Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common liver primary cancer with a high rate of mortality. Since the results of IMbrave150, immunotherapy have emerged as a standard of care for HCC patients advanced and/or unresectable in first line of treatment. The objective response rate was about 30%, but half of patients would present only stable disease and about 20% progressive disease.

Faecalibacterium prausnitzii is one of the most abundant bacterial in human gut microbiota, around 5% of total bacteria in feces.

For patients with metastatic melanoma, treated with ipilimumab, an antibody targeting CTLA-4 (Cytotoxic T-lymphocyte-associated antigen 4), patients with a baseline gut microbiota enriched with Faecalibacterium had a significantly better clinical outcomes. In patients with metastatic melanoma, the level of Faecalibacterium prausnitzi at baseline was predictive of response to anti-PD-1 (programmed death-1) or anti-CTLA-4 therapy. EXL01 is a pharmacological preparation of Faecalibacterium prausnitzii strains. Preclinical murine study suggests that the administration of EXL01 could reverse the resistance to ICI induced by antibiotics (unpublished data).

We thus plan to test the concept of microbiota modification in patients treated with atezolizumab-bevacizumab for advanced HCC. We would include patients refractory to first-line treatment, and test the addition of EXL01 to atezolizumab-bevacizumab in order to reverse resistance.


Eligibility Criteria:
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 as described by EASL
4. Locally advanced or metastatic and/or unresectable HCC according a Multidisciplinary Team meeting
5. Progressive disease after exposure to atezolizumab plus bevacizumab combination
6. Decision made by the physician to continue atezolizumab plus bevacizumab beyond progression
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 persistent toxicity 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 / or gastric varices within 6 months' prior inclusion
7. Pregnant woman, or breastfeeding or women of child-bearing potential with no adequate 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; HBV patients with cirrhosis should be treated
12. HIV infection
13. Immunosuppression, including subjects with a condition requiring systemic treatment with 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 recovered adequately from any toxicity and/or complications from the surgery or trauma prior to starting study intervention.
17. 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.
18. Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to screening.
19. 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
20. Has a history of hypersensitivity to the atezolizumab or to any of the excipients listed in section 6.1 of the SmPC of atezolizumab
21. Has a history of hypersensitivity to bevacizumab or to any of the excipients listed in section 6.1 of the SmPC of bevacizumab
22. Has a history of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
23. Uncontrolled hypertension
24. Clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure
25. Proteinuria
26. Has 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
27. Current probiotics administration, or planned probiotics administration during treatment course.