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

Study Overview
=================
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.

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

Conditions
-----------------
Carcinoma, Hepatocellular

Intervention / Treatment
-----------------
* Drug: Atezolizumab
* Drug: Bevacizumab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (atezolizumab plus bevacizumab)<br>Participants will receive Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity. | Drug: Atezolizumab<br>* Atezolizumab 1200 mg will be administered by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.<br>* Other names: Avastin;|
| No Intervention: Arm B (active surveillance)<br>Active surveillance of participants. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Baseline up to approximately 91 months | 
| 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 | 
| 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 | 
| RFS Rate at 24 and 36 Months, as Assessed by the IRF |  | Randomization up to 24 months and up to 36 months | 
| RFS Rate at 24 and 36 Months, as Assessed by the Investigator |  | Randomization up to 24 months and up to 36 months | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of Participants With Adverse Events |  | Baseline up to approximately 91 months | 
| 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) | 
| 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 |