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

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 achieve or maintain a complete or partial radiological response (according to mRECIST) 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 II, 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.

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 or with 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