A Prospective Phase II Study of Fatty Acid Degradation (FAD) Subtype-Guided Comprehensive Therapy for Unresectable Hepatocellular Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
This study is a prospective, multicenter Phase II trial evaluating a personalized treatment strategy for patients with unresectable hepatocellular carcinoma (HCC). The study uses a metabolic classification system called the fatty acid degradation (FAD) subtype to guide therapy selection. Patients will be assigned to different treatment groups based on their tumor's FAD subtype, determined through RNA-seq analysis of the tumor tissue obtained from liver biopsy.
详细描述
This prospective, multicenter Phase II study evaluates a precision-medicine treatment strategy for unresectable hepatocellular carcinoma (HCC) using a metabolic classification system based on fatty acid degradation (FAD). Prior translational research has shown that HCC exhibits heterogeneous metabolic phenotypes, and that tumors with distinct FAD signatures demonstrate different immune microenvironments and therapeutic sensitivities. Building on these findings, this study applies FAD subtype profiling in clinical practice to guide individualized treatment selection.
All enrolled patients will undergo tumor tissue analysis for transcriptomic assessment and FAD scoring. When tumor tissue is not immediately obtainable, MRI fat-fraction measurement may be used temporarily to facilitate enrollment, with tissue-based classification performed afterward. Based on the predefined FAD subtypes (F1, F2, and F3), patients will be allocated to tailored therapeutic strategies designed to align with each subtype's metabolic and microenvironmental characteristics.
Patients with F1 or F2 subtypes will receive systemic therapy with camrelizumab and apatinib, reflecting prior evidence that these subtypes may benefit from immunotherapy combined with anti-angiogenic therapy. Patients with the F3 subtype that characterized by enhanced lipid metabolic activity will receive TACE in addition to camrelizumab and apatinib.
Treatment is delivered in 3-week cycles, with imaging assessments performed regularly to evaluate tumor response. Safety will be closely monitored throughout the study, including immunotherapy-related toxicities, anti-angiogenic drug-associated events, and TACE-related complications. After discontinuation of study treatment, participants will enter a structured follow-up schedule to monitor survival and subsequent treatments.
In addition to evaluating clinical outcomes, the study incorporates exploratory biomarker analyses, including transcriptomics, metabolomics, and imaging-based fat quantification. These analyses aim to improve understanding of how metabolic subtypes influence therapeutic response and resistance mechanisms, and to assess whether MRI-based fat fraction can serve as a noninvasive surrogate for molecular FAD classification.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults ≥18 years of age who voluntarily agree to participate and sign informed consent.
- •Histologically or cytologically confirmed hepatocellular carcinoma (HCC).
- •Unresectable or not suitable for curative local therapy, or progression after prior surgery or local therapy.
- •BCLC stage B or C.
- •No prior systemic therapy for HCC.
- •At least one measurable lesion according to RECIST v1.
- •Availability of fresh or archival tumor tissue for FAD subtype testing; if not available at screening, MRI fat fraction may be used temporarily.
- •Child-Pugh class A or B (≤7 points).
- •ECOG performance status 0-
- •Adequate organ function, including:
- •ANC ≥1.5 × 10⁹/L
- •Platelets ≥75 × 10⁹/L
- •Hemoglobin ≥90 g/L
- •Albumin ≥30 g/L
- •Total bilirubin ≤1.5 × ULN
- •ALT and AST ≤3 × ULN
- •Serum creatinine ≤1.5 × ULN or creatinine clearance >50 mL/min
- •INR ≤1.2 or PT within 2 seconds above ULN
- •Urine protein <2+ or 24-hour urine protein <1.0 g
- •Controlled HBV infection (HBV-DNA <2000 IU/mL; if above this level, ≥1 week of antiviral therapy with ≥1-log reduction prior to first dose). HCV-positive individuals must be managed per clinical guidelines.
- •Life expectancy ≥12 weeks.
- •Women of childbearing potential must have a negative pregnancy test; participants of reproductive potential must agree to effective contraception during treatment and for 6 months afterward.
排除标准
- •Non-HCC primary liver cancers (e.g., cholangiocarcinoma, combined HCC-CCA).
- •F3 subtype without liver lesions on imaging.
- •Clinically significant ascites requiring therapeutic intervention, or uncontrolled pleural/pericardial effusion.
- •Interstitial lung disease, pneumonitis requiring steroids, or active pulmonary infection.
- •Active or history of autoimmune disease requiring systemic treatment (exceptions allowed per protocol, e.g., controlled hypothyroidism).
- •Recent use (within 2 weeks) of systemic immunosuppressive therapy >10 mg/day prednisone equivalent.
- •Gastrointestinal bleeding within 6 months, high-risk varices, active ulcers, fistula, perforation, or intra-abdominal abscess.
- •Known bleeding or clotting disorders; therapeutic anticoagulation not permitted.
- •Thromboembolic events within 6 months (e.g., stroke, PE).
- •Significant cardiovascular disease, including NYHA class ≥II heart failure, recent MI (within 1 year), unstable angina, clinically significant arrhythmias, or QTc prolongation.
- •Uncontrolled hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg despite treatment), or history of hypertensive crisis.
- •Major vascular disease within 6 months (e.g., arterial thrombosis, aneurysm requiring repair).
- •Serious non-healing wounds, active ulcers, or fractures.
- •Inability to swallow oral medication or conditions affecting drug absorption.
- •Severe infection within 4 weeks, therapeutic antibiotics within 14 days, fever ≥38.5°C within 7 days before enrollment, or WBC >15 × 10⁹/L.
- •Known HIV infection or other causes of immunodeficiency.
- •Receipt of live attenuated vaccines within 28 days before treatment.
- •Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of results, including substance abuse, severe psychiatric illness, or social factors.
研究组 & 干预措施
F1/F2 Subtype: Camrelizumab Plus Apatinib
Participants whose tumors are classified as F1 or F2 based on the fatty acid degradation (FAD) subtype will receive systemic therapy with camrelizumab and apatinib. Camrelizumab is administered intravenously at 200 mg every 3 weeks, and apatinib is taken orally at 250 mg once daily. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment duration. Imaging assessments are conducted every 6 weeks to evaluate tumor response.
干预措施: Camrelizumab Plus Apatinib (Drug)
F3 Subtype: TACE Plus Camrelizumab and Apatinib
Participants with the F3 metabolic subtype, characterized by high fatty acid degradation activity, will receive transarterial chemoembolization (TACE) in addition to systemic therapy. Camrelizumab (200 mg IV every 3 weeks) and apatinib (250 mg orally once daily) are administered on the same schedule as the F1/F2 arm. TACE is performed 2-4 weeks after systemic therapy initiation, with up to two treatments per tumor (maximum four sessions total). Apatinib is paused 3-5 days before TACE and restarted 3-5 days afterward. Treatment continues until disease progression, unacceptable toxicity, or discontinuation for clinical reasons. Imaging assessments occur every 6 weeks.
干预措施: TACE Plus Camrelizumab and Apatinib (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.
ORR is defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1, as assessed by imaging every 6 weeks. ORR will be calculated separately for each FAD subtype cohort (F1/F2 and F3).
次要结局
- Objective Response Rate (ORR) by mRECIST(From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.)
- Disease Control Rate (DCR)(From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.)
- Progression-Free Survival (PFS)(From first dose until radiographic disease progression or death, whichever occurs first, assessed up to 24 months.)
- Overall Survival (OS)(From first dose until death from any cause, assessed up to 24 months.)
- Duration of Response (DoR)(From first documented response (CR or PR) until disease progression or death, whichever occurs first, assessed up to 24 months.)
- Conversion-to-Surgery or Local Ablative Therapy Rate(Throughout study treatment, up to 24 months)
- Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose through 90 days after last dose)
研究者
YU DE CAI
Professor
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School