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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Immunotherapy

Intervention / Treatment
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* Drug: Fecal microbiota transfer
* Drug: Vancomycin Oral Capsule
* Drug: Atezolizumab + Bevacizumab
* Drug: Placebo Vancomycin Oral Capsule
* Drug: Placebo Fecal microbiota transfer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Confirmed imaging or histological diagnosis of unresectable HCC, BCLC stadium C ECOG performance status of 0-1 Exclusion Criteria: Advanced liver cirrhosis (Child-Pugh Score C) Diagnosis of immunodeficiency (e.g. HIV, immunosuppressants) Usage of antibiotics within 2 weeks prior enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Interventional, randomized, controlled, single blind trial phase II with two arms (verum/placebo) in a parallel group design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vancomycin + A/B + FMT<br>Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC). Vancomycin orally (125 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota. Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21. | Drug: Fecal microbiota transfer<br>* FMT via capsule (50 g of fecal matter) on day 0 and day 21.<br>* Other names: FMT;Drug: Vancomycin Oral Capsule<br>* Vancomycin orally (125 mg 4xd, day -3 to 0).<br>Drug: Atezolizumab + Bevacizumab<br>* Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).<br>* Other names: A/B;|
| Placebo Comparator: Placebo Vancomycin + A/B + Placebo FMT<br>Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC). Placebo Vancomycin orally (125 mg 4xd, day -3 to 0) for reduction of original patient gut microbiota. Placebo Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21. | Drug: Atezolizumab + Bevacizumab<br>* Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).<br>* Other names: A/B;Drug: Placebo Vancomycin Oral Capsule<br>* Placebo Vancomycin orally (125 mg 4xd, day -3 to 0).<br>Drug: Placebo Fecal microbiota transfer<br>* Placebo Fecal microbiota transfer (FMT) via capsule (50 g of fecal matter) on day 0 and day 21.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differential tumoral CD8 T-cell infiltration | Tumoral CD8 T-cells in IHC before treatment initiation and 6 weeks after (CD8-cells/area of tumor tissue in formalin embedded tumor tissue) | 6 weeks after treatment initiation | 
| Adverse event documentation of FMT in advanced HCC | Adverse event documentation [AE] & immune-related adverse events [irAE]) | Follow up 3 months after treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Progression-free survival as by RECIST1.1 criteria | Follow up 3 months after treatment initiation | 
| Overall survival (OS) | Overall survival | Follow up 12 months after treatment initiation | 
| Change of Hepatic function | Assessment of Model of End-Stage Liver Disease Score in blood (MELD-Score, 6-40, higher score refers to worse hepatic function) | Follow up 3 months after treatment initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, fecal microbiota transfer, HCC, gut microbiota, tumor microenvironment