EDN Combined With TACE/HAIC and Second-Line Immune-Targeted Treatment Versus TACE/HAIC Alone in Locally Advanced HCC With Portal Vein Tumor Thrombosis After First-Line Therapy Failure: A Prospective, Multicenter, Randomized Controlled Trial

Official title

Evaluating Endervascular Denervation (EDN) Combined With Transarterial Intervention (TACE/HAIC) and Second-Line Immune-Targeted Therapy in Locally Advanced Hepatocellular Carcinoma (HCC) With Portal Vein Tumor Thrombosis After Progression on First-Line Systemic Therapy: A Prospective, Multicenter, Randomized Controlled Study

Overview

The goal of this clinical trial is to evaluate the efficacy and safety of combining endovascular denervation (EDN) with transarterial chemoembolization/ hepatic arterial infusion chemotherapy (TACE/HAIC) plus second-line immune-targeted therapy in patients with locally advanced hepatocellular carcinoma (HCC) who have progressed after first-line systemic therapy and present with portal vein tumor thrombus (PVTT). The main questions this study aims to answer are: Does the addition of EDN to standard TACE/HAIC and immune-targeted therapy improve intrahepatic progression-free survival (hPFS) based on RECIST 1.1 criteria? What is the safety profile of the combined treatment, including device-related adverse events? Researchers will compare the experimental group (EDN + TACE/HAIC + immune-targeted therapy) with the control group (TACE/HAIC + immune-targeted therapy alone) in a 1:1 randomized design. A total of 62 participants will be enrolled across 8 centers, with an expected enrollment period of 12 months and a 12-month follow-up period. Participants will: Undergo screening assessments including imaging (CT/MRI), blood tests, and ECG within specified time windows. Receive assigned interventions (EDN procedure or control) during the baseline visit (Day 0). Attend follow-up visits at 1 month (±7 days), 3 months (±14 days), 6 months (±30 days), 9 months (±30 days), and 12 months (±30 days) for repeated imaging, laboratory tests, and safety evaluations. Have their tumor response, survival outcomes, and adverse events monitored throughout the study.

Interventions

• Combination product EDN combined with TACE/HAIC and Immuno-Targeted Therapy
  Experimental Intervention (Treatment Group): This arm evaluates a novel combination strategy. Participants will undergo a single session of Endovascular Denervation (EDN) in conjunction with standard care. The complete intervention includes: Endovascular Denervation (EDN): A one-time, catheter-based percutaneous procedure for the ablation of peri-arterial sympathetic nerves surrounding the common hepatic artery and/or proper hepatic artery. The procedure utilizes a multi-electrode radiofrequen
• Combination product TACE/HAIC plus Immuno-Targeted Therapy
  This is the active comparator intervention representing the current standard-of-care regimen for the study population. Participants randomized to the control group will receive a combination of locoregional and systemic therapy, specifically excluding the experimental Endovascular Denervation (EDN) procedure.

Primary outcome measures

• hPFS [Time frame: From date of randomization until the date of first documented intrahepatic progression or date of death from any cause, whichever comes first, assessed up to 12 months.]

Secondary outcome measures (6)

• ORR [Time frame: From date of randomization until the first documented objective response (CR or PR), assessed up to 12 months.]
• OS [Time frame: From date of randomization until date of death from any cause, assessed up to 12 months.]
• PFS [Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.]
• DCR [Time frame: From date of randomization until the first documented objective response (CR or PR) or stable disease (SD), assessed up to 12 months.]
• MAE [Time frame: From the time of the baseline procedure (ablation surgery) through 30 days post-procedure]
• SAEs [Time frame: From date of randomization until the end of study visit at 12 months.]

Eligibility criteria

Inclusion criteria

• Aged 18 to 75 years (inclusive), regardless of gender.
• Diagnosis of CNLC Stage IIIa HCC with portal vein tumor thrombus (vp type 1-3) confirmed by histopathology, cytology, or imaging.
• Progression of disease after first-line systemic therapy.
• At least one measurable lesion according to RECIST 1.1 criteria.
• Child-Pugh class A or B.
• ECOG performance status of 0 to 2.
• Scheduled to undergo TACE or HAIC treatment.
• Adequate hematological, hepatic, and renal function within 14 days prior to study initiation, defined as:

White blood cell count ≥2.0×10⁹/L AND neutrophil count ≥1.0×10⁹/L. Platelet count ≥60×10⁹/L. Hemoglobin concentration ≥90 g/L. Total bilirubin ≤2.0 × upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN. Albumin ≥2.8 g/dL. International normalized ratio (INR) ≤1.6. Creatinine ≤1.5 × ULN AND calculated creatinine clearance ≥30 mL/min.

Exclusion criteria

• Preoperative abdominal CT or MR enhanced scan suggests celiac trunk anatomy is unsuitable for EDN procedure.
• History of orthostatic hypotension.
• Diffuse liver tumors or extensive extrahepatic metastases with an expected survival of <3 months.
• Cachexia or multi-organ failure.
• Severe hepatic dysfunction (Child-Pugh class C).
• Uncorrectable coagulation dysfunction.
• Presence of severe concurrent infection.
• Accompanied by Vp4 type portal vein tumor thrombus.
• Abnormal blood supply to the target lesion that precludes transarterial interventional therapy.
• History of bilioenteric anastomosis within the past year.
• Severe allergy to known contrast agents or embolization materials.
• Pregnant or lactating women, or individuals with childbearing potential planning pregnancy during the trial period.
• Clinically significant (e.g., active) cardiovascular disease, including:

Unstable angina within ≤6 months prior to randomization. New York Heart Association (NYHA) class ≥II congestive heart failure. Poorly controlled arrhythmia despite medication (patients with controlled atrial fibrillation are eligible), or any clinically significant abnormality found on resting ECG.

≥Grade 3 peripheral vascular disease (e.g., symptomatic and interfering with activities of daily living, requiring intervention).

Transient ischemic attack or subarachnoid hemorrhage within 6 months prior to randomization, or participation in other drug or device clinical trials within 3 months.

• History of other malignancies within the past 5 years or concurrent other malignancies.
• Any other condition deemed by the investigator as unsuitable for participation in this study.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Zhongda Hospital Affiliated to Southeast University, Department of Interventional and Vasc — Nanjing

Publications

• Shi DD, Guo JA, Hoffman HI, Su J, Mino-Kenudson M, Barth JL, Schenkel JM, Loeffler JS, Shih HA, Hong TS, Wo JY, Aguirre AJ, Jacks T, Zheng L, Wen PY, Wang TC, Hwang WL. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. Lancet Oncol. 2022 Feb;23(2):e62-e74. doi: 10.1016/S1470-2045(21)00596-9. PMID 35114133
• Chang A, Botteri E, Gillis RD, Lofling L, Le CP, Ziegler AI, Chung NC, Rowe MC, Fabb SA, Hartley BJ, Nowell CJ, Kurozumi S, Gandini S, Munzone E, Montagna E, Eikelis N, Phillips SE, Honda C, Masuda K, Katayama A, Oyama T, Cole SW, Lambert GW, Walker AK, Sloan EK. Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer. Sci Transl Med. 2023 Apr 26;15(693):eadf114 PMID 37099632
• Mancusi R, Monje M. The neuroscience of cancer. Nature. 2023 Jun;618(7965):467-479. doi: 10.1038/s41586-023-05968-y. Epub 2023 Jun 14. PMID 37316719
• Silverman DA, Martinez VK, Dougherty PM, Myers JN, Calin GA, Amit M. Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk. Cancer Res. 2021 Mar 15;81(6):1431-1440. doi: 10.1158/0008-5472.CAN-20-2793. Epub 2020 Dec 17. PMID 33334813
• Miller BM, Oderberg IM, Goessling W. Hepatic Nervous System in Development, Regeneration, and Disease. Hepatology. 2021 Dec;74(6):3513-3522. doi: 10.1002/hep.32055. Epub 2021 Aug 15. PMID 34256416
• Fu Y, Shen K, Wang H, Wang S, Wang X, Zhu L, Zheng Y, Zou T, Ci H, Dong Q, Qin LX. Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis. Signal Transduct Target Ther. 2024 Mar 8;9(1):63. doi: 10.1038/s41392-024-01761-z. PMID 38453934
• Cui Q, Jiang D, Zhang Y, Chen C. The tumor-nerve circuit in breast cancer. Cancer Metastasis Rev. 2023 Jun;42(2):543-574. doi: 10.1007/s10555-023-10095-1. Epub 2023 Mar 31. PMID 36997828
• Globig AM, Zhao S, Roginsky J, Maltez VI, Guiza J, Avina-Ochoa N, Heeg M, Araujo Hoffmann F, Chaudhary O, Wang J, Senturk G, Chen D, O'Connor C, Pfaff S, Germain RN, Schalper KA, Emu B, Kaech SM. The beta1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature. 2023 Oct;622(7982):383-392. doi: 10.1038/s41586-023-06568-6. Epub 2023 Sep 20. PMID 37731001

Identifiers

NCT: NCT07187284 · 2025ZDSYLL382-P01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗