FMT in IT-refractory HCC - FAB-HCC Pilot Study

Sponsor

Medical University of Vienna (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05750030

Collaborator

(none)

Enrollment

Location

Arm

34.1

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This single-center, pilot study (phase IIa) will evaluate the safety, feasibility, and efficacy of FMT from patients with HCC who responded to PD-(L)1-based immunotherapy to patients with HCC who failed to respond to atezolizumab/bevacizumab.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Combination Product: FMT combined with Atezolizumab plus Bevacizumab	Phase 2

Detailed Description

The main purpose of this phase IIa pilot study is to test the safety and efficacy of fecal microbiota transplant (FMT) combined with atezolizumab plus bevacizumab in patients who failed to respond to prior immunotherapy for advanced hepatocellular carcinoma (aHCC).

The primary objective is to assess the safety of FMT combined with atezolizumab plus bevacizumab, as measured by incidence and severity of treatment-related adverse events.

The secondary objectives are to assess the efficacy of FMT in combination with atezolizumab plus bevacizumab as measured by best radiological response, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Furthermore, the objective is to evaluate the impact of FMT with atezolizumab plus bevacizumab on the quality of life, as assessed by EQ-5D-5L questionnaires.

Finally, this study also aims to assess the following exploratory endpoints:

the effect of FMT on recipient gut microbiota composition, diversity, rate of change from baseline, and similarity to donor stool composition over time (compared between responders and non-responders)
the effect of FMT on immune activity in the gut
metagenome assemblies and functional profiling before and after FMT
single cell analyses of circulating immune cells before and after FMT
serum and stool metabolomic and lipidomic signatures before and after FMT

This is a phase IIa, single-center, open-label pilot study. Twelve patients suffering from advanced-stage hepatocellular carcinoma will be enrolled in this trial. The planned duration for this study are 48 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

12 Patients with HCC who failed to achieve a complete or partial response (according to mRECIST) to atezolizumab plus bevacizumab12 Patients with HCC who failed to achieve a complete or partial response (according to mRECIST) to atezolizumab plus bevacizumab

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Fecal Microbiota Transplant (FMT) Combined With Atezolizumab Plus Bevacizumab in Patients With HepatoCellular Carcinoma Who Failed to Respond to Prior Immunotherapy - the FAB-HCC Pilot Study

Anticipated Study Start Date :

Mar 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2025

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FMT combined with Atezolizumab plus Bevacizumab	Combination Product: FMT combined with Atezolizumab plus Bevacizumab Single FMT from patients with HCC who responded to PD-(L)1-based immunotherapy to patients with HCC who failed to achieve complete or partial response (according to mRECIST) to atezolizumab/bevacizumab. After single FMT, patients will continue to receive atezolizumab/bevacizumab every 21-days according to protocol.

Arm

Intervention/Treatment

Experimental: FMT combined with Atezolizumab plus Bevacizumab

Combination Product: FMT combined with Atezolizumab plus Bevacizumab

Single FMT from patients with HCC who responded to PD-(L)1-based immunotherapy to patients with HCC who failed to achieve complete or partial response (according to mRECIST) to atezolizumab/bevacizumab. After single FMT, patients will continue to receive atezolizumab/bevacizumab every 21-days according to protocol.

Outcome Measures

Primary Outcome Measures

Safety of atezolizumab/bevacizumab in combination with FMT, measured by incidence and severity of treatment-related adverse events, determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. [24 months]

Secondary Outcome Measures

Efficacy assessed by the number of study participants achieving complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) as best radiological response evaluated according to mRECIST/ RECIST v1.1 criteria. [24 months]
Efficacy as assessed by objective response rate (ORR) and disease control rate (DCR). Objective response is defined as either complete or partial response, while disease control rate comprises complete/partial response as well as stable disease. [24 months]
Efficacy as assessed by progression-free survival (PFS) and overall survival (OS). [24 months]
Quality of life (QoL) as assessed by the patient-reported outcome EQ-5D-5L (European Quality of Life 5 Dimensions 3 Level Version) questionnaire. [24 months]

Other Outcome Measures

Effect of FMT on recipient gut microbiota composition, diversity (alpha and beta), rate of change from baseline and similarity to donor stool composition over time as well as comparison of responders and non-responders. [24 months]
Effect of FMT on immune activity in the gut by analyzing gut tissue samples with immunohistochemistry staining of immune cells of patients receiving FMT. [24 months]
Differences in metagenome assemblies and functional profiling using shotgun metagenomic analysis of donor and recipient stool samples before and after FMT. [24 months]
Differences in single cell analyses of circulating immune cells in patients before and after FMT. [24 months]
Differences in serum and stool metabolomic and lipidomic signatures in patients before and after FMT. [24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent form
Age ≥ 18 years
Histologically or radiologically confirmed HCC
Patients with progressive disease (according to mRECIST) during treatment with atezolizumab/bevacizumab (without prior complete or partial response as best radiological response according to mRECIST) OR patients with stable disease as best radiological response (according to mRECIST) after the first 12 months of atezolizumab/bevacizumab treatment
Negative HIV test
Patients with chronic hepatitis B must be under antiviral treatment and hepatitis B DNA must be < 500 IU/mL
Variceal status must be known and if present, adequate medical or endoscopic treatment is required
ECOG Performance Status 0-1
Child-Pugh class A-B8
Adequate hematological and end-organ function, defined as follows:
AST and ALT < 10 x ULN
Serum bilirubin < 3.5 mg/dL
Albumin ≥ 28 g/L
Serum creatinine ≤ 1.5 mg/dL
Hemoglobin ≥ 8 mg/dL
Platelet count ≥ 50 G/L
Leukocytes ≥ 2.5 G/L
Patients not receiving therapeutic anticoagulation: INR ≤ 2.3 or thromboplastin time ≥ 40%
Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods
Men must agree to remain abstinent (refrain from heterosexual intercourse) or use a condom

Exclusion Criteria:

Known fibrolamellar carcinoma or mixed cholangiocellular carcinoma
Massive tumor progression (> 100% increase in target lesions or progression associated with significant clinical deterioration)
Uncontrolled ascites
Overt hepatic encephalopathy or concomitant treatment with rifaximin
Prior allogeneic stem cell or solid organ transplantation
Active or history of severe autoimmune disease
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to study inclusion or unstable angina
Severe infection within 4 weeks prior to study inclusion
Pregnant or breastfeeding women
Treatment with systemic immunosuppressive medication with the following exceptions:
Acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for contrast allergy)
Mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for adrenal insufficiency
Significant vascular disease (e.g., peripheral arterial thrombosis) within 6 months prior to study inclusion
Major surgery within 4 weeks prior to study inclusion or minor surgery (excluding placement of a vascular access device) within 3 days prior to study inclusion
History of gastrointestinal fistula or perforation, or intraabdominal abscess within 6 months prior to study inclusion
Serious, non-healing wound or active ulcer