MICROBIOTA MODIFICATION FOR IMMUNO-ONCOLOGY IN HEPATOCELLULAR CARCINOMA - “MOTHER”

Prior treatment

• Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to screening
• Immunosuppression, including subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent)
• Transplanted liver, or patient with intent for transplantation
• Has undergone major surgery or significant trauma ≤4 weeks prior to Screening
• Is currently participating in or has participated in a study with an investigational compound or device within 3 months prior to the first dose of study intervention.
• CTCAE Grade ≥3 or more toxicity under first-line immunotherapy-based combination or persistent toxicity Grade >1
• Specific contra-indication to atezolizumab-bevacizumab: 1) Thromboembolic events in the 3 months prior to inclusion 2) Prior bleeding event due to untreated or incompletely treated esophageal and / or gastric varices within 6 months’ prior inclusion 3) Has a history of hypersensitivity to the atezolizumab or to any of the excipients listed in section 6.1 of the SmPC of atezolizumab and bevacizumab or to any of the excipients listed in section 6.1 of the SmPC 4) Uncontrolled hypertension 5) Clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure 6) Proteinuria

Other illness

• specific contra-indication for durvalumab : Has a history of hypersensitivity to the durvalumab or to any of the excipients listed in section 6.1 of the SmPC of durvalumab
• Interstitial lung disease
• HBV chronic infection with HBV DNA > 100 IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated
• HIV infection
• Has a history of hypersensitivity to EXL01 and/or any excipients, which are listed in the IB, and/or to soybean or soy-containing products
• History of serious autoimmune disease

Other

• Has difficulties in swallowing.
• Liver involvement > 50%
• Presence of major macro vascular invasion (except Vp1/Vp2)
• Pregnant woman, or breastfeeding or women of child-bearing potential with no adequate contraception
• Under curatorship, guardianship, safeguard of justice or deprived of liberty

• Male or female
• Disease measurable by RECIST 1.1
• Signed written Informed consent
• Aged ≥18 years at time of signing informed consent
• Presenting with HCC, diagnosed either by histological or radiological criteria as described by EASL
• Locally advanced or metastatic and/or unresectable HCC according a Multidisciplinary Team meeting
• Progressive disease after exposure to standard-of-care approved first-line immunotherapy-based
• Either no initial objective response to immunotherapy (best response of SD or PD, cohort 1), or initial objective response to immunotherapy (best response of PR or CR, cohort 2)
• Child-Pugh A within 7 days prior to inclusion
• ECOG Performance status 0 to 1
• Adequate hematological (Hemoglobin >8.5g/dL, platelets >60G/L, neutrophils >1.5G/L) and renal (creatinine clearance > 50 mL/min according to Cockcroft or MDRD formula) functions