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

Phase 2

Not yet recruiting

• Conditions: Immunotherapy
• Interventions: Drug: Atezolizumab + Bevacizumab; Drug: Fecal microbiota transfer; Drug: Vancomycin Oral Capsule; Drug: Placebo Vancomycin Oral Capsule; Drug: Placebo Fecal microbiota transfer

• Registration Number: NCT05690048
• Lead Sponsor: Michael Dill

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.

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 Timeline

• Study First Submitted: 2022-12-13
• Status Verified: 2023-01
• Study First Submitted QC: 2023-01-09
• Study First Posted: 2023-01-19
• Last Update Submitted: 2023-01-19
• Last Update Posted: 2023-01-23
• Study Start: 2024-01-01
• Primary Completion: 2026-07-31
• Study Completion: 2027-03-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 48

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Vancomycin + A/B + Placebo FMT	Atezolizumab + Bevacizumab	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.
Vancomycin + A/B + FMT	Vancomycin Oral Capsule	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.
Vancomycin + A/B + FMT	Fecal microbiota transfer	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.
Placebo Vancomycin + A/B + Placebo FMT	Placebo Fecal microbiota transfer	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.
Vancomycin + A/B + FMT	Atezolizumab + Bevacizumab	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.
Placebo Vancomycin + A/B + Placebo FMT	Placebo Vancomycin Oral Capsule	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.

Primary Outcome Measures

Name	Time	Method
Differential tumoral CD8 T-cell infiltration	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)
Adverse event documentation of FMT in advanced HCC	Follow up 3 months after treatment initiation	Adverse event documentation \[AE\] \& immune-related adverse events \[irAE\])

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	Follow up 12 months after treatment initiation	Overall survival
Progression-free survival (PFS)	Follow up 3 months after treatment initiation	Progression-free survival as by RECIST1.1 criteria
Change of Hepatic function	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)

Trial Locations

Locations (1)

University Hospital Heidelberg; 🇩🇪 Heidelberg, Baden-Württemberg, Germany