Deep, Multi-omics Phenotyping to Predict Response, Resistance and Recurrence to Adjuvant Atezolizumab Plus Bevacizumab in Resected Hepatocellular Carcinoma

Patient is willing, able and mentally competent to provide written informed consent prior to any testing undertaken for this study protocol, including screening tests and evaluations that are not considered to be part of the patient's routine care.Male and female patients, age 21 to 90 at the time of signature of the informed consent form. Patient is able to comply with scheduled visits, assessments and other study procedures.

Patient diagnosed with HCC or its histological variants who has undergone a resection within 4-12 weeks prior to Day 1 of Cycle 1.

Multimodality treatment is not permitted, for example resection and ablationCombination treatment is not permitted.

Patient has clinically AND histologically proven HCC after liver resection as described below:

Patients must have documented histological HCC confirmation of negative surgical margins (R0) which is documented in a pathology report (patients with microscopically positive [R1] or grossly positive [R2] resection margins or unknown margins will be excluded from the study).Patients must have disease-free status documented within 4 weeks prior to Day 1 of Cycle 1 by a complete physical examination and radiographic images, with no subsequent evidence of residual or recurrent disease prior to Day 1 of Cycle 1. A complete set of baseline (post-resection) radiographic images and accompanying report must be available prior to Day 1 of Cycle 1. Patient has an absence of major macrovascular (gross vascular) invasion of the portal vein (Vp3 or Vp4) or major macrovascular invasion in the inferior vena cava (Vv3). Patient has an absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following resection . If head scan was not performed prior to resection, this must be performed after resection. Patient has a full recovery from surgical resection within 4 weeks prior to Day 1 of Cycle 1.

Patient is at high risk for HCC recurrence after resection as defined in Table 1:

Up to three tumours, with largest tumour > 5 cm regardless of vascular invasion (microvascular invasion or macrovascular invasion of the portal vein - Vp1/Vp2 or hepatic vein - Vv1/Vv2), or poor tumour differentiation (Grade 3 or 4)Up to three tumours, with largest tumour ≤ 5cm with vascular invasion (microvascular invasion or macrovascular invasion of the portal vein - Vp1/Vp2 or hepatic vein - Vv1/Vv2) and/or poor tumour differentiation (Grade 3 or 4) Four or more tumours, with largest tumour ≤ 5 cm regardless of microvascular invasion (microvascular invasion or macrovascular invasion of the portal vein - Vp1/Vp2 or hepatic vein - Vv1/Vv2) or poor tumour differentiation (Grade 3 or 4) In the event that the pathology and the pre- resection radiology report are discordant with regards to tumour size and number, the modality demonstrating the largest tumour size and number should be used to determine high risk features. Pathological findings should be used to assess for microvascular invasion and/or poor tumour differentiation. If macrovascular invasion of Vp1 or Vp2 or Vv1 or Vv2 is detected on either the pre-operative CT/MRI scan or the pathology report, this should be a high risk feature

Patient has baseline tumour tissue samples that meet the following criteria:

Good DNA/RNA quality (Refer to Biosamples Collection Protocol)High tumour viability (Refer to Biosamples Collection Protocol) Patient is known to be negative for the Human Immunodeficiency Virus (HIV).

Patient with documented virology status of hepatitis, as confirmed by screening HBV and 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 Day 1 of Cycle 1 and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir). Patients with HBV DNA > 500 IU/mL should be continued on antiviral treatment to obtain HBV DNA < 500 IU/mL before Day 1 of Cycle 1. Antiviral treatment shall continue throughout the entire Atezo+Bev treatment phase.Patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidenced by detectable HCV RNA), are eligible For patients with detectable HCV RNA and for whom HCV treatment is deemed appropriate by the investigator, treatment should begin no sooner than 6 months following resection consistent with AASLD guidelines Patient is willing to receive an esophagogastroduodenoscopy, either before resection as part of pre-procedure work-up or following resection, and assessment and treatment of varices of all sizes per local standard of care prior to Day 1 of Cycle 1. Patient is willing to receive an electrocardiogram, either before resection as part of pre-procedure work-up or following resection, prior to Day 1 of Cycle 1. Patient with Child-Pugh A (up to 6 points) without clinical ascites before surgery Patient with ECOG performance status 0-1.

Patient has adequate hematological, renal and hepatic function, defined by the following laboratory test results, obtained within 7 days prior to Day 1 of Cycle 1 unless otherwise specified:

AST, ALT, and ALP ≤ 5 × ULNSerum bilirubin ≤ 3 × ULN Albumin ≥ 28 g/L (2.8 g/dL) Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula) Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion. Platelet count ≥ 75 × 10**9/L (75,000/µL) without transfusion Lymphocyte count ≥ 0.5 × 10**9/L (500/µL) ANC ≥ 1.5 × 10**9/L (1500/µL) without granulocyte colony-stimulating factor support For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2 × ULN Urine dipstick for proteinuria < 2 + (within 7 days prior to Day 1 of Cycle 1) Patients discovered to have ≥ 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection (or an alternative method such as protein:creatinine ratio, per local guidance) and must demonstrate < 1 g of protein in 24 hours. Patient is estimated to have a life expectancy of at least 3 months without any active treatment. Patient is deemed suitable for protocol treatment as determined by clinical assessment undertaken by the site Investigator. (For female patients) Patient is either postmenopausal or, if premenopausal, must have a negative pregnancy test and agree to use two forms of contraception if sexually active during the treatment period, for at least 5 months after the last dose of atezolizumab and 6 months after the last dose of bevacizumab. (For male patients) Patient is surgically sterile, or if sexually active and having a pre-menopausal female partner, must be using an acceptable form of contraception during the treatment period and for 6 months after the last dose of bevacizumab.