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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Препарат 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.
• Лучевая терапия 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.

Первичные конечные точки

• Progression-free survival (PFS) [Срок оценки: From randomization to the first occurrence of disease progression or death from any cause up to approximately 24 months]

Вторичные конечные точки (6)

• Overall Survival (OS) [Срок оценки: From randomization to death due to any cause up to approximately 24 months]
• Objective Response Rate (ORR) [Срок оценки: From date of randomization until the date of first documented progression, assessed up to 24 months]
• Disease Control Rate (DCR) [Срок оценки: From date of randomization until the date of first documented progression, assessed up to 24 months]
• Number of participants with adverse events (AEs) [Срок оценки: Up to 24 months]
• Changes in gut microbiota indicators [Срок оценки: At baseline (prior to FMT), first efficacy evaluation (approximately 9 weeks post-FMT), and exit from the group]
• Changes in tumor immune microenvironment indicators [Срок оценки: At baseline (prior to FMT), first efficacy evaluation (approximately 9 weeks post-FMT), and exit from the group]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• West China Hospital — Чэнду

Идентификаторы

NCT: NCT07463248 · PROFIT

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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