Microbiota Modification for Immuno-oncology in Hepatocellular Carcinoma (MOTHER)

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murine study suggests that the administration of EXL01 could reverse the resistance to ICI induced by antibiotics (unpublished data).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 standard-of-care approved first-line immunotherapy for advanced HCC. We would include patients refractory to first-line treatment, and test the addition of EXL01 to standard-of-care approved first-line immunotherapy in order to reverse resistance.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: EXL01

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Valérie JOLAINE; Phone Number: +33 0299253036; Email: v.jolaine@rennes.unicancer.fr
• Study Contact Backup: Name: Marion TROCHET; Email: m.trochet@rennes.unicancer.fr

Study Locations

• France
  • Bobigny, France, 93000
    • Active, not recruiting
    • Hôpital Avicenne
  • Bordeaux, France
    • Active, not recruiting
    • CHU de Bordeaux
  • Clichy, France, 92100
    • Recruiting
    • Hôpital Beaujon
    • Contact: Mohamed BOUATTOUR; Phone Number: 0140875614; Email: mohamed.bouattour@aphp.fr
    • Principal Investigator: Mohamed BOUATTOUR, Dr
  • Nantes, France, 44 000
    • Active, not recruiting
    • CHU de Nantes hotel Dieu
  • Rennes, France, 35000
    • Recruiting
    • Centre de luttre contre le cancer Eugène Marquis
    • Contact: Héloise BOURIEN; Phone Number: 0299253296; Email: h.bourien@rennes.unicancer.fr
    • Principal Investigator: Héloise BOURIEN, DR
  • Villejuif, France, 94805
    • Active, not recruiting
    • Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and Female
2. Age ≥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 standard-of-care approved first-line immunotherapy
6. Decision made by the physician to continue the same standard-of-care approved first-line immunotherapy 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 standard-of-care approved first-line immunotherapy
2. CTCAE Grade ≥3 or more toxicity under standard-of-care approved first-line immunotherapy, or persistent toxicity Grade >1
3. Liver involvement > 50%
4. Presence of major macro vascular invasion (except Vp1/Vp2)
5. Pregnant woman, or breastfeeding or women of child-bearing potential with no adequate contraception (see §4.3.1)
6. Under curatorship, guardianship, safeguard of justice or deprived of liberty
7. History of serious autoimmune disease
8. Interstitial lung disease
9. HBV chronic infection with HBV DNA > 100 IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated
10. HIV infection
11. Immunosuppression, including subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent)
12. Transplanted liver, or patient with intent for transplantation
13. Has difficulties in swallowing.
14. 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.

15. 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.

16. Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to Screening.
17. 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
18. Has a history of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
19. 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
20. Current probiotics administration, or planned probiotics administration during treatment course.
21. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: standard-of-care approved first-line immunotherapy- EXL01; Patients treated with atezolizumab-bevacizumab ou durvalumab with the addition of the experimental treatment exl01, 1 capsule per day for a maximum of 12 months.	Drug: EXL01; EXL01 contains an unmodified single strain of F. prausnitzii

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall tumor response	Overall tumor response according to the mRECIST, RECIST 1.1 and iRECIST.	At week6; at week12; at month 6, at month12
Objective Response Rate at week12	ORR at week 12 according to mRECIST and iRECIST criteria	at week 12
Objective Response Rate at M6 and M12	The ORR at M6, M12, according to the mRECIST, RECIST 1.1 and iRECIST criteria.	At month 6, at month 12
The Disease control rate (DCR),	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.	At week12; at month 6, at month12
The Progression-Free Survival	The Progression-Free Survival, defined as the time from patient inclusion to progression or death from any cause.	Maximum 12 month after the fisrt EXL01 administration
Overall survival (OS)	The Overall Survival, defined as the time from patient inclusion to death from any cause	Maximum 15 month after the fisrt EXL01 administration of the last patient

Collaborators and Investigators

• Sponsor: Center Eugene Marquis
• Investigators: Principal Investigator: Héloise BOURIEN, Dr, Centre de lutte contre le cancer Eugène Marquis

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2025
• Primary Completion (Estimated): March 12, 2026
• Study Completion (Estimated): December 12, 2026

Study Registration Dates

• First Submitted: August 9, 2024
• First Submitted That Met QC Criteria: August 9, 2024
• First Posted (Actual): August 13, 2024

Study Record Updates

• Last Update Posted (Actual): August 5, 2025
• Last Update Submitted That Met QC Criteria: July 31, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Immunotherapy; microbiome; resistance; dysbiosis; Faecalibacterium prausnitzii
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 2023-1-69-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No