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

Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR) Combined With Fecal Microbiota Transplantation (FMT) for Reversing Resistance to First-Line Targeted-Immunotherapy in Advanced HCC: A Clinical Application Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma (HCC)
• Intervention / Treatment: Drug: Tislelizumab Combined With TKI; Drug: Fecal Microbiota Transplantation; Radiation: PULSAR

Detailed Description

Based on previous studies, the investigators aim to further explore the difference in efficacy between continuing the original targeted-immunotherapy regimen combined with FMT and PULSAR, versus standard second-line therapy, in patients with acquired resistance who experienced disease progression (PD) after achieving disease control (CR, PR or SD) with first-line targeted-immunotherapy.

The investigators will investigate whether fecal microbiota transplantation reshapes the tumor immune microenvironment by altering gut microbiota composition, and whether it can enhance immunogenicity and reverse the efficacy of immunotherapy plus TKI treatment when combined with radiotherapy. The investigators will also explore the immune-activating effect and synergistic mechanism of the PULSAR radiotherapy modality.

Primary Objective: Progression-Free Survival (PFS); Secondary Objectives: Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), incidence and severity of Adverse Events (AE), changes in gut microbiota indices, and changes in tumor immune microenvironment indices.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xin Wang; Phone Number: +86 28 85423609; Email: wangxin213@sina.com
• Study Contact Backup: Name: Feng Wen; Phone Number: +86 28 85422589; Email: 172571964@qq.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital
      • Contact: Feng Wen; Phone Number: +86 28 85422589; Email: 172571964@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PULSAR Combined with FMT and the Original Regimen; 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; 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.; Drug: Fecal Microbiota Transplantation; 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.; Radiation: PULSAR; 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.; Other Names: Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy
Active Comparator: Standard second-line treatment; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from the date of randomization until death due to any cause.	From randomization to death due to any cause up to approximately 24 months
Objective Response Rate (ORR)	ORR (per RECIST 1.1 as assessed by the Investigator) was defined as the number (%) of participants with at least 1 confirmed visit response of CR or PR until progression, or the last evaluable assessment in the absence of progression.	From date of randomization until the date of first documented progression, assessed up to 24 months
Disease Control Rate (DCR)	Number (%) of participants with CR, PR, or SD.	From date of randomization until the date of first documented progression, assessed up to 24 months
Number of participants with adverse events (AEs)	Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 5.0, vital signs, and clinical laboratory test results in the Safety Analysis Set	Up to 24 months
Changes in gut microbiota indicators	Changes in patient microbiome will be determined by analysis of gut bacterial composition in patient stool samples at baseline and post-FMT.	At baseline (prior to FMT), first efficacy evaluation (approximately 9 weeks post-FMT), and exit from the group
Changes in tumor immune microenvironment indicators	Effects on the patient immune microenvironment will be assessed by examining changes in peripheral blood immune cells （including CD3, CD4, CD8 T cells, B cells, macrophages, NK cells, Th1, Th2, Th17, and Treg cells）at baseline and post-FMT.	At baseline (prior to FMT), first efficacy evaluation (approximately 9 weeks post-FMT), and exit from the group

Collaborators and Investigators

• Sponsor: Wang Xin

Study record dates

Study Major Dates

• Study Start (Estimated): March 5, 2026
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): January 31, 2029

Study Registration Dates

• First Submitted: February 28, 2026
• First Submitted That Met QC Criteria: March 10, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Advanced Hepatocellular Carcinoma; Fecal Microbiota Transplantation (FMT); PULSAR; targeted-immunotherapy; reverse drug resistance
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Therapeutics; Carbohydrates; Polysaccharides; Glucans; Biological Therapy; Dextrans; Fecal Microbiota Transplantation; DEAE-Dextran
• Other Study ID Numbers: PROFIT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No