Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma

Inclusion Criteria:

1. Male or female

2. Aged ≥18 years at time of signing informed consent

3. Presenting with HCC, diagnosed either by histological or radiological criteria asdescribed by EASL

4. Locally advanced or metastatic and/or unresectable HCC according a MultidisciplinaryTeam meeting

5. Progressive disease after exposure to atezolizumab plus bevacizumab combination

6. Decision made by the physician to continue atezolizumab plus bevacizumab beyondprogression

7. Child-Pugh A within 7 days prior to inclusion

8. ECOG Performance status 0 to 1

9. 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

10. Disease measurable by RECIST 1.1

11. Signed written Informed consent

Exclusion Criteria:

1. Partial response achieved under atezolizumab-bevacizumab

2. CTCAE Grade ≥3 or more toxicity under atezolizumab-bevacizumab or persistenttoxicity Grade >1

3. Liver involvement > 50%

4. Thromboembolic events in the 3 months prior to inclusion,

5. Presence of major macro vascular invasion (except Vp1/Vp2)

6. Prior bleeding event due to untreated or incompletely treated esophageal and / orgastric varices within 6 months' prior inclusion

7. Pregnant woman, or breastfeeding or women of child-bearing potential with noadequate contraception (see §4.3.1)

8. Under curatorship, guardianship, safeguard of justice or deprived of liberty

9. History of serious autoimmune disease

10. Interstitial lung disease

11. HBV chronic infection with HBV DNA > 100 IU/mL or without antiviral therapy; HBVpatients with cirrhosis should be treated

12. HIV infection

13. Immunosuppression, including subjects with a condition requiring systemic treatmentwith either corticosteroids (> 10 mg/day prednisone equivalent)

14. Transplanted liver, or patient with intent for transplantation

15. Has difficulties in swallowing.

16. Has undergone major surgery or significant trauma ≤4 weeks prior to Screening. Note:Participants who had surgery >4 weeks prior to Screening must have recoveredadequately from any toxicity and/or complications from the surgery or trauma priorto starting study intervention.

17. Is currently participating in or has participated in a study with an investigationalcompound 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 studymay participate so long as it has been at least 3 months since the last dose of theprevious investigational agent.

18. Has a systemic infection or other serious infection requiring systemic treatmentwithin 30 days prior to screening.

19. Has a history of hypersensitivity to EXL01 and/or any excipients, which are listedin the IB, and/or to soybean or soy-containing products

20. Has a history of hypersensitivity to the atezolizumab or to any of the excipientslisted in section 6.1 of the SmPC of atezolizumab

21. Has a history of hypersensitivity to bevacizumab or to any of the excipients listedin section 6.1 of the SmPC of bevacizumab

22. Has a history of hypersensitivity to Chinese Hamster Ovary (CHO) cell products orother recombinant human or humanised antibodies

23. Uncontrolled hypertension

24. Clinically significant cardiovascular disease such as pre-existing coronary arterydisease, or congestive heart failure

25. Proteinuria

26. Has active inflammatory intestinal disease (Crohn disease, Hemorrhagicrecto-colitis, coeliac disease) or any serious chronic intestinal disease withuncontrolled diarrhea, or other inflammatory disease requiring anti-inflammatorymedications

27. Current probiotics administration, or planned probiotics administration duringtreatment course.