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

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.

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.

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.