An Integrated Phase II/III Randomized Study Comparing Durvalumab and Tremelimumab +/- Hepatic ArteriaL Infusion Chemotherapy With GEMOX in Hepatocellular Carcinoma With High Tumor burdEn
Liver cancer is a highly lethal malignancy and has become increasingly important in western countries. The management of liver cancer is complex. In advanced disease, two combinations of immunotherapies are recommanded as first line (atezolizumab-bevacizumab or durvalumab-tremelimumab). Results in patients with high tumor burden (Portal vein thrombosis Vp3 or Vp4, or tumoral liver involvement \>50%) are less impressive. Innovative combinations are necessary to improve the outcome of patients. Recently, control trials conducted in Asia highlighted the benefit of hepatic arterial infusion chemotherapy, especially in patients with high tumor burden. Studies including a limited number of patients shown that the combination seems feasible. ALICE is a randomized multicentric Phase II/Phase III trial conducted in French medical centers, evaluating the efficacy and safety of durvalumab+tremelimumab with or without Hepatic Arterial Infusion Chemotherapy of the GEMOX regimen (gemcitabine + oxaliplatin), in patients with high tumor burden. Oxaliplatin induce immunogenic cell death, and gemcitabin deplete regulatory immune cells. The GEMOX regimen thus has the potential for a synergic effect with immunotherapy in HCC. The trial will provide an innovative treatment to patients with no alternative for locoregional treatment, and with limited results with actual systemic treatments. It will also be the first trial of Hepatic Arterial infusion for such patients in the western population.
• Age ≥18 years old,
• Patient presenting with hepatocellular carcinoma (HCC), diagnosed either by histological or radiological criteria as described by EASL criteria, if no biopsy could be performed safely.
• High-tumor burden, defined as at least one of the three criteria: (i) Vp4 PVTT, (ii) Vp3 PVTT with bilobar tumoral involvement and/or (iii) liver involvement \>50% (as assessed by the investigator). Extra-hepatic spread is allowed.
• Child-Pugh A liver function
• Performance status Eastern Cooperative Oncology Group (ECOG) 0 to 1
• Must have a life expectancy of at least 12 weeks
• Body weight \>30 kg
• At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization
• Adequate organ and marrow function as indicated by the following laboratory values
‣ Haemoglobin ≥ 7.5 g/dL. Participants with 7.5 g/dL \< haemoglobin \< 9.0 g/dL having active or chronic bleeding to be excluded,
⁃ Platelet count ≥75 × 109/L,
⁃ Absolute neutrophil count (ANC ≥1.0 × 109 /L)
⁃ creatinine clearance \> 40 mL/min (according to Cockcroft or MDRD formula)
⁃ AST (SGOT)/ALT (SGPT) ≤5x ULN
⁃ Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
⁃ International normalised ratio (INR) \< 2.3
• Women of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and ≥90 days after the last dose of study drug, and have a negative urine or serum pregnancy test ≤7 days of first dose of study drug. In case of a urine pregnancy test, it must be a highly sensitive urine pregnancy test.
• Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥90 days after the last dose of study drug. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. Males with known low sperm counts (consistent with sub-fertility) are not to be considered sterile for purposes of this study.
• Men and women patients must consent to not donate or bank sperm or ova during treatment and for 180 days after treatment stop
• Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Patient affiliated to a social security regimen