Fecal Microbiota Transplantation in Reversing Drug Resistance in Unresectable HCC (TALENP004)

October 13, 2024 updated by: Mao-Lin Yan, Fujian Provincial Hospital

Safety and Efficacy of Fecal Microbiota Transplantation in Reversing Drug Resistance in Patients With Intermediate-advanced Unresectable Hepatocellular Carcinoma Undergoing Transcatheter Arterial Chemoembolization Combined With Lenvatinib Plus Sintilimab.

This study aims to evaluate the safety and efficacy of fecal microbiota transplantation (FMT) in reversing drug resistance to the triple therapy regimen in patients with unresectable hepatocellular carcinoma (HCC). The triple therapy consists of transarterial chemoembolization (TACE), lenvatinib, and Sintilimab. The study is a prospective, single-arm, multicenter clinical trial involving 15 participants with mid-to-late stage HCC that has progressed despite the triple therapy. FMT capsules will be prepared by matching the gut microbiome profiles of healthy donors to those of patients who achieved complete response (CR) with the triple therapy. The primary endpoints include objective response rate (ORR), treatment-related adverse events (AEs). Secondary endpoints will assess overall survival (OS), progression-free survival (PFS), and disease control rate (DCR), changes in gut microbiome, metabolomics, and immune subsets before and after FMT.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The study is designed to investigate the potential of FMT in overcoming resistance to a combined treatment approach for HCC. The triple therapy under investigation includes TACE, lenvatinib, and a PD-1 inhibitor, which has shown promise in treating HCC but has encountered issues with drug resistance.

This prospective, single-arm, multicenter trial will enroll 15 patients diagnosed with mid-to-late stage HCC that has progressed despite treatment with the triple therapy. The primary objective is to assess the safety and efficacy of FMT in this patient population, with the primary endpoints being ORR, AEs, OS, PFS, and DCR. Secondary endpoints will evaluate the changes in the gut microbiome composition, metabolomic profiles, and immune cell subsets before and after FMT.

Eligible participants must have HCC that has progressed following the triple therapy and meet specific inclusion criteria, including having at least one measurable lesion, an expected survival time greater than three months, and no prior FMT treatment. Exclusion criteria include a history of other malignancies within the past five years, autoimmune diseases, and the use of immunosuppressive agents.

FMT capsules will be made by analyzing the gut microbiome and metabolite profiles of patients who achieved a complete response to the triple therapy, and matching these with healthy donor profiles from a biobank. Patients will receive FMT capsules daily for three days, along with the continuation of the triple therapy. The study will also include procedures for dose adjustments based on adverse events and specific guidelines for managing toxicities related to the study treatments.

The study will conclude with a comprehensive analysis of the primary and secondary endpoints. This trial aims to provide valuable insights into the role of FMT in enhancing the efficacy of cancer treatments and overcoming drug resistance in HCC.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The study population consists of adults aged 18 to 75 with unresectable hepatocellular carcinoma that has progressed after triple therapy, eligible for fecal microbiota transplantation to overcome treatment resistance.

Description

Inclusion Criteria:

  1. Patients with intermediate to advanced Hepatocellular Carcinoma (HCC) who have experienced disease progression (PD) after treatment with the triple therapy of Transarterial Chemoembolization (TACE), lenvatinib, and sintilimab.
  2. Patients must have at least one measurable lesion according to the mRECIST 1.1 criteria (the longest diameter of measurable lesions on CT/MRI scan ≥10mm).
  3. Expected survival time greater than 3 months.
  4. No prior treatment with Fecal Microbiota Transplantation (FMT).
  5. No history of taking probiotics after the diagnosis of HCC.
  6. Child-Pugh class A/B.
  7. ECOG performance status: ≤1.
  8. Age between 18 and 75 years old.
  9. No other antitumor treatments except the triple therapy before enrollment.

  10. Key organ function indicators meet the following requirements:

    Hematology: Absolute neutrophil count ≥1.5×10^9/L, Hb ≥9.0g/L, Platelets ≥75×10^9/L Liver function: Total bilirubin ≤1.5 times the upper limit of normal (ULN) (≤2.5 times ULN after biliary drainage for obstructive jaundice); Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) ≤5 times ULN, Albumin ≥30g/L Renal function: Serum creatinine ≤1.5mg/dL, Creatinine clearance rate ≥60ml/min Coagulation function: International normalized ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤1.5 times ULN

  11. No history of severe arrhythmias, heart failure, severe ventilatory dysfunction, or severe pulmonary infections.
  12. Women of childbearing age must agree to use contraceptive measures during the treatment period and for 6 months after the end of treatment, with a negative serum or urine pregnancy test within 7 days before study enrollment, and must not be breastfeeding. Men must agree to use contraceptive measures during the study period and for 6 months after the end of the study.

Exclusion Criteria:

  1. Mixed hepatocellular-cholangiocarcinoma.
  2. Severe tumor progression (tumor volume occupies two-thirds or more of the liver volume or diffuse intrahepatic lesions).
  3. History of allergy to PD-1, lenvatinib, or their components.
  4. History of other malignant tumors within the past 5 years, except for cured basal cell carcinoma of the skin, cervical carcinoma in situ, and papillary thyroid cancer.
  5. Patients who have undergone organ transplantation or are planning to undergo organ transplantation.
  6. Any active autoimmune disease or autoimmune disease with expected recurrence (such as interstitial pneumonia, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases and syndromes).
  7. History of immunodeficiency; patients who are using immunosuppressants or systemic corticosteroid therapy for immunosuppression and have continued use within 2 weeks before signing the informed consent.
  8. Known hereditary or acquired bleeding (such as coagulation disorders) or thrombotic tendencies, such as hemophilia patients; currently using or have recently (within 10 days before the start of the study treatment) used full-dose oral or injectable anticoagulants or thrombolytic drugs for therapeutic purposes (preventive use of low-dose aspirin, low molecular weight heparin is allowed).
  9. Serious infections within 4 weeks before enrollment, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc.; baseline chest imaging indicates active pulmonary inflammation, presence of infection symptoms and signs or need for oral or intravenous antibiotic treatment within 2 weeks before the first use of the study drug (excluding the use of antibiotics for prevention).
  10. Patients with mental illness; history of abuse of psychotropic drugs, alcoholism, and drug addiction.
  11. Chronic intestinal diseases (such as celiac disease, malabsorption, etc.).
  12. Pregnant or breastfeeding women.
  13. Deemed by the investigator to be unsuitable for participation in this trial for other reasons.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
FMT-Resistant HCC Cohort

The triple therapy consists of:

Transarterial Chemoembolization (TACE): This procedure will be performed every 4-6 weeks based on the presence of significant arterial blood supply to the tumor, with a maximum of 4 TACE treatments allowed.

Lenvatinib: The generic name of the drug is lenvatinib. It will be administered orally in a dosage of 12mg per day for patients weighing 60kg or more, and 8mg per day for patients weighing less than 60kg. The treatment will be continuous with a fixed daily dosing schedule.

Sintilimab: It will be given every 3 weeks (Q3W). Fecal Microbiota Transplantation (FMT): The FMT capsules will be prepared by matching the gut microbiome profiles of healthy donors with those of patients who achieved a complete response to the triple therapy. The FMT capsules will be taken orally at a dosage of 30 capsules per day for the first 3 days of each treatment cycle.

The FMT intervention will be administered in 6 cycles, with each cycle lasting for 21 days (Q3W).
Other: Fecal Microbiota Transplantation
The FMT capsules will be prepared by matching the gut microbiome profiles of healthy donors with those of patients who achieved a complete response to the triple therapy. The FMT capsules will be taken orally at a dosage of 30 capsules per day for the first 3 days of each treatment cycle. The FMT intervention will be administered in 6 cycles, with each cycle lasting for 21 days (Q3W). The duration of the treatment will be determined by the response to therapy, with a maximum of 6 cycles or until disease progression, intolerable toxicity, or participant withdrawal of consent. The FMT capsules are intended to modify the gut microbiome to reverse the resistance to the triple therapy and enhance the therapeutic response.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Objective response rate, ORR
Time Frame: Four weeks after the initiation of medication until the day before surgery
The Objective response rate (ORR) was defined as the complete response (CR) rate or the partial response (PR) rate according to RECIST1.1.
Four weeks after the initiation of medication until the day before surgery
Adverse events
Time Frame: From the initiation of medication, with recordings made whenever an adverse reaction occurs, assessed up to 12 months
Grade 1-5 AEs according to NCI-CTCAE V5.0.
From the initiation of medication, with recordings made whenever an adverse reaction occurs, assessed up to 12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall survival, OS
Time Frame: From date of enrollment until the date of death from any cause, assessed up to 60 months
The Overall survival (OS) was defined as the time between receiving treatment and observing death or loss of follow-up for any reason.
From date of enrollment until the date of death from any cause, assessed up to 60 months
Progression free survival, PFS
Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
The Progression free survival (PFS) was defined as the time between the start of treatment and the progression of intrahepatic and/or extrahepatic tumors, or the occurrence of death or loss of follow-up for any reason.
From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Disease control rate, DCR
Time Frame: Four weeks after the initiation of medication until the day before surgery
The Disease control rate (DCR) was defined as the complete response (CR) rate or the partial response (PR) rate or stable disease (SD) rate according to RECIST1.1.
Four weeks after the initiation of medication until the day before surgery
Gut Microbiome Composition after Fecal Microbiota Transplantation
Time Frame: Baseline and at the end of each treatment cycle (up to 6 cycles)
The changes in the gut microbiome composition before and after FMT treatment, including diversity and similarity to the donor microbiome.
Baseline and at the end of each treatment cycle (up to 6 cycles)
Gut Microbiome Metabolomic Changes after Fecal Microbiota Transplantation
Time Frame: Baseline and at the end of each treatment cycle (up to 6 cycles)
The changes in serum and fecal metabolomics before and after FMT.
Baseline and at the end of each treatment cycle (up to 6 cycles)
Gut Microbiome Immune Subset Variations after Fecal Microbiota Transplantation
Time Frame: Baseline and at the end of each treatment cycle (up to 6 cycles)
The changes in immune cell subsets before and after FMT.
Baseline and at the end of each treatment cycle (up to 6 cycles)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fujian Provincial Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 11, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 13, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 16, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 16, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 13, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • TALENP004

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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