Fecal Microbiota Transfer in Liver Cancer to Overcome Resistance to Atezolizumab/Bevacizumab – A randomized, placebo-controlled, double-blind Phase II trial (FLORA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Heidelberg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jul 2025 → ongoing

Decision date (initial)

2024-02-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

NCT funding

External identifiers

EU CT number

2023-506887-15-00

ClinicalTrials.gov

NCT05690048

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To assess immunogenicity, measured as tumoral CD8+ T cell infiltration after 2 cycles of treatment with Vancomycin, A/B + INTESTIFIX 001 in compar-ison to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo, and safety of the therapeutic combina-tion in advanced HCC.

Secondary objectives 8

1. Overall survival (OS)
2. Progression free survival (PFS)
3. Disease control (DC)
4. Objective response (OR)
5. Duration of response (DoR)
6. Alpha-fetoprotein serological response rate
7. Hepatic function
8. Health-related quality of life

Conditions and MedDRA coding

Hepatocellular carcinoma

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Subjects must be ≥ 18 years at the time of screening.
2. 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).
3. 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).
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.
8. 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).
9. Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test
10. 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
11. 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.
12. 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
13. Use of reliable contraception for women of childbearing potential and men.
14. Negative pregnancy test for women of childbearing potential
15. Ability of subject to understand character and individual consequences of clinical trial and to comply with the study protocol and dosing regimen.
16. Written informed consent (must be available before enrolment in the clinical trial)
17. Subject willing to undergo tumor biopsy. This requires a tumor lesion accessible for a biopsy.

Exclusion criteria 20

1. 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.
2. 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.
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 en-doscopy 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 investiga-tional product.
8. 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.
9. Any history of nephrotic or nephritic syndrome.
10. Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Ate-zolizumab/Bevacizumab (C1d1).
11. Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab (C1d1).
12. Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed chol-angiocarcinoma and HCC.
13. 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.
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 compet-ing 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary immunological patient variable is the count of tumor-infiltrating CD8+ T lymphocytes in the tumor biopsy after two cycles of A/B (d38). CD8+T lymphocyte density will be quantitatively assessed after manual delineation of tumor area in the biopsy (count of CD8+ cells per square millimeter tumor area). Tumor areas with crush artifacts or necrosis will be excluded from analysis.
2. Incidence and severity of AEs and SAEs from treatment start until 42 days after the fourth cycle of A/B (d105). The occurrence of AEs and SAEs is assessed for each patient, including incidence, severity, timing, seriousness, relatedness to study treatment, action taken with study medication and outcome. Detailed information is provided in section 8.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Heidelberg AöR

Sponsor organisation

Universitaetsklinikum Heidelberg AöR

Address

Im Neuenheimer Feld 672, Neuenheim Neuenheim

City

Heidelberg

Postcode

69120

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Study office

Public contact point

Organisation

Universitaetsklinikum Heidelberg AöR

Contact name

Study office

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications