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

NCT05690048 | Recruiting Phase 2

• 1 other identifier: Version 3.1/11.02.2025
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 7

Brief Summary

The interventional, randomized, placebo-controlled, double-blind phase II-trial FLORA will assess safety and immunogenicity of fecal microbiota transfer in combination with standard of care immunotherapy in advanced hepatocellular carcinoma (HCC) in a parallel group design. Subjects will be randomized 2:1 into either the FMT or placebo group.

Conditions

Immunotherapy; HCC - Hepatocellular Carcinoma

Keywords

immunotherapy; fecal microbiota transfer; HCC; gut microbiota; tumor microenvironment

Outcome Measures

Primary Outcomes (2)

• Assessment of immunogenicity

  Tumoral CD8+ T cell infiltration after 2 cycles of treatment with Vancomycin, A/B + FMT in comparison to Vancomycin-placebo, A/B + FMT-placebo

  6 weeks after treatment initiation

• Safety of the therapeutic combination in advanced HCC

  Occurence of Adverse Events (AE) \& immune-related adverse events (irAE)

  The observational period begins with the first administration of the 1st IMP (Vancomycin/Placebo) on day -3 and ends with either the Follow-up visit after 15 weeks (Day 105) or the initiation of a subsequent anticancer treatment.

Secondary Outcomes (12)

• Overall survival (OS)

  From start of treatment until the date of death from any cause, assessed up to 4 years.

• Progression free survival (PFS)

  From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

• Disease control (DC)

  From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

• Objective Response (OR)

  From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

• Duration of Response (DoR)

  From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

Study Arms (2)

Vancomycin + A/B + FMT

EXPERIMENTAL

1. Atezolizumab 1200mg i.v. \& Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC). 2. Vancomycin orally (250 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota. 3. Fecal microbiota transfer (FMT) via capsules (total 50 g of fecal matter) on day 0 and day 21.

Drug: Fecal microbiota transfer; Drug: Vancomycin Oral Capsule; Drug: Atezolizumab + Bevacizumab

Placebo Vancomycin + A/B + Placebo FMT

PLACEBO COMPARATOR

1. Atezolizumab 1200mg i.v. \& bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC). 2. Placebo vancomycin orally (4xd, day -3 to 0) for reduction of original patient gut microbiota. 3. Placebo fecal microbiota transfer (FMT) via capsules on day 0 and day 21.

Drug: Atezolizumab + Bevacizumab; Drug: Placebo Vancomycin Oral Capsule; Drug: Placebo Fecal microbiota transfer

Interventions

Fecal microbiota transfer DRUG

FMT via capsule (50 g of fecal matter) on day 0 and day 21.

Also known as: FMT, INTESTIFIX 001

Vancomycin + A/B + FMT

Vancomycin Oral Capsule DRUG

Vancomycin orally (250 mg 4xd, day -3 to 0).

Vancomycin + A/B + FMT

Atezolizumab + Bevacizumab DRUG

Atezolizumab 1200mg i.v. \& Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).

Also known as: A/B

Placebo Vancomycin + A/B + Placebo FMT; Vancomycin + A/B + FMT

Placebo Vancomycin Oral Capsule DRUG

Placebo Vancomycin orally (4xd, day -3 to 0).

Placebo Vancomycin + A/B + Placebo FMT

Placebo Fecal microbiota transfer DRUG

Placebo Fecal microbiota transfer (FMT) via capsule on day 0 and day 21.

Also known as: Placebo FMT, Placebo INTESTIFIX 001

Placebo Vancomycin + A/B + Placebo FMT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab.
• Active or prior documented autoimmune or inflammatory disorders
• 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.
• Known to have tested positive for human immunodeficiency virus (HIV) infection.
• 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.
• Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.
• 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.
• 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.
• Any history of nephrotic or nephritic syndrome.
• Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab.
• Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab.
• Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.
• History of another primary malignancy.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
• Pregnancy or lactation.

Sponsors & Collaborators

• Michael Dill: lead
• National Center for Tumor Diseases, Heidelberg: collaborator
• German Cancer Research Center: collaborator
• Heidelberg University: collaborator
• University of Cologne: collaborator
• Universitätsmedizin Mannheim: collaborator

Study Sites (7)

University Hospital Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

RECRUITING

University Hospital Augsburg

Augsburg, 86156, Germany

NOT YET RECRUITING

University Hospital Essen

Essen, 45147, Germany

NOT YET RECRUITING

University Hospital Mannheim

Mannheim, 68167, Germany

NOT YET RECRUITING

University Hospital Regensburg

Regensburg, 93053, Germany

NOT YET RECRUITING

University Hospital Tübingen

Tübingen, 72076, Germany

NOT YET RECRUITING

University Hospital Ulm

Ulm, 89081, Germany

NOT YET RECRUITING

Related Publications (1)

• Rauber C, Roberti MP, Vehreschild MJ, Tsakmaklis A, Springfeld C, Teufel A, Ettrich T, Jochheim L, Kandulski A, Missios P, Mohr R, Reichart A, Waldschmidt DT, Sauer LD, Sander A, Schirmacher P, Jager D, Michl P, Dill MT. Protocol: Faecal microbiota transfer in liver cancer to overcome resistance to atezolizumab/bevacizumab - a multicentre, randomised, placebo-controlled, double-blind phase II trial (the FLORA trial). BMJ Open. 2025 Sep 9;15(9):e097802. doi: 10.1136/bmjopen-2024-097802.

  PMID: 40930564 DERIVED

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Fecal Microbiota Transplantation; Vancomycin; atezolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins

Study Officials

• Michael T Dill, PhD

  University Hospital Heidelberg, Heidelberg, Baden-Württemberg 69120

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michael T Dill, PhD

CONTACT

06221 568611; michael.dill@med.uni-heidelberg.de

Conrad Rauber, MD/PhD

CONTACT

06221568611; conrad.rauber@med.uni-heidelberg.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Interventional, randomized, placebo-controlled, double-blind, phase II with two arms (verum/placebo) in a parallel group design

Study Record Dates

• First Submitted: December 13, 2022
• First Posted: January 19, 2023
• Study Start: July 16, 2025
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028
• Last Updated: August 6, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

DE (7)