Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma

Phase 2

Not yet recruiting

• Conditions: Hepatocellular Carcinoma
• Interventions: Drug: EXL01

• Registration Number: NCT06551272
• Lead Sponsor: Center Eugene Marquis

Brief Summary

Hepatocellular carcinoma (HCC) is the most common liver primary cancer with a high rate of mortality. Since the results of IMbrave150 (1), 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 (4).

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 (5-7). 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 (8,9). 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murine study suggests that the administration of EXL01 could reverse the resistance to ICI induced by antibiotics (unpublished data).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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2024-08
• Study First Submitted: 2024-08-09
• Study First Submitted QC: 2024-08-09
• Last Update Submitted: 2024-08-09
• Study First Posted: 2024-08-13
• Last Update Posted: 2024-08-13
• Study Start: 2024-12-01
• Primary Completion: 2025-11-23
• Study Completion: 2026-11-23

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 34

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
EXL01 arm	EXL01	Patients treated with atezolizumab-bevacizumab with the addition of the experimental treatment exl01, 1 capsule per day for a maximum of 12 months.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate at week12	At week12	ORR defined as the best observed overall tumor response (BOR) from inclusion to W12, according RECIST 1.1 criteria
Adverse event	Maximum 15 month after le first EXL01 administration	safety of atezolizumab-bevacizumab with bacterial supplementation EXL01

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate at week12	at week 12	ORR at week 12 according to mRECIST and iRECIST criteria
Overall tumor response	At week6; at week12; at month 6, at month12	Overall tumor response according to the mRECIST, RECIST 1.1 and iRECIST.
Objective Response Rate at M6 and M12	At month 6, at month 12	The ORR at M6, M12, according to the mRECIST, RECIST 1.1 and iRECIST criteria.
The Disease control rate (DCR),	At week12; at month 6, at month12	The Disease control rate (DCR), as the proportion of patients with BOR as CR, PR or stable disease (SD) defined according to the mRECIST, RECIST 1.1 and iRECIST criteria at W12, M6, M12.
The Progression-Free Survival	Maximum 12 month after the fisrt EXL01 administration	The Progression-Free Survival, defined as the time from patient inclusion to progression or death from any cause.
Overall survival (OS)	Maximum 15 month after the fisrt EXL01 administration of the last patient	The Overall Survival, defined as the time from patient inclusion to death from any cause

Trial Locations

Locations (4)

Hôpital Beaujon; 🇫🇷 Clichy, France

Gustave ROUSSY; 🇫🇷 Villejuif, France

Centre de luttre contre le cancer Eugène Marquis; 🇫🇷 Rennes, France

hôpital Avicenne; 🇫🇷 Bobigny, France