Fecal microbiota transfer to overcome resistance to atezolizumab/bevacizumab in liver cancer

Fecal Microbiota Transfer in Liver Cancer to Overcome Resistance to Atezolizumab/Bevacizumab (FLORA)

This will test whether adding fecal microbiota transfer to standard atezolizumab/bevacizumab helps adults with advanced hepatocellular carcinoma respond better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University Hospital Heidelberg (Academic / other)
• Drugs / interventions: Atezolizumab, Bevacizumab, immunotherapy
• Locations: 7 sites (Heidelberg, Baden-Wurttemberg and 6 other locations)
• Trial ID: NCT05690048 on ClinicalTrials.gov

What this trial studies

FLORA is a randomized, double-blind, placebo-controlled phase II trial with 2:1 randomization to receive encapsulated fecal microbiota transfer (FMT) or placebo alongside standard atezolizumab/bevacizumab for advanced HCC. Before dosing, participants undergo sigmoidoscopy with mucosal biopsies and receive oral vancomycin or placebo on days -3 to 0 to condition the gut. Encapsulated FMT or placebo is given on day 0 and day 21 concurrent with the first two cycles of atezolizumab/bevacizumab, and a tumor biopsy plus repeat sigmoidoscopy are performed around day 40–42. Safety, immunologic changes in the gut and tumor microenvironment, and radiologic response after four cycles will be measured per protocol.

Who should consider this trial

Good fit: Adults (≥18) with unresectable HCC who are eligible for atezolizumab/bevacizumab, have measurable disease, preserved liver function (Child‑Pugh A or B ≤7), and ECOG 0–1.

Not a fit: Patients with prior immune‑checkpoint therapy, active autoimmune or inflammatory disorders, recent immunosuppression, uncontrolled HIV or HBV/HCV co‑infection, or poor liver function/ECOG status are unlikely to qualify or benefit.

Why it matters

Potential benefit: If successful, this approach could increase response rates to atezolizumab/bevacizumab and potentially delay disease progression in advanced HCC.

How similar studies have performed: Early reports in melanoma and other solid tumors have shown promising signals that FMT can improve checkpoint inhibitor responses, but randomized data in HCC are limited.

Eligibility criteria

Inclusion Criteria:

1. Age 18 years or older
2. Confirmed radiologic or histological diagnosis of HCC
3. Disease not amenable to resection, liver transplantation or loco-regionary therapy
4. Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care
5. Measurable disease per RECIST 1.1
6. Preserved liver function with a Child-Pugh score A or B (maximally 7 points)
7. Performance status ECOG 0-1

Exclusion Criteria:

1. Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab.
2. Active or prior documented autoimmune or inflammatory disorders
3. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-VEGF antibodies.
4. Known to have tested positive for human immunodeficiency virus (HIV) infection.
5. Co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
6. Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.
7. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism or excretion of investigational product.
8. Uncontrolled arterial hypertension defined by a systolic pressure \> 150 mm Hg or diastolic pressure \> 90 mm Hg or other hypertensive cardiovascular complications despite standard medical treatment.
9. Any history of nephrotic or nephritic syndrome.
10. Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab.
11. Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab.
12. Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.
13. History of another primary malignancy.
14. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
15. Pregnancy or lactation.
16. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
17. Participation in other interventional clinical trials or observation period of competing clinical trials, respectively.
18. Held in an institution by legal or official order.
19. Legally incapacitated.
20. Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.

Where this trial is running

Heidelberg, Baden-Wurttemberg and 6 other locations

• University Hospital Heidelberg — Heidelberg, Baden-Wurttemberg, Germany (Recruiting)
• University Hospital Augsburg — Augsburg, Germany (Not_yet_recruiting)
• University Hospital Essen — Essen, Germany (Not_yet_recruiting)
• University Hospital Mannheim — Mannheim, Germany (Not_yet_recruiting)
• University Hospital Regensburg — Regensburg, Germany (Not_yet_recruiting)
• University Hospital Tübingen — Tübingen, Germany (Not_yet_recruiting)
• University Hospital Ulm — Ulm, Germany (Not_yet_recruiting)

Study contacts

• Principal investigator: Michael T Dill, PhD — University Hospital Heidelberg, Heidelberg, Baden-Württemberg 69120
• Study coordinator: Michael T Dill, PhD

Conditions Immunotherapy; HCC - Hepatocellular Carcinoma; immunotherapy; fecal microbiota transfer; HCC; gut microbiota; tumor microenvironment