TACE or Ablation Combined With Sintilimab and Ipilimumab N01 as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma With Intermediate-High Recurrence Risk (ACTION-001)

TACE or Ablation Combined With Sintilimab and Ipilimumab N01 as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma With Intermediate-High Recurrence Risk: A Multicenter, Multigroup, Randomized, Phase Ⅱ Exploratory Clinical Trial

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The recurrence rate after curative resection for early-stage HCC remains extremely high, with 2-year and 5-year recurrence rates reaching 50% and 70%, respectively. Currently, no standard perioperative treatment is recommended in domestic and international guidelines.

Recently, data from a phase III clinical study, investigating neoadjuvant and adjuvant therapy with camrelizumab plus apatinib in resectable HCC patients at intermediate-to-high risk of recurrence, demonstrated that the neoadjuvant and adjuvant therapy combining targeted therapy and immunotherapy could significantly reduce postoperative recurrence. The median recurrence-free survival (RFS) in the target-immunotherapy group was 42.1 months, which was remarkably longer than 19.4 months in the surgery-alone group.

Local therapies (TACE, ablation) can induce immunogenic cell death of tumors and remodel the tumor microenvironment, thereby exerting synergistic effects with immunotherapy. This strategy is expected to further improve recurrence-free survival in HCC patients after surgery.

This clinical trial aims to explore the efficacy and tolerability of the following regimens compared with surgery alone:

1. TACE or ablation combined with anti-CTLA-4 and anti-PD-1 immunotherapy;
2. TACE or ablation combined with anti-CTLA-4 + anti-PD-1 + lenvatinib;
3. Dual immunotherapy with anti-CTLA-4 and anti-PD-1;
4. Anti-CTLA-4 + anti-PD-1 + lenvatinib. Efficacy differences between groups will be compared using Bayesian statistical methods based on non-informative priors.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepato Cellular Carcinoma (HCC)
• Intervention / Treatment: Drug: sintilimab; Drug: ipilimumab N01; Procedure: TACE; Procedure: ablation; Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Estimated): 105
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ming Ming; Phone Number: +86 020-87755766; Email: kuangm@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1) Age: 18-75 years old; 2) Patients with hepatocellular carcinoma (HCC) classified as CNLC stage Ib-IIIa (excluding patients with Vp3 and Vp4), and deemed resectable by multidisciplinary team (MDT) discussion;

  3) No prior tumor-related treatment received;

  4) At least one measurable target lesion according to the RECIST 1.1 criteria;

  5) ECOG PS score of 0-1;

  6) Liver function classification: Child-Pugh Class A;

  7) Estimated survival time ≥ 12 weeks;

  8) Hematological, liver, and renal functions meet the following criteria:

  1. Hemoglobin concentration ≥ 90 g/L;
  2. Neutrophil count ≥ 1.5 × 10⁹/L;
  3. Platelet count ≥ 75 × 10⁹/L;
  4. Total bilirubin ≤ 1.5 × ULN (Upper Limit of Normal);
  5. AST and ALT < 5 × ULN; ALP < 4 × ULN;
  6. Creatinine ≤ 1.5 × ULN;
  7. INR ≤ 1.5 × ULN; APTT ≤ 1.5 × ULN;

  8. Serum albumin concentration ≥ 30 g/L;

     9) Women of childbearing age must be excluded from pregnancy;

     10) For patients with other concurrent malignant tumors, MDT discussion must confirm that the history and treatment history of other tumors will not interfere with the efficacy and safety evaluation of this study protocol;

     11) Ability to understand and sign the informed consent form.

     Exclusion Criteria:

• 1) Prior history of HCC treatment; 2) Tumor rupture and bleeding, or suspected peritoneal metastasis;

  3) History of other complex surgeries within 6 weeks;

  4) Prior history of organ transplantation;

Currently receiving treatment in other clinical trials;

5) Prior history of autoimmune diseases, inflammatory disorders (such as inflammatory bowel disease, etc.), diverticulitis, systemic lupus erythematosus, sarcoidosis syndrome, Wegener's syndrome (granulomatosis with polyangiitis, rheumatoid arthritis, etc.), except for the following cases: vitiligo or alopecia areata, hypothyroidism with stable condition after drug replacement therapy, chronic skin diseases that do not require systemic treatment, and celiac disease controllable by diet alone;

6) Prior history of allergy to anti-PD1 drugs or anti-CTLA4 drugs, or allergy to chemical molecules similar to the above drugs, or prior severe allergic reaction to other monoclonal antibodies;

7) Uncontrollable intermittent recurrent diseases, including but not limited to: persistent infections (including tuberculosis), hypertension uncontrollable by drugs (> 140/90 mmHg), interstitial lung disease, severe chronic gastrointestinal diseases complicated with diarrhea, mental illness or social disorders that cannot comply with clinical research requirements, factors with high risk of side effects, and inability to sign the informed consent form;

8) Patients with prior hepatic encephalopathy, refractory ascites, or esophagogastric varices with high bleeding risk; patients with upper gastrointestinal bleeding within 1 year before the first administration;

9) Untreated active hepatitis B subjects (HBsAg positive and HBV-DNA exceeding 5000 copies/mL (1000 IU/mL) or higher than the lower limit of detection, whichever is higher); for subjects with hepatitis B, anti-hepatitis B virus treatment is required during the study treatment; active hepatitis C subjects (HCV antibody positive and HCV-RNA level higher than the lower limit of detection);

10) Patients with primary brain tumors (except meningiomas or other benign brain tumors), or any brain metastases, leptomeningeal carcinomatosis, epilepsy uncontrollable by conventional drugs, or new-onset stroke within 1 year;

11) Primary immunodeficiency disease;

12) Prior positive HIV test or acquired immunodeficiency syndrome (AIDS);

13) Use of immunosuppressive drugs within 14 days before the start of study treatment. The following situations are exempt:

1. Intranasal, inhaled, topically used steroids or local steroid injections;
2. Systemic application of corticosteroids not exceeding the physiological dose (e.g., 10 mg/day prednisone or its equivalent);

3. Steroid application for the treatment of allergic reactions;

   14) Vaccination with live-attenuated vaccines within 30 days before the start of study treatment. Note: Live-attenuated vaccines should also be avoided during the study treatment and within 30 days after the end of treatment;

   15) Receipt of systemic immunostimulant treatment within the prior 4 weeks;

   16) Prior history of severe systemic diseases, including: myocardial infarction or unstable angina pectoris, hypertensive crisis or hypertensive encephalopathy, congestive heart failure of NYHA Class II or above, unstable symptomatic arrhythmia requiring drug intervention, severe vascular disease or symptomatic peripheral vascular disease, occurring within 12 months before the start of study treatment;

   17) History of coagulative, hemorrhagic or thrombotic diseases within 12 months before the start of study treatment;

   18) Severe, irreversible trauma, ulcers or fractures;

   19) Pregnant or lactating women, or subjects planning to have children during the trial period;

   20) Dependent on parenteral nutrition to maintain life;

   21) Other acute or chronic diseases, mental and psychological diseases, etc., which are not suitable for participating in this study, as judged by the researcher.

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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TACE/ablation+ anti-CTLA-4+anti-PD-1 therapy; Patients in this trial group will receive two cycles of neoadjuvant therapy with sintilimab combined with ipilimumab N01, administered every 3 weeks (q3w). One week after the first cycle of treatment, the multidisciplinary team (MDT) will determine to perform either TACE or ablation according to the lesion status. Surgical treatment will be performed 2 weeks after the completion of the second cycle of neoadjuvant drug therapy. Adjuvant therapy with sintilimab will be initiated 4 weeks postoperatively, given every 3 weeks for a maximum of 15 cycles.	Drug: sintilimab; 200mg ivdrip q3w; Drug: ipilimumab N01; 3mk/kg ivdrip q3w; Procedure: TACE; TACE will be performed in accordance with the standard procedures of the respective medical centers.Based on the judgment of the MDT team, patients with at least one lesion amenable to complete ablation will receive ablation therapy.Patients without any lesion amenable to complete ablation will receive TACE therapy.; Procedure: ablation; Ablation will be performed in accordance with the standard procedures of the respective medical centers.Based on the judgment of the MDT team, patients with at least one lesion amenable to complete ablation will receive ablation therapy.Patients without any lesion amenable to complete ablation will receive TACE therapy.
Experimental: TACE/ablation+ anti-CTLA-4+anti-PD-1+lenvatinib therapy; Patients in this trial group will receive two cycles of neoadjuvant therapy with sintilimab combined with ipilimumab N01 and lenvatinib, administered every 3 weeks (q3w). One week after the first cycle of treatment, the multidisciplinary team (MDT) will determine to perform either TACE or ablation according to the lesion status. Surgical treatment will be performed 2 weeks after the completion of the second cycle of neoadjuvant drug therapy. Adjuvant therapy with sintilimab and lenvatinib will be initiated 4 weeks postoperatively, given every 3 weeks for a maximum of 15 cycles.	Drug: sintilimab; 200mg ivdrip q3w; Drug: ipilimumab N01; 3mk/kg ivdrip q3w; Procedure: TACE; TACE will be performed in accordance with the standard procedures of the respective medical centers.Based on the judgment of the MDT team, patients with at least one lesion amenable to complete ablation will receive ablation therapy.Patients without any lesion amenable to complete ablation will receive TACE therapy.; Procedure: ablation; Ablation will be performed in accordance with the standard procedures of the respective medical centers.Based on the judgment of the MDT team, patients with at least one lesion amenable to complete ablation will receive ablation therapy.Patients without any lesion amenable to complete ablation will receive TACE therapy.; Drug: Lenvatinib; 8mg P.O QD
Experimental: anti-CTLA-4+anti-PD-1 therapy; Patients in this trial group will receive two cycles of neoadjuvant therapy with sintilimab combined with ipilimumab N01, administered every 3 weeks (q3w). Surgical treatment will be performed 2 weeks after the completion of the second cycle of neoadjuvant drug therapy. Adjuvant therapy with sintilimab will be initiated 4 weeks postoperatively, given every 3 weeks for a maximum of 15 cycles.	Drug: sintilimab; 200mg ivdrip q3w; Drug: ipilimumab N01; 3mk/kg ivdrip q3w
Experimental: anti-CTLA-4+anti-PD-1+lenvatinib therapy; Patients in this trial group will receive two cycles of neoadjuvant therapy with sintilimab combined with ipilimumab N01 and lenvatinib, administered every 3 weeks (q3w). Surgical treatment will be performed 2 weeks after the completion of the second cycle of neoadjuvant drug therapy. Adjuvant therapy with sintilimab and lenvatinib will be initiated 4 weeks postoperatively, given every 3 weeks for a maximum of 15 cycles.	Drug: sintilimab; 200mg ivdrip q3w; Drug: ipilimumab N01; 3mk/kg ivdrip q3w; Drug: Lenvatinib; 8mg P.O QD
No Intervention: Surgery alone; Patients in this trial arm will undergo resection within 7 days after randomization, followed by regular postoperative follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-year recurrence-free survival rate	The proportion of subjects who did not experience tumor recurrence or death within 1 year after surgery.	One year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
major pathological response rate, MPR rate	The proportion of patients with histologically confirmed tumor necrosis of more than 90% in the surgically resected specimens.	5 weeks
Objective response rate, ORR	The proportion of patients who achieve complete response (CR) and partial response (PR) in tumor assessment according to the RECIST 1.1 criteria after neoadjuvant therapy and before surgical resection.	5 weeks
Adverse Events, AE	The proportion of patients who experienced grade ≥3 hematological or non-hematological adverse events from the start of treatment to the end of follow-up.	One year

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Innovent Biologics (Suzhou) Co. Ltd.

Publications and helpful links

General Publications

• Wang Z, Fan J, Zhou S, Sun Y, Liang F, Ji Y, Gu F, Li T, Peng L, Peng T, Huang X, Ding Z, Bai D, Xiang B, Tan G, Wen T, Zeng Y, Han F, Zhang Y, Wu S, Zhao H, Chen Y, Shi G, Hou Z, Sun Y, Zhu W, Zhou J. Perioperative camrelizumab plus rivoceranib versus surgery alone in patients with resectable hepatocellular carcinoma at intermediate or high risk of recurrence (CARES-009): a randomised phase 2/3 trial. Lancet. 2025 Nov 1;406(10515):2089-2099. doi: 10.1016/S0140-6736(25)01720-9. Epub 2025 Oct 19.
• Llovet JM, De Baere T, Kulik L, Haber PK, Greten TF, Meyer T, Lencioni R. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 May;18(5):293-313. doi: 10.1038/s41575-020-00395-0. Epub 2021 Jan 28.
• Vogel A, Chan SL, Dawson LA, Kelley RK, Llovet JM, Meyer T, Ricke J, Rimassa L, Sapisochin G, Vilgrain V, Zucman-Rossi J, Ducreux M; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025 May;36(5):491-506. doi: 10.1016/j.annonc.2025.02.006. Epub 2025 Feb 20. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): March 18, 2026
• Primary Completion (Estimated): March 17, 2028
• Study Completion (Estimated): March 17, 2028

Study Registration Dates

• First Submitted: March 17, 2026
• First Submitted That Met QC Criteria: March 17, 2026
• First Posted (Actual): March 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: sintilimab; lenvatinib
• Other Study ID Numbers: ACTION-001; IIT-2026-010 (Other Identifier: the First Affliated Hospital of Sun Yat-sen University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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