FAD Subtype-Guided Combination Therapy for Unresectable Hepatocellular Carcinoma

Official title

A Prospective Phase II Study of Fatty Acid Degradation (FAD) Subtype-Guided Comprehensive Therapy for Unresectable Hepatocellular Carcinoma

Overview

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.

Detailed description

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.

Overall, this study seeks to translate metabolic phenotyping into clinical decision-making and to determine whether FAD-guided personalized therapy can improve treatment outcomes for patients with unresectable HCC.

Interventions

• Drug Camrelizumab Plus Apatinib
  Camrelizumab is administered intravenously at 200 mg every 3 weeks, and apatinib is taken orally at 250 mg once daily.
• Drug TACE Plus Camrelizumab and Apatinib
  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.

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.]

Secondary outcome measures (7)

• Objective Response Rate (ORR) by mRECIST [Time frame: From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.]
• Disease Control Rate (DCR) [Time frame: From first dose until first documented disease progression or death, whichever occurs first, assessed up to 24 months.]
• Progression-Free Survival (PFS) [Time frame: From first dose until radiographic disease progression or death, whichever occurs first, assessed up to 24 months.]
• Overall Survival (OS) [Time frame: From first dose until death from any cause, assessed up to 24 months.]
• Duration of Response (DoR) [Time frame: 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 [Time frame: Throughout study treatment, up to 24 months]
• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: From first dose through 90 days after last dose]

Eligibility criteria

Inclusion criteria

• 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 v1.1.
• 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 0-1.
• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School — Nanjing

Publications

• Li B, Wen J, Xu Z, Yan P, Han B, Yu D. Comprehensive analysis of transcriptomic biomarkers for predicting response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma. Clin Mol Hepatol. 2025 Jan;31(1):e31-e34. doi: 10.3350/cmh.2024.0628. Epub 2024 Sep 20. No abstract available. PMID 39300923
• Li B, Li Y, Zhou H, Xu Y, Cao Y, Cheng C, Peng J, Li H, Zhang L, Su K, Xu Z, Hu Y, Lu J, Lu Y, Qian L, Wang Y, Zhang Y, Liu Q, Xie Y, Guo S, Mehal WZ, Yu D. Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma. Hepatology. 2024 Feb 1;79(2):289-306. doi: 10.1097/HEP.0000000000000553. Epub 2023 Aug 7. PMID 37540187

Identifiers

NCT: NCT07314372 · FAD-HCC-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗