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PULSAR Combined With Fecal Microbiota Transplantation for Advanced Hepatocellular Carcinoma Progressing After First-Line Targeted-Immunotherapy

Sponsor: Wang Xin • ClinicalTrials.gov ID: NCT07463248

Registry updated: 2026-09-02

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Description

This is an open-label, multicenter, randomized controlled Phase II trial. Patients with advanced hepatocellular carcinoma (HCC) who developed secondary resistance to first-line targeted-immunotherapy were randomly assigned to receive either the original first-line targeted-immunotherapy combined with FMT and PULSAR (experimental group), or second-line targeted-immunotherapy (control group). The first-line targeted-immunotherapy regimens consisted of tislelizumab combined with one of the first-line evidence-based tyrosine kinase inhibitors (TKIs), including lenvatinib, donafenib, apatinib, and sorafenib. Given that this study enrolled patients who progressed after an initial response to first-line targeted-immunotherapy, the second-line regimen in the control group continued tislelizumab immunotherapy while switching the TKI to regorafenib, an agent with second-line evidence.

Interventions

Tislelizumab Combined With TKI (Drug)
Tislelizumab: 200mg, intravenous infusion, once every 3 weeks, D1. Targeted therapy (TKI): first-line treatment options such as lenvatinib, donafenib, apatinib, sorafenib, etc. The second-line control group was treated with Regorafenib 80mg once a day, taken for three weeks and rested for one week. Combination therapy is administered every 21 days as a cycle until disease progression, death, or intolerable toxicity occurs.
Fecal Microbiota Transplantation (Drug)
Fecal Microbiota Transplantation (FMT): 30g, orally administered, once every 3 weeks, D-3 (3 days before systemic treatment). After the preparation of the microbiota solution or capsule, store it in a -80 ℃ refrigerator. Transfer the microbiota solution or capsule to room temperature and seal it 15 minutes before use. Fasting is required 4 hours before microbiota transplantation and 1 hour after transplantation.
PULSAR (Radiation)
PULSAR : Choose 3-5 lesions, but cannot include all newly progressing lesions (new progressing lesions must not be treated with radiotherapy to observe efficacy), once a month for 8Gy, for a total of 3-5 times.

Eligibility criteria

Key Inclusion Criteria: 1. Clinically or pathologically confirmed unresectable primary hepatocellular carcinoma; 2. Liver cancer patients with BCLC stage B or C; 3. Not receiving systematic treatment before enrollment; 4. Patients with acquired resistance who achieved disease control (DCR: CR, PR, or SD) following first-line targeted-immunotherapy but later experienced disease progression (PD); 5. Child Pugh score ≤ 7 points; 6. Subject must have at least 1 measurable target lesion examined by CT or MRI according to RECIST1.1 criteria; 7. The Eastern Oncology Consortium (ECOG) Behavioral status score was 0 or 1. Key Exclusion Criteria: 1. Failure to recover to NCI-CTC AE Grade ≤1 (excluding alopecia and fatigue) or to baseline level from toxicities and/or complications of prior interventions before PD-1 monoclonal antibody re-challenge; 2. Subjects requiring systemic therapy with corticosteroids (\>10 mg prednisone equivalent daily) or other immunosuppressive agents within 14 days prior to PD-1 monoclonal antibody re-challenge； 3. Received abdominal radiotherapy or administered radioactive substances within 28 days prior to PD-1 monoclonal antibody re-challenge; 4. History of gastrointestinal perforation and/or fistula within 6 months prior to PD-1 monoclonal antibody re-challenge; 5. Active gastrointestinal bleeding within 1 week before the first fecal microbiota transplantation. 6. Occurrence of infection within 28 days prior to PD-1 monoclonal antibody re-challenge; 7. Active infection requiring systemic antimicrobial therapy before PD-1 monoclonal antibody re-challenge and intestinal microbiota transplantation, excluding local infections requiring only topical antibiotics (e.g., skin infections); 8. Received live or attenuated vaccines within 30 days prior to PD-1 monoclonal antibody re-challenge, or planned vaccination during the study period; 9. Known history of primary immunodeficiency or HIV infection; 10. Active or previously documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea), except patients with chronic diarrhea who had no recurrence within 2 years before enrollment; 11. Known history of active tuberculosis (TB)； 12. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; 13. Suffering from active, known or suspected autoimmune disease, or with a history of autoimmune disease; 14. History of cardiovascular or cerebrovascular events or accidents within 6 months; 15. Other conditions deemed by the investigator to be inappropriate for enrollment, including patients with hyperprogressive disease.

Conditions

Hepatocellular Carcinoma (HCC)

Locations

West China Hospital — Chengdu, Sichuan, China

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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

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