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

TRIPLET HCC is a phase II-III trial that assess the effectivness of addition of ipilimumab to the combination atezolizumab-bevacizumab, on global survival and response to the treatment, for patients with advanced or metastatic hepatocellular carcinoma. The theoretical duration of the study is 5 years. In the scope of this study, each patient will have 2 years of treatment and 2 years of follow-up from their enrollment date.

Inclusion Criteria:Age ≥ 18 yearsHistologically 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 1HCC 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 CELNormal Troponin-TPatients with controlled cardiovascular disease for at least 6 monthsNo clinically evident ascites, no history of clinical ascites, or encephalopathy due to liver failureAdequate 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 criteriaOesophageal 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 treatmentsAbility of the patient to understand, sign and date the informed consent form before randomisationPatient affiliated to a social security schemeExclusion Criteria:Patients who have already received systemic therapy for HCCBleeding related to portal hypertension in the last 6 monthsHistory of abdominal or oesophageal fistula, gastrointestinal perforation or intra-abdominal abscess, diverticulitis or colitis within 6 months prior to randomisationPatients on double anti-platelet aggregation therapyPatients 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 colitisMajor 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 trialHypersensitivity to any of the study drugs or their excipientsAllergy 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 diseaseInterstitial lung diseaseChronic HBV infection with HBV DNA > 500 IU/ml, infected patients, cirrhotic or not, should be treated with nucleotide/nucleoside analogues.Known HIV infectionImmunosuppression, including subjects with conditions requiring systemic corticosteroid treatment (>10 mg/day prednisone equivalent)History of organ transplantationNon-healing decaying wound, active ulcer or untreated bone fractureProteinuria ≥ 2+ on urine dipstick if confirmation of 24h proteinuria showing a level ≥ 2 g/24 hoursMedically uncontrolled hypertension (≥ 150 mm Hg and/or diastolic blood pressure superior to 90 mm Hg)History of arterial aneurysm at high risk of bleedingAlive attenuated vaccine within 28 days prior to randomisationHistory 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 therapyPatients 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 embolizationCentral nervous system metastasesActive bacterial infectionPatients with uncontrolled cardiovascular diseaseHistory 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 oldPregnant 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