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

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ClinicalTrials.gov Identifier: NCT05690048
Recruitment Status : Not yet recruiting
First Posted : January 19, 2023
Last Update Posted : January 23, 2023
Sponsor:
Collaborators:
National Center for Tumor Diseases, Heidelberg
German Cancer Research Center
Heidelberg University
University of Cologne
Universitätsmedizin Mannheim
Information provided by (Responsible Party):
Michael Dill, University Hospital Heidelberg

Study Description
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Brief Summary:

The interventional, randomized, placebo-controlled, single 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.


Condition or disease Intervention/treatment Phase
Immunotherapy Drug: Fecal microbiota transfer Drug: Vancomycin Oral Capsule Drug: Atezolizumab + Bevacizumab Drug: Placebo Vancomycin Oral Capsule Drug: Placebo Fecal microbiota transfer Phase 2

Detailed Description:
Eligible HCC patients visiting the outpatient clinics of LCCH at the study sites at NCT Heidelberg and University Medical Center Mannheim will be enrolled into the study after informed consent. Patients undergo 2:1 randomization into either the FMT or placebo group. Study lead in with a first sonographically guided tumor biopsy, if not already performed for diagnostic purposes, and a sigmoidoscopy will be scheduled within 10 days after study enrollment in an outpatient setting. Start of active pharmacotherapy with A/B will begin within five working days after sigmoidoscopy. A/B administration will be administered as standard of care every 21 days. At day -3 to 0 oral Vancomycin will be given 4x 250mg to the verum group. At day 0 and 21, concurrent to the first and second cycle of A/B, encapsulated FMT will be administered on the same day. At day 40-42, before the third cycle of A/B, a second biopsy of the liver lesion and a sigmoidoscopy will be performed. Clinical efficacy and safety will be assessed as indicated per protocol analysis.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Interventional, randomized, controlled, single blind trial phase II with two arms (verum/placebo) in a parallel group design
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Fecal Microbiota Transfer in Liver Cancer to Overcome Resistance to Atezolizumab/Bevacizumab (FLORA)
Estimated Study Start Date : January 1, 2024
Estimated Primary Completion Date : July 31, 2026
Estimated Study Completion Date : March 1, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Vancomycin + A/B + FMT
  1. Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
  2. Vancomycin orally (125 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota.
  3. Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21.
 Drug: Fecal microbiota transfer
FMT via capsule (50 g of fecal matter) on day 0 and day 21.
Other Name: FMT

Drug: Vancomycin Oral Capsule
Vancomycin orally (125 mg 4xd, day -3 to 0).

Drug: Atezolizumab + Bevacizumab
Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
Other Name: A/B
Placebo Comparator: Placebo Vancomycin + A/B + Placebo FMT
  1. Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
  2. Placebo Vancomycin orally (125 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota.
  3. Placebo Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21.
 Drug: Atezolizumab + Bevacizumab
Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).
Other Name: A/B

Drug: Placebo Vancomycin Oral Capsule
Placebo Vancomycin orally (125 mg 4xd, day -3 to 0).

Drug: Placebo Fecal microbiota transfer
Placebo Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21.


Outcome Measures
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Primary Outcome Measures :
  1. Differential tumoral CD8 T-cell infiltration [ Time Frame: 6 weeks after treatment initiation ]
    Tumoral CD8 T-cells in IHC before treatment initiation and 6 weeks after (CD8-cells/area of tumor tissue in formalin embedded tumor tissue)

  2. Adverse event documentation of FMT in advanced HCC [ Time Frame: Follow up 3 months after treatment initiation ]
    Adverse event documentation [AE] & immune-related adverse events [irAE])


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Follow up 3 months after treatment initiation ]
    Progression-free survival as by RECIST1.1 criteria

  2. Overall survival (OS) [ Time Frame: Follow up 12 months after treatment initiation ]
    Overall survival

  3. Change of Hepatic function [ Time Frame: Follow up 3 months after treatment initiation ]
    Assessment of Model of End-Stage Liver Disease Score in blood (MELD-Score, 6-40, higher score refers to worse hepatic function)


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 years or older
  2. Confirmed imaging or histological diagnosis of unresectable HCC, BCLC stadium C
  3. ECOG performance status of 0-1

Exclusion Criteria:

  1. Advanced liver cirrhosis (Child-Pugh Score C)
  2. Diagnosis of immunodeficiency (e.g. HIV, immunosuppressants)
  3. Usage of antibiotics within 2 weeks prior enrollment
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05690048


Contacts
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Contact: Michael T Dill, PhD 06221 568611 michael.dill@med.uni-heidelberg.de
Contact: Conrad Rauber, MD/PhD 06221568611 conrad.rauber@med.uni-heidelberg.de

Locations
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Germany
University Hospital Heidelberg
Heidelberg, Baden-Württemberg, Germany, 69120
Contact: Michael Dill, PhD         
Contact: Conrad Rauber, PhD         
University Hospital Heidelberg
Heidelberg, Baden-Württemberg, Germany, 69120
Sponsors and Collaborators
Michael Dill
National Center for Tumor Diseases, Heidelberg
German Cancer Research Center
Heidelberg University
University of Cologne
Universitätsmedizin Mannheim
More Information
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Responsible Party: Michael Dill, Principal Investigator, University Hospital Heidelberg
ClinicalTrials.gov Identifier: NCT05690048    
Other Study ID Numbers: Version 1.0/07.12.2022
First Posted: January 19, 2023    Key Record Dates
Last Update Posted: January 23, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Michael Dill, University Hospital Heidelberg:
immunotherapy
fecal microbiota transfer
HCC
gut microbiota
tumor microenvironment
Additional relevant MeSH terms:
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Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Vancomycin
Bevacizumab
Atezolizumab
Antineoplastic Agents, Immunological
 Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents