Overview
The interventional, randomized, placebo-controlled, double-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.
Description
Eligible HCC patients visiting the outpatient clinics at the study sites of the NCT Germany will be enrolled into the study after informed consent. Patients undergo 2:1 randomization into either the FMT or placebo group. Prior to the intervention, a sigmoidoscopy with mucosal biopsies will be performed. At day -3 to 0 oral Vancomycin 4x 250mg or placebo will be given. Atezolizumab/bevacizumab (A/B) will be administered as standard of care every 21 days, starting on day 0. At day 0 and 21, concurrent to the first and second cycle of A/B, encapsulated FMT or placebo will be administered on the same day. At day 40-42, before the third cycle of A/B, a tumor biopsy and a sigmoidoscopy will be performed. The first radiologic assessment will be performed after 4 cycles of A/B. Clinical efficacy and safety will be assessed as indicated per protocol analysis.
Eligibility
Inclusion Criteria:
- Age 18 years or older
- Confirmed radiologic or histological diagnosis of HCC
- Disease not amenable to resection, liver transplantation or loco-regionary therapy
- Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care
- Measurable disease per RECIST 1.1
- Preserved liver function with a Child-Pugh score A or B (maximally 7 points)
- Performance status ECOG 0-1
Exclusion Criteria:
- Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab.
- Active or prior documented autoimmune or inflammatory disorders
- Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-VEGF antibodies.
- Known to have tested positive for human immunodeficiency virus (HIV) infection.
- Co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
- Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.
- Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism or excretion of investigational product.
- Uncontrolled arterial hypertension defined by a systolic pressure > 150 mm Hg or diastolic pressure > 90 mm Hg or other hypertensive cardiovascular complications despite standard medical treatment.
- Any history of nephrotic or nephritic syndrome.
- Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab.
- Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab.
- Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.
- History of another primary malignancy.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
- Pregnancy or lactation.
- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
- Participation in other interventional clinical trials or observation period of competing clinical trials, respectively.
- Held in an institution by legal or official order.
- Legally incapacitated.
- Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.