A 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 Ablatio
- Conditions
- High-risk hepatocellular carcinoma (HCC)MedDRA version: 21.0Level: LLTClassification code 10019829Term: Hepatocellular carcinoma recurrentSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2019-002491-14-NL
- Lead Sponsor
- F. Hoffmann-La Roche Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 662
- Confirmation by the: Medical Monitor approval prior to randomization in order to monitor adherence to key eligibility criteria
- Age >= 18 years
- Participants with a first diagnosis of HCC who have undergone a curative resection or ablation within 4-12 weeks of randomization (not applicable for crossover)
- Documented diagnosis of HCC that has been completely resected or ablated (not applicable for crossover)
- Absence of major macrovascular (gross vascular) invasion and of the portal vein (Vp3 or Vp4) or any grade of macrovascular invasion in the hepatic vein or inferior vena cava (not applicable for crossover)
Note: Patients undergoing resection with minor vascular invasion of the portal vein (Vp1 or Vp2) as detected by either imaging or pathological examination are allowed
- 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
- Negative HIV test at screening
- Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) tests
- For patients with active HBV: HBV DNA < 500 IU/mL during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study
- Patients with HCV, either with resolved infection or chronic infection, are eligible
- For patients enrolled in the extended China enrollment phase: current resident of mainland China and of Chinese ancestry
- Performance of an esophagogastroduodenoscopy either before resection or ablation as part of pre-procedure work-up or during screening, and assessment and treatment of varices of all sizes per local standard of care prior to randomization
- Eastern Cooperative Oncology Group 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 or use contraceptive methods and agreement to refrain from donating eggs for 5 months after the final dose of atezolizumab and for 6 months after the final dose of bevacizumab
- For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm for during the treatment period and for 6 months after the final dose of bevacizumab to avoid exposing the embryo
Additional Inclusion Criteria for Crossover for Patients in Arm B
- Documentation of unequivocal recurrence as defined by European Association for the Study of the Liver Clinical Practice Guidelines or RECIST v1.1 criteria that is confirmed by the IRF
- For Arm B patients who undergo surgical resection or ablation for first recurrence: full recovery from surgical resection or ablation within 4 weeks prior to Day 1 of Cycle 1
- Availability of a representative tumor specimen obtained at the time of recurrence for exploratory biomarker research
- After recurrence assessments are performed by the investigator and IRF, confirmation for crossove
-Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
-Evidence of residual, recurrent, or metastatic disease at randomization (not applicable for crossover)
-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 clinically significant 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, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
-Active tuberculosis
-Severe infection within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that in the opinion of the investigator, could impact patient safety
-Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
-Prior allogeneic stem cell or solid organ transplantation
-On the waiting list for liver transplantation
-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
-Co-infection with HBV and HCV
-Co-infection with HBV and hepatitis D viral infection
-Clinically significant uncontrolled or symptomatic hypercalcemia
-History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
-Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulations
-Any treatment for HCC prior to resection or ablation, including systemic therapy and locoregional therapy such as TACE
-Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 of Cycle 1, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
-Treatment with investigational therapy within 4 weeks prior to Day 1 of Cycle 1
-Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
-Treatment with systemic immune stimulatory agents within 4 weeks or 5 drug elimination half-lives prior to Day 1 of Cycle 1
-Treatment with systemic immunosuppressive medication within 2 weeks prior to Day 1 of Cycle 1, or anticipation of need for systemic immunosuppressive medication during study treatment
-Inadequately controlled arterial hypertension, based on an average of at least three B
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the efficacy of atezolizumab plus bevacizumab compared with active surveillance on the basis of recurrence-free survival (RFS);Secondary Objective: 1. To evaluate the efficacy of atezolizumab plus bevacizumab compared with active surveillance on the basis of overall survival (OS), RFS after randomization as determined by the investigator and by an Independent Review Facility (IRF), time to recurrence (TTR), IRF-assessed RFS and investigator-assessed RFS rate after randomization and OS rate at 24 months and 36 months, Time to extrahepatic spread or macrovascular invasion after randomization<br>2. To evaluate the safety of atezolizumab plus bevacizumab compared with active surveillance<br>3. To characterize the PK profile of atezolizumab when given in combination with bevacizumab<br>4. To evaluate the immune response to atezolizumab <br>;Primary end point(s): 1. RFS;Timepoint(s) of evaluation of this end point: 1. Up to 91 months
- Secondary Outcome Measures
Name Time Method