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

Phase 2RecruitingNCT05690048

Michael Dill48 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Immunotherapy HCC - Hepatocellular Carcinoma

Interventions

Fecal microbiota transferDRUG

FMT via capsule (50 g of fecal matter) on day 0 and day 21.

Vancomycin Oral CapsuleDRUG

Vancomycin orally (250 mg 4xd, day -3 to 0).

Atezolizumab + BevacizumabDRUG

Atezolizumab 1200mg i.v. \& Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 18 years or older 2. Confirmed radiologic or histological diagnosis of HCC 3. Disease not amenable to resection, liver transplantation or loco-regionary therapy 4. Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care 5. Measurable disease per RECIST 1.1 6. Preserved liver function with a Child-Pugh score A or B (maximally 7 points) 7. Performance status ECOG 0-1 Exclusion Criteria: 1. Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab. 2. Active or prior documented autoimmune or inflammatory disorders 3. 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. 4. Known to have tested positive for human immunodeficiency virus (HIV) infection. 5. 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. 6. Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization. 7. 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. 8. 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. 9. Any history of nephrotic or nephritic syndrome. 10. Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab. 11. Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab. 12. Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC. 13. History of another primary malignancy. 14. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. 15. Pregnancy or lactation. 16. 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. 17. Participation in other interventional clinical trials or observation period of competing clinical trials, respectively. 18. Held in an institution by legal or official order. 19. Legally incapacitated. 20. Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.

Locations (7)

University Hospital Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

RECRUITING

University Hospital Augsburg

Augsburg, Germany

NOT_YET_RECRUITING

University Hospital Essen

Essen, Germany

Outcomes

Primary Outcomes

Assessment of immunogenicity

Tumoral CD8+ T cell infiltration after 2 cycles of treatment with Vancomycin, A/B + FMT in comparison to Vancomycin-placebo, A/B + FMT-placebo

Time frame: 6 weeks after treatment initiation

Safety of the therapeutic combination in advanced HCC

Occurence of Adverse Events (AE) \& immune-related adverse events (irAE)

Time frame: The observational period begins with the first administration of the 1st IMP (Vancomycin/Placebo) on day -3 and ends with either the Follow-up visit after 15 weeks (Day 105) or the initiation of a subsequent anticancer treatment.

Secondary Outcomes

Overall survival (OS)

To evaluate the efficacy of Vancomycin, A/B + INTESTIFIX 001 in comparison to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Overall Survival (OS). OS is defined as the time from start of treatment (first dose of A/B) to time of death from any cause in days. Administrative censoring is applied for patients who survive the end of the trial. Death cases will either become known during the clinical study treatment, or information will be obtained on the occasion of follow-up calls, or from e.g. treating physicians. Otherwise, patients for whom the date of death is unknown are censored at the last time point they are known to be alive.

Time frame: From start of treatment until the date of death from any cause, assessed up to 4 years.

Progression free survival (PFS)

To evaluate the efficacy of Vancomycin, A/B + INTESTIFIX 001as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Progression Free Survival (PFS). PFS is defined as the time from start of treatment (first dose A/B) until objective tumor progression as determined by the radiologist per RECIST 1.1 or death, whichever occurs first.

Time frame: From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

Central Contacts

Michael T Dill, PhD

CONTACT

06221 568611 michael.dill@med.uni-heidelberg.de

Conrad Rauber, MD/PhD

CONTACT

06221568611 conrad.rauber@med.uni-heidelberg.de

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Placebo Vancomycin orally (4xd, day -3 to 0).

Placebo Fecal microbiota transferDRUG

Placebo Fecal microbiota transfer (FMT) via capsule on day 0 and day 21.

University Hospital Mannheim

Mannheim, Germany

NOT_YET_RECRUITING

University Hospital Regensburg

Regensburg, Germany

NOT_YET_RECRUITING

University Hospital Tübingen

Tübingen, Germany

NOT_YET_RECRUITING

University Hospital Ulm

Ulm, Germany

NOT_YET_RECRUITING

Disease control (DC)

To evaluate the efficacy of Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Disease Control (DC). DC is defined as achieving complete response (CR), partial response (PR) or stable disease (SD) as best overall response during observation period as determined by the radiologist per RECIST 1.1 criteria.

Time frame: From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

Objective Response (OR)

To evaluate the efficacy of Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Objective Response (OR). OR is defined as tumor size reduction, meaning PR or CR, as determined by the radiologist per RECIST 1.1 criteria assessed by best overall response during the observation period.

Time frame: From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

Duration of Response (DoR)

To evaluate the efficacy of Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Duration of Response (DoR). DoR is defined as the time from first documented response (either PR or CR per RECIST 1.1, whichever is recorded first) to first subsequent progression (first assessment of PD per RECIST 1.1 or death). DoR is only defined for the patients who experienced a response.

Time frame: From start of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years.

AFP serological response rate

To evaluate the efficacy Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to AFP serological response rate. AFP serological response rate is defined as defined as a \>20% de- crease in serum AFP (ng/ml)