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

Summary

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.

Eligibility

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.

Conditions4

Interventions2

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