Evaluation of Fecal Microbiota Transfer to Overcome Atezolizumab and Bevacizumab Resistance in Advanced Hepatocellular Carcinoma: A Phase II Randomized Controlled Trial
- Trial ID
- 2023-506887-15-00
- Protocol
- FLORA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **immunogenicity** of a treatment regimen in patients with advanced **hepatocellular carcinoma** (HCC). This is measured by evaluating tumoral CD8+ T cell infiltration after two cycles of treatment with Vancomycin, Atezolizumab/Bevacizumab (A/B) combined with INTESTIFIX 001, compared to a placebo regimen. The clinical relevance of this objective lies in its potential to enhance the immune response against HCC, thereby overcoming resistance to standard therapies and improving patient outcomes.
Secondary objectives include evaluating: - Overall survival (OS) - Progression-free survival (PFS) - Disease control (DC) - Objective response (OR) - Duration of response (DoR) - Alpha-fetoprotein serological response rate - Hepatic function - Health-related quality of life
Participants
The clinical trial involves participants diagnosed with **hepatocellular carcinoma** (HCC), a type of liver cancer. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who are part of a vulnerable population. Participants are required to have adequate organ and marrow function, as well as preserved liver function with a Child-Pugh score of A or B. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Subjects must have a confirmed diagnosis of HCC that is not amenable to resection, liver transplantation, or loco-regional therapy. They should also be eligible for therapy with Atezolizumab and Bevacizumab according to the standard of care. Lifestyle considerations such as the use of reliable contraception for women of childbearing potential and men, and a negative pregnancy test for women of childbearing potential, are required. Participants must be willing to undergo a tumor biopsy and have measurable disease per RECIST 1.1 criteria. The trial population was selected based on these criteria to ensure the safety and efficacy of the treatment being assessed.
Plans and Procedures
The clinical trial is designed to evaluate the **immunogenicity** and safety of a therapeutic combination in patients with advanced **hepatocellular carcinoma**. This is a randomized, placebo-controlled, double-blind Phase II trial. The primary objective is to assess the infiltration of CD8+ T cells in tumor tissue after two cycles of treatment with Vancomycin, Atezolizumab/Bevacizumab, and INTESTIFIX 001, compared to a placebo regimen. The trial is expected to commence recruitment on June 1, 2025, and conclude by March 31, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, virology status, and organ function. Following randomization, participants will receive treatment over a maximum period of 16 weeks, with regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will occur 42 days after the fourth cycle of Atezolizumab/Bevacizumab, marking the completion of the participant's involvement.
The expected duration of participant involvement is approximately 16 weeks, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. The trial will adhere to rigorous standards to ensure the reliability and validity of the data collected, with a focus on maintaining participant safety and scientific integrity throughout the study.
Treatment
The clinical trial involves the administration of **INTESTIFIX 001**, an experimental medication formulated as a capsule. The active substance, **INTESTIFIX**, is classified as a structurally diverse substance. The medication is administered orally with a maximum daily dose of 25 grams and a total maximum dose of 50 grams over a treatment period of 2 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**ATEZOLIZUMAB** is utilized as a comparator treatment in the trial. It is administered via intravenous infusion, with a maximum daily dose of 1200 milligrams and a total maximum dose of 4800 milligrams over a 16-week period. The pharmaceutical form is designated as PHF00230MIG, and the active substance is a protein. Compliance with the dosing schedule is monitored through infusion records and participant follow-up visits.
The trial also includes a placebo control, specifically the **Intestifix 001 placebo**, which is used to assess the efficacy of the experimental treatment. The placebo is administered in a manner consistent with the experimental medication to maintain blinding and ensure the integrity of the trial results.
**Vancomycin ENTEROCAPS® 250 mg, Hartkapseln** is another treatment used in the study, administered orally in the form of hard capsules. The active substance is **vancomycin hydrochloride**, a chemical compound. The maximum daily dose is 1000 milligrams, with a total maximum dose of 3000 milligrams over a 3-week period. Participant adherence to the dosing regimen is monitored through capsule counts and patient diaries.
Additionally, **BEVACIZUMAB** is administered as part of the trial, delivered via intravenous infusion. The active substance is a protein, and the dosing is calculated based on body weight, with a maximum daily dose of 15 mg/kg and a total maximum dose of 60 mg/kg over a 16-week period. Compliance is tracked through infusion logs and regular participant evaluations.
The trial also includes a **Vancomycin Placebo** to serve as a control for the vancomycin treatment. This placebo is administered in a manner consistent with the active treatment to ensure blinding and maintain the study's methodological rigor.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **tumor-infiltrating CD8+ T lymphocytes** in tumor biopsies. This immunological parameter will be evaluated after two cycles of treatment with Vancomycin, Atezolizumab/Bevacizumab (A/B), and INTESTIFIX 001, compared to a placebo regimen. The density of CD8+ T lymphocytes will be quantitatively assessed by counting the number of CD8+ cells per square millimeter of tumor area, following manual delineation of the tumor area in the biopsy. Tumor areas with crush artifacts or necrosis will be excluded from the analysis to ensure accuracy.
Additionally, the incidence and severity of adverse events (AEs) and serious adverse events (SAEs) will be monitored from the start of treatment until 42 days after the fourth cycle of A/B. This will include an assessment of the incidence, severity, timing, seriousness, and relatedness of these events to the study treatment, as well as the action taken with the study medication and the outcome. These parameters will provide a comprehensive evaluation of the safety and efficacy of the therapeutic combination in patients with advanced hepatocellular carcinoma (HCC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subjects must be ≥ 18 years at the time of screening.
- Confirmed HCC (either by imaging in a cirrhotic liver [liver lesions that show typ-ical features of HCC on IV contrast-enhanced CT or MRI scans, i.e., hypervas-cularity in the arterial phase with washout in the portal or the late venous phase] or histopathologically from biopsy specimen or surgery).
- Disease not amenable to resection, liver transplantation or loco-regionary ther-apy, such as curative ablation, trans-arterial chemoembolization (TACE) or trans-arterial radio-embolization (TARE).
- 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.
- Available CT scan of thorax and MRI or CT scan of abdomen with contrast agent not older than 30 days before start of treatment (A/B C1d1).
- Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test
- For patients with active HBV: HBV DNA < 500 IU/ml obtained within 28 days prior to initiation of study treatment and anti-HBV treatment per local standard of care for a minimum of 14 days prior to study entry and willingness to continue treat-ment for the length of the study
- For patients with active HCV infection (as characterized by the presence of de-tectable HCV RNA): must be managed per local institutional practice for the length of the study.
- Adequate organ and marrow function measured within 72 hours prior to random-ization as follows: a. Hemoglobin ≥ 8 g/dL b. Absolute neutrophil count ≥ 1.0 x 109/L c. Platelet count ≥ 50 x 109/L d. Total bilirubin ≤ 3.0 x the upper limit of normal (ULN) e. Alanine aminotransferase (ALT) and aspartate aminotransferase ≤ 5 x ULN f. International normalized ratio ≤ 1.6. g. Calculated creatinine clearance ≥ 30 mL/min as determined by Cockroft-Gault
- Use of reliable contraception for women of childbearing potential and men.
- Negative pregnancy test for women of childbearing potential
- Ability of subject to understand character and individual consequences of clinical trial and to comply with the study protocol and dosing regimen.
- Written informed consent (must be available before enrolment in the clinical trial)
- Subject willing to undergo tumor biopsy. This requires a tumor lesion accessible for a biopsy.
Exclusion Criteria
- Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids or local steroid injections (e.g. intra-articular injection). b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent c. Steroids as premedication for hypersensitivity reactions or as an anti-emetic.
- Active or prior documented autoimmune or inflammatory disorders (including in-flammatory bowel disease, diverticulitis, systemic lupus erythematosus, sar-coidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune myocarditis, etc.). The following are exceptions to this criterion: a. Subjects with vitiligo or alopecia. b. Subjects with hypothyroidism stable on hormone replacement. c. Any chronic skin condition that does not require systemic therapy. d. Subjects with coeliac disease controlled by diet alone. e. Subjects without active disease in the last 5 years may be included but only after consultation with the study clinical lead.
- 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 en-doscopy 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 investiga-tional product.
- Uncontrolled arterial hypertension defined by a systolic pressure > 150 mm Hg or diastolic pressure > 90 mm Hg or other hypertensive cardiovascular complica-tions 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 Ate-zolizumab/Bevacizumab (C1d1).
- Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab (C1d1).
- Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed chol-angiocarcinoma and HCC.
- History of another primary malignancy. Exceptions include: a. malignancy treated with curative intent or has low potential risk for recur-rence with no known active disease ≥ 5 years before the first dose of study intervention; b. malignancy which occurred < 5 years before the first study intervention, is not active, and not expected to recur or be clinically relevant in the next 2 years.
- 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 compet-ing 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Jun 2025 | 48 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Vancomycin Placebo | Placebo | N/A | — | — | — | N/A |
BEVACIZUMAB | Other | PHF00230MIG | INTRAVENOUS INFUSION | 15 | 16 | SCP29096188 |
Intestifix 001 placebo | Placebo | N/A | — | — | — | N/A |
INTESTIFIX 001 | Test | CAPSULE | ORAL | 25 | 2 | PRD10296060 |
ATEZOLIZUMAB | Other | PHF00230MIG | INTRAVENIOUS INFUSION | 1200 | 16 | SCP65091812 |
Vancomycin ENTEROCAPS® 250 mg, Hartkapseln | Test | HARTKAPSELN | ORAL | 1000 | 3 | PRD780980 |