumamoto University Hospital	Kumamoto
Japan	Kindai University Hospital	Osaka
Japan	Osaka Red Cross Hospital	Osaka
Japan	Tokushima University Hospital	Tokushima
Japan	Japanese Red Cross Musashino Hospital	Tokyo
Japan	The University of Tokyo Hospital	Tokyo
Japan	Toranomon Hospital	Tokyo
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Ajou University Medical Center	Gyeonggi-do
Korea, Republic of	CHA Bundang Medical Center	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Borame Medical Center	Seoul
Korea, Republic of	Gangnam Severance Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Ulsan University Hosiptal	Ulsan
Mexico	Centro Medico Dalinde	Cdmx	Mexico CITY (federal District)
Mexico	Filios Alta Medicina	Monterrey	Nuevo LEON
Mexico	Oaxaca Site Management Organization	Oaxaca de Juárez	Oaxaca
Netherlands	Maastricht University Medical Center	Maastricht
New Zealand	Auckland City Hospital	Auckland
Peru	Clínica San Gabriel; Unidad de Investigación Oncológica de la Clínica San Gabriel	Lima
Peru	Instituto Nacional de Enfermedades Neoplasicas	Lima
Poland	Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie; Klinika Onkologii i Radioterapii,	Warszawa
Russian Federation	First Moscow State Medical University n.a. I.M. Sechenov	Moscow	Moskovskaja Oblast
Russian Federation	Group of companies "Medci"	Moskva	Moskovskaja Oblast
Russian Federation	Clinical hospital #1, FBHI Volga district medical center, Federal Medical and Biological Agency	Nizhny Novgorod	Niznij Novgorod
Russian Federation	Russian Scientific Center of Radiology and Surgical Technologies; Dept of Radiology	Pesochny	Sankt Petersburg
Singapore	National Cancer Centre	Singapore
Singapore	Tan Tock Seng Hospital; Oncology	Singapore
Spain	Hospital Universitario Infanta Cristina; Servicio de Oncologia	Badajoz
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
Taiwan	Changhua Christian Hospital	Chang Hua
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City
Taiwan	National Taiwan Uni Hospital; Dept of Oncology	Taipei
Taiwan	Taipei Veterans General Hospital; Gastroenterology Division	Taipei
Taiwan	Chang Gung Medical Foundation - Linkou; Dept. of Hepato-Gastroenterology	Taoyuan
Thailand	Rajavithi Hospital; Division of Medical Oncology	Bangkok
Thailand	Siriraj Hospital; Medical Oncology Unit	Bangkok
Thailand	Chiang Rai Prachanukroh Hospital; Department Of Medicine	Chiang Rai
Thailand	Chulabhorn Hospital; Medical Oncology	Lak Si
Turkey	Adana Baskent University Hospital; Medical Oncology	Adana
United States	Mercy Medical Center	Baltimore	Maryland
United States	The University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	MD Anderson Cancer Center	Houston	Texas
United States	Kaiser Permanente Los Angeles	Los Angeles	California
United States	Columbia University Medical Center	New York	New York
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Swedish Cancer Inst.	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  China,  Costa Rica,  Czechia,  France,  Germany,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Peru,  Poland,  Russian Federation,  Singapore,  Spain,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrence-Free Survival (RFS), as Determined by IRF	RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an IRF, or death from any cause (whichever occurs first).	Baseline up to approximately 33 months
Secondary	Overall Survival (OS)	OS is defined as the time from randomization to death from any cause.	Baseline up to approximately 91 months
Secondary	RFS as Determined by the Investigator	RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an investigator, or death from any cause (whichever occurs first).	Baseline up to approximately 91 months
Secondary	Time to Recurrence (TTR)	TTR defined as the time from randomization to first documented occurrence of intrahepatic or extrahepatic HCC, as determined by the investigator and by an IRF.	Baseline up to approximately 91 months
Secondary	RFS Rate at 24 and 36 Months, as Assessed by the IRF		Randomization up to 24 months and up to 36 months
Secondary	RFS Rate at 24 and 36 Months, as Assessed by the Investigator		Randomization up to 24 months and up to 36 months
Secondary	OS Rate at 24 and 36 Months	OS rate defined as the proportion of patients who have not experienced death from any cause at 24 and 36 months after randomization.	Baseline to 24 and 36 months
Secondary	Time to Extrahepatic Spread (EHS) or Macrovascular Invasion	Time to EHS or macrovascular invasion after randomization, defined as the time from randomization to the first appearance of EHS or macrovascular invasion, as determined by the investigator.	Baseline up to approximately 91 months
Secondary	RFS in Pd-L1-High Subgroup	RFS after randomization as determined by the investigator and by an IRF, among patients in the PD-L1-high subgroup.	Baseline up to approximately 91 months
Secondary	Percentage of Participants With Adverse Events		Baseline up to approximately 91 months
Secondary	Serum Concentration of Atezolizumab	Serum concentration of atezolizumab.	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)
Secondary	Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab	Number of participants with anti-drug antibodies to atezolizumab.	Prior to any drug administration up to approximately 33 month