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

NCT07463248 | Not Yet Recruiting Phase 2

• 1 other identifier: PROFIT
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

Advanced Hepatocellular Carcinoma; Fecal Microbiota Transplantation (FMT); PULSAR; targeted-immunotherapy; reverse drug resistance

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  PFS is defined as the time from the date of randomization until the date of disease progression according to RECIST 1.1 or death by any cause.

  From randomization to the first occurrence of disease progression or death from any cause up to approximately 24 months

Secondary Outcomes (6)

• Overall Survival (OS)

  From randomization to death due to any cause up to approximately 24 months

• Objective Response Rate (ORR)

  From date of randomization until the date of first documented progression, assessed up to 24 months

• Disease Control Rate (DCR)

  From date of randomization until the date of first documented progression, assessed up to 24 months

• Number of participants with adverse events (AEs)

  Up to 24 months

• Changes in gut microbiota indicators

  At baseline (prior to FMT), first efficacy evaluation (approximately 9 weeks post-FMT), and exit from the group

Study Arms (2)

PULSAR Combined with FMT and the Original Regimen

EXPERIMENTAL

The experimental group patients will receive PULSAR combined with FMT and the original first-line target immunotherapy regimen (Tislelizumab+TKI) as second-line treatment until disease progression, death, or intolerable toxicity occurs.

Drug: Tislelizumab Combined With TKI; Drug: Fecal Microbiota Transplantation; Radiation: PULSAR

Standard second-line treatment

ACTIVE COMPARATOR

The control group patients will receive second-line treatment with Tislelizumab combined with regorafenib until disease progression, death, or intolerable toxicity occurs.

Drug: Tislelizumab Combined With TKI

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.

PULSAR Combined with FMT and the Original Regimen; Standard second-line treatment

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 Combined with FMT and the Original Regimen

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.

Also known as: Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy

PULSAR Combined with FMT and the Original Regimen

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinically or pathologically confirmed unresectable primary hepatocellular carcinoma;
• Liver cancer patients with BCLC stage B or C;
• Not receiving systematic treatment before enrollment;
• Patients with acquired resistance who achieved disease control (DCR: CR, PR, or SD) following first-line targeted-immunotherapy but later experienced disease progression (PD);
• Child Pugh score ≤ 7 points;
• Subject must have at least 1 measurable target lesion examined by CT or MRI according to RECIST1.1 criteria;
• The Eastern Oncology Consortium (ECOG) Behavioral status score was 0 or 1.

You may not qualify if:

• 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;
• 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；
• Received abdominal radiotherapy or administered radioactive substances within 28 days prior to PD-1 monoclonal antibody re-challenge;
• History of gastrointestinal perforation and/or fistula within 6 months prior to PD-1 monoclonal antibody re-challenge;
• Active gastrointestinal bleeding within 1 week before the first fecal microbiota transplantation.
• Occurrence of infection within 28 days prior to PD-1 monoclonal antibody re-challenge;
• 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);
• Received live or attenuated vaccines within 30 days prior to PD-1 monoclonal antibody re-challenge, or planned vaccination during the study period;
• Known history of primary immunodeficiency or HIV infection;
• 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;
• Known history of active tuberculosis (TB)；
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
• Suffering from active, known or suspected autoimmune disease, or with a history of autoimmune disease;
• History of cardiovascular or cerebrovascular events or accidents within 6 months;
• Other conditions deemed by the investigator to be inappropriate for enrollment, including patients with hyperprogressive disease.

Sponsors & Collaborators

• Wang Xin: lead

Study Sites (1)

West China Hospital

Chengdu, Sichuan, 610041, China

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Fecal Microbiota Transplantation; DEAE-Dextran

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Dextrans; Glucans; Polysaccharides; Carbohydrates

Central Study Contacts

Xin Wang

CONTACT

+86 28 85423609; wangxin213@sina.com

Feng Wen

CONTACT

+86 28 85422589; 172571964@qq.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Professor

Study Record Dates

• First Submitted: February 28, 2026
• First Posted: March 11, 2026
• Study Start: March 5, 2026
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2029
• Last Updated: March 11, 2026

Record last verified: 2026-02

Locations

CN (1)