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| Name | Class |
|---|---|
| National Center for Tumor Diseases, Heidelberg | OTHER |
| German Cancer Research Center | OTHER |
| Heidelberg University | OTHER |
| University of Cologne |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vancomycin + A/B + FMT | Experimental |
|
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| Placebo Vancomycin + A/B + Placebo FMT | Placebo Comparator |
|
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fecal microbiota transfer | Drug | FMT via capsule (50 g of fecal matter) on day 0 and day 21. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 6 weeks after treatment initiation |
| Safety of the therapeutic combination in advanced HCC | Occurence of Adverse Events (AE) & immune-related adverse events (irAE) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| 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 |
| Name | Affiliation | Role |
|---|---|---|
| Michael T Dill, PhD | University Hospital Heidelberg, Heidelberg, Baden-Württemberg 69120 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Heidelberg | Recruiting | Heidelberg | Baden-Wurttemberg | 69120 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40930564 | Derived | Rauber C, Roberti MP, Vehreschild MJ, Tsakmaklis A, Springfeld C, Teufel A, Ettrich T, Jochheim L, Kandulski A, Missios P, Mohr R, Reichart A, Waldschmidt DT, Sauer LD, Sander A, Schirmacher P, Jager D, Michl P, Dill MT. Protocol: Faecal microbiota transfer in liver cancer to overcome resistance to atezolizumab/bevacizumab - a multicentre, randomised, placebo-controlled, double-blind phase II trial (the FLORA trial). BMJ Open. 2025 Sep 9;15(9):e097802. doi: 10.1136/bmjopen-2024-097802. |
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all IPD that underlie results in a publication
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| OTHER |
| Universitätsmedizin Mannheim | OTHER |
Interventional, randomized, placebo-controlled, double-blind, phase II with two arms (verum/placebo) in a parallel group design
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| Vancomycin Oral Capsule | Drug | Vancomycin orally (250 mg 4xd, day -3 to 0). |
|
| Atezolizumab + Bevacizumab | Drug | Atezolizumab 1200mg i.v. & Bevacizumab 15mg/kg body weight i.v. (A/B) as standard of care (SOC). |
|
|
| Placebo Vancomycin Oral Capsule | Drug | Placebo Vancomycin orally (4xd, day -3 to 0). |
|
| Placebo Fecal microbiota transfer | Drug | Placebo Fecal microbiota transfer (FMT) via capsule on day 0 and day 21. |
|
|
| 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. | 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. |
| 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. | 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. | 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. | 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) | From start until end of treatment (11 weeks). |
| Hepatic Function measured by model of end-stage liver disease (MELD) score | To evaluate the efficacy Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Hepatic function measured by model of end-stage liver disease (MELD) score (Range 6-40 points, with higher points indicating worsening of function). The hepatic function endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| Hepatic Function measured by Child-Pugh score | To evaluate the efficacy Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Hepatic function measured by Child-Pugh Score (CPS) (Range 5-15, with higher scores indicating worsening). The CPS endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| Hepatic Function measured by ALBI grade | To evaluate the efficacy Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Hepatic function measured by ALBI grade (Range 1-3, with higher scores indicating worsening). The ALBI grade endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| Hepatic Function measured by Psychometric Hepatic Encephalopathy Score (PHES) | To evaluate the efficacy Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo with respect to Hepatic function measured Psychometric Hepatic Encephalopathy Score (PHES) questionnaire (Range -15 tp +15, with higher scores indicating better cognitive function). The PHES endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| Health-related quality of life - general | To evaluate the effect of Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo in respect to Health-related quality of life. Patient reported outcomes (PRO) via are assessed by questionnaire (EORTC QLQ-C30) and are collected during treatment. Final scores are transformed such that they range from 0 to 100, where higher scores indicate greater level of symptoms. The PRO endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| Health-related quality of life - disease-specific | To evaluate the effect of Vancomycin, A/B + INTESTIFIX 001 as relative to Vancomycin-placebo, A/B + INTESTIFIX 001-placebo in respect to Health-related quality of life. Patient reported outcomes (PRO) are assessed by HCC-specific questionnaire (EORTC QLQ-HCC18) and are collected during treatment. Final scores are transformed such that they range from 0 to 100, where higher scores indicate greater level of symptoms. The PRO endpoints are the absolute scores at all assessed time points as well as the change to baseline. | From start until end of treatment (11 weeks). |
| University Hospital Augsburg | Not yet recruiting | Augsburg | 86156 | Germany |
|
| University Hospital Essen | Not yet recruiting | Essen | 45147 | Germany |
|
| University Hospital Mannheim | Not yet recruiting | Mannheim | 68167 | Germany |
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| University Hospital Regensburg | Not yet recruiting | Regensburg | 93053 | Germany |
|
| University Hospital Tübingen | Not yet recruiting | Tübingen | 72076 | Germany |
|
| University Hospital Ulm | Not yet recruiting | Ulm | 89081 | Germany |
|
| ID | Term |
|---|---|
| D006528 | Carcinoma, Hepatocellular |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008113 | Liver Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
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| ID | Term |
|---|---|
| D000069467 | Fecal Microbiota Transplantation |
| D014640 | Vancomycin |
| C000594389 | atezolizumab |
| D000068258 | Bevacizumab |
| ID | Term |
|---|---|
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D006020 | Glycopeptides |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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