Ezurpimtrostat autophagy inhibitor in association with Atezolizumab-Bevacizumab in first line treatment of unresectable hepatocellular carcinoma, a phase 2b randomized trial. ABE-LIVER

Prior treatment

• Any known history of encephalopathy ≤ 6 months prior to first planned dose of treatment
• Treatment with systemic immunostimulatory agents
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Known esophageal varices with recent history of bleeding (within previous 6 months)
• Persistent toxicities related to prior treatment of grade greater than 1
• Subjects requiring corticosteroid therapy at a dose equivalent to more than 10 mg of prednisone equivalent dose per day (corticosteroid administration is permitted by a route resulting in minimal systemic exposure [cutaneous, rectal, articular, ocular or inhalation] is authorized)
• Chronic treatment with immunosuppressive agents (like steroids) ≤ 6 weeks prior to first planned dose of treatment
• Major surgical procedures, open biopsy or significant traumatic injury ≤ 4 weeks prior to first dose of treatment or anticipation of major surgical procedure during the course of the trial, minor surgical procedures ≤ 1 week of first planned dose (the surgical wound must be fully healed)
• Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
• Any clinically significant cardiovascular condition as judged by the Investigator (such as New York Heart Association Class II or greater cardiac failure, myocardial infarction, or cerebrovascular accident within 3 months prior to Day 1 of Cycle 1, uncontrolled arterial hypertension, unstable arrhythmia, or unstable angina)
• Patients who experienced immune-mediated pericardial disorders during previous treatment by immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1 therapeutic antibodies
• Use of any prohibited concomitant medications within 14 days of the Baseline/Day 1 visit

Other illness

• History of leptomeningeal disease
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
• Active or history of autoimmune disease
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
• Known active tuberculosis
• History of malignancy other than HCC within 3 years prior to screening, with the exception of adequately treated skin basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, in-situ carcinoma of the uterine cervix, or prostate cancer that is controlled by hormone therapy (patients may continue hormone therapy while on study)
• Severe or uncontrolled renal condition
• Evidence of bleeding diathesis or significant coagulopathy
• History of intestinal obstruction and/or clinical signs or symptoms of gastrointestinal (GI) obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• Known clinically significant or life threatening organ or systemic disease such that in the opinion of the Investigator, the significance of the disease will compromise the patient's participation in the trial
• Known intolerance or hypersensitivity to the active ingredient or to one of the components of the study drug
• Untreated chronic hepatitis B
• Subjects with active infection
• History of bone marrow allograft or solid organ transplant
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
• History of gastrointestinal perforations and fistulae
• Untreated HCV infection
• Known history of immunodeficiency diseases (e.g., active HIV)

Other

• Malabsorption issues (e.g., gastric bypass or gastrectomy patients)
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 6 months after the last dose of treatment
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic proteinuria
• Active aneurysm considered as unstable and/or at high risk of complication
• Subject in exclusion period for another study
• Subject who cannot be contacted in case of emergency
• All protected persons: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Contraindication to additional liver biopsy planned between C4 and C5
• Contraindication to iodinated contrast agent infusion
• Known current alcohol (> 20g/ Day in women and > 30g/ Day in men) or substance abuse

• Males or females ≥ 18 years of age
• Life expectancy ≥ 12 weeks
• In case of cirrhosis, last esophageal varices detection by esogastroduodenal endoscopy have to be performed within last the 6 months before inclusion and since macro-vascular invasion diagnosis
• Adequate hematologic function prior to the first dose of Ezurpimtrostat, defined as: 12.1. Absolute neutrophils count ≥ 1500 cells/μL 12.2. Hemoglobin ≥ 9 g/dL with no transfusion within 4 weeks prior to first planned dose of Ezurpimtrostat 12.3. Platelet count > 50,000/μL with no transfusion within 2 weeks prior to first planned dose of Ezurpimtrostat
• Adequate renal function prior to first dose, defined as 13.1. Serum creatinine < 1.5 × Upper limit of normal (ULN) 13.2. Creatinine clearance ≥ 30 mL/min/m2 (by Cockroft-Gault equation of 24-hour urine) if creatinine ≥ 1.5 × ULN
• Adequate hepatic function prior to first dose, defined as AST/ALT ≤ 5 × ULN
• Women patients of childbearing potential must have a negative serum pregnancy test at screening and baseline, and be willing to use a highly effective contraception. The patient should be advised to continue the contraception for at least 6 months following the completion of dosing. Women with cessation for > 24 months of previously occurring menses, or women of any age who have had a hysterectomy, or have had both ovaries removed will be considered to be of non-childbearing potential
• Male patients of reproductive potential must be willing to use one acceptable method of contraception, as judged by Investigator and Sponsor, and/or to refrain from donating sperm from the time of screening through at least 6 months following the completion of dose administration
• Amenable to computed tomography (CT) with 3 or 4 phase liver or magnetic resonance imaging (MRI) of abdomen and pelvis, and CT of chest, or MRI of whole body, for initial tumor size measurements and subsequent follow-up
• Absence of other clinically relevant abnormalities (i.e., those which require medical intervention) for all screening laboratory test results as judged by the Investigator and Sponsor
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
• Histologically confirmed (liver biopsy within 6 previous months) and documented non resectable or metastatic HCC
• Able to understand and provide written informed consent
• Patients covered by Health Insurance System
• Patients with a BCLC C status, as per the Barcelona Clinic Liver Cancer (BCLC) staging system
• No prior systemic therapy for advanced HCC
• Liver tumor burden < 50% of the liver (per Investigator judgment)
• Child-Pugh A (≤ 6) without any history of cirrhotic decompensation within the past 6 months
• Antiviral therapy required in hepatitis B virus patients (Hepatitis B antigen positive)
• Presence of a measurable tumor per RECIST v1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1