Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma

Inclusion criteria

• Male and Female
• Age ≥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
• Decision made by the physician to continue the same standard-of-care approved first-line immunotherapy beyond progression
• 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
• Disease measurable by RECIST 1.1
• Signed written Informed consent

Exclusion criteria

• Partial response achieved under standard-of-care approved first-line immunotherapy
• CTCAE Grade ≥3 or more toxicity under standard-of-care approved first-line immunotherapy, or persistent toxicity Grade >1
• 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 (see §4.3.1)
• Under curatorship, guardianship, safeguard of justice or deprived of liberty
• History of serious autoimmune disease
• 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
• 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 difficulties in swallowing.
• Has undergone major surgery or significant trauma ≤4 weeks prior to Screening. Note: Participants who had surgery >4 weeks prior to Screening must have recovered adequately from any toxicity and/or complications from the surgery or trauma prior to starting study intervention.
• 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.

Note: Participants who have entered the follow-up phase of an investigational study may participate so long as it has been at least 3 months since the last dose of the previous investigational agent.

• Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to Screening.
• 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
• Has a history of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
• Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea, or other inflammatory disease requiring anti-inflammatory medications
• Current probiotics administration, or planned probiotics administration during treatment course.
• Specific contra-indication to the continuation of the standard-of-care approved first-line immunotherapy :

21.1: for atezolizumab-bevacizumab:

• Thromboembolic events in the 3 months prior to inclusion
• Prior bleeding event due to untreated or incompletely treated esophageal and / or gastric varices within 6 months' prior inclusion
• Has a history of hypersensitivity to the atezolizumab or to any of the excipients listed in section 6.1 of the SmPC of atezolizumab
• Has a history of hypersensitivity to bevacizumab or to any of the excipients listed in section 6.1 of the SmPC of bevacizumab
• Uncontrolled hypertension
• Clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure
• Proteinuria 21.2: 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.