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 years old. 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 liver transplantation, or to intra-arterial palliative treatment (IAP) for intermediate BCLC-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 due to 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 renal function (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 of any grade should be treated with β-blockers prior to initiation of therapy, in the absence of contraindications.
* Women of childbearing potential must agree to use contraception during the trial treatment and for at least 6 months after discontinuation of the experimental treatments. Men who have sex with women of childbearing potential must agree to use contraception during treatment and for at least 6 months after discontinuation of the experimental treatments
* Ability of the patient to understand, sign and date the informed consent form before randomisation
* 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 or intra-abdominal abscess, diverticulitis or colitis within 6 months prior to randomisation
* 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 initiation of treatment - including but not limited to - active peptic ulcer, diverticulitis or colitis
* Major surgery or significant traumatic injury within 28 days prior to treatment, abdominal surgery or significant abdominal traumatic injury within 60 days prior to treatment, 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 the uterus 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 systemic corticosteroid 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 a level ≥ 2 g/24 hours
* Medically uncontrolled hypertension (≥ 150 mm Hg and/or diastolic blood pressure superior 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 or cardiac tamponade)
* Patient who has received immunotherapy (including anti-CTLA-4, anti-PD-1 or anti-PD-L1 agents) or anti-VEGF antibody therapy
* Patients who has previously received external radiotherapy up to 1 month before the start of the study treatment, or 3 months before the start of the study treatment in case of radio embolization
* Central nervous system metastases
* Active bacterial infection
* Patients with uncontrolled cardiovascular disease
* History of arterial thromboembolic events, including stroke, transient ischemic attack 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 or psychological reasons