Study Evaluating the Benefit of Adding Ipilimumab to the Combination of Atezolizumab and Bevacizumab in Patients With Hepatocellular Carcinoma Receiving First-line Systemic Therapy

Inclusion Criteria:

• Age ≥ 18 years

• Histologically proven hepatocellular carcinoma (HCC) on biopsy less than two yearsold. If no histological evidence, a tumour (mandatory) and non-tumour (optional)liver biopsy is required.

• WHO 0 or 1

• HCC not amenable to curative treatment by surgery, thermo-ablation or livertransplantation, or to intra-arterial palliative treatment (IAP) for intermediateBCLC-B HCC.

Advanced (BCLC-C) or intermediate (BCLC-B) HCC after failure or contraindication of the CEL

• Normal Troponin-T

• Patients with controlled cardiovascular disease for at least 6 months

• No clinically evident ascites, no history of clinical ascites, or encephalopathy dueto liver failure

• Adequate liver function: AST and ALT ≤ 5 x ULN (upper normal limit), total bilirubin ≤ 35 µM/L, albumin ≥ 28 g/L and Child-Pugh A score (if associated cirrhosis)

• Hematological (hemoglobin > 8.5 g/dL, platelets > 60 G/L, PNN > 1.5 G/L) and renalfunction (creatinine clearance ≥ 40ml/min according to the appropriate MDRD formula)

• At least one target lesion measurable according to RECIST v1.1 criteria

• Oesophageal endoscopy less than 6 months old. All patients with varicose veins ofany grade should be treated with β-blockers prior to initiation of therapy, in theabsence of contraindications.

• Women of childbearing potential must agree to use contraception during the trialtreatment and for at least 6 months after discontinuation of the experimentaltreatments. Men who have sex with women of childbearing potential must agree to usecontraception during treatment and for at least 6 months after discontinuation ofthe experimental treatments

• Ability of the patient to understand, sign and date the informed consent form beforerandomisation

• Patient affiliated to a social security scheme

Exclusion Criteria:

• Patients who have already received systemic therapy for HCC

• Bleeding related to portal hypertension in the last 6 months

• History of abdominal or oesophageal fistula, gastrointestinal perforation orintra-abdominal abscess, diverticulitis or colitis within 6 months prior torandomisation

• Patients on double anti-platelet aggregation therapy

• Patients on chronic non-steroidal anti-inflammatory drugs (except aspirin).

• History of intra-abdominal inflammatory process within 6 months prior to initiationof treatment - including but not limited to - active peptic ulcer, diverticulitis orcolitis

• Major surgery or significant traumatic injury within 28 days prior to treatment,abdominal surgery or significant abdominal traumatic injury within 60 days prior totreatment, or the need for major surgery during the therapeutic trial

• Hypersensitivity to any of the study drugs or their excipients

• Allergy to one of the components of Chinese hamster ovary cells.

• Other malignant tumours within the last 2 years, except for carcinoma in situ of theuterus or basal cell or squamous cell skin carcinoma or any other carcinoma in situ,considered curedHistory of severe active life-threatening autoimmune disease

• Interstitial lung disease

• Chronic HBV infection with HBV DNA > 500 IU/ml, infected patients, cirrhotic or not,should be treated with nucleotide/nucleoside analogues.

• Known HIV infection

• Immunosuppression, including subjects with conditions requiring systemiccorticosteroid treatment (>10 mg/day prednisone equivalent)

• History of organ transplantation

• Non-healing decaying wound, active ulcer or untreated bone fracture

• Proteinuria ≥ 2+ on urine dipstick if confirmation of 24h proteinuria showing alevel ≥ 2 g/24 hours

• Medically uncontrolled hypertension (≥ 150 mm Hg and/or diastolic blood pressuresuperior to 90 mm Hg)

• History of arterial aneurysm at high risk of bleeding

• Alive attenuated vaccine within 28 days prior to randomisation

• History of pericardial abnormalities possibly immune-related (pericarditis orcardiac tamponade)

• Patient who has received immunotherapy (including anti-CTLA-4, anti-PD-1 oranti-PD-L1 agents) or anti-VEGF antibody therapy

• Patients who has previously received external radiotherapy up to 1 month before thestart of the study treatment, or 3 months before the start of the study treatment incase of radio embolization

• Central nervous system metastases

• Active bacterial infection

• Patients with uncontrolled cardiovascular disease

• History of arterial thromboembolic events, including stroke, transient ischemicattack and myocardial infarction, if less than 6 months old and unresolved.

• History of venous thromboembolic disease, if less than 6 months old

• Pregnant or breastfeeding women.

• Person under guardianship, or person deprived of liberty.

• Inability to undergo the medical follow-up of the trial for geographical, social orpsychological reasons