Neoadjuvant HAIC and PD-1 Plus Adjuvant PD-1 for High-risk Recurrent HCC

Neoadjuvant Hepatic Arterial Infusion Chemotherapy Plus Tislelizumab Combined With Adjuvant Tislelizumab in Preventing Postoperative Recurrence for High-risk Hepatocellular Carcinoma: a Prospective, Single-arm, Phase II Clinical Study

Surgical resection is the primary curative treatment for patients with hepatocellular carcinoma (HCC), with a 5-year overall survival rate of 60-80% post-surgery. Therefore, guidelines recommend surgical resection as the first-line choice for early to mid-stage HCC (CNLC stages IA-IIA or BCLC stages A/B) patients with well liver reserve function. However, the high postoperative recurrence rate is the main factor limiting long-term survival in HCC patients, with literature reporting recurrence rates exceeding 70%. Among these, half of the patients experience recurrence within two years post-surgery, imposing a heavy burden on patients' physical and mental health as well as on societal medical resources. Adopting effective treatment to improve surgical curability and reduce postoperative recurrence rates is one of the current research hotspots.

Recent studies from the investigators' center indicate that hepatic arterial infusion chemotherapy (HAIC) and immunotherapy can provide definite efficacy for patients with advanced HCC, extending their survival time. Mechanistically, chemotherapy and immunotherapy have synergistic effects: tumor cell necrosis induced by chemotherapy can promote immune activation, while cytokines and neutralizing antibodies secreted by immune cells can enhance the toxicity of chemotherapeutic drugs.

Therefore, this study aims to conduct a prospective, single-arm, phase II clinical study, targeting HCC patients with high-risk recurrence factors, to evaluate whether neoadjuvant HAIC combined with a PD-1 monoclonal antibody (Tislelizumab) followed by adjuvant Tislelizumab post-surgery can reduce postoperative recurrence rates in HCC patients. The primary endpoint is the 1-year recurrence-free survival (RFS) rate post-surgery, while secondary endpoints include the objective response rate (ORR) of neoadjuvant therapy, the incidence of perioperative complications, the incidence of treatment-related adverse events, overall survival (OS) time, pathological complete response (pCR) rate of neoadjuvant therapy, and major pathological response (MPR) of neoadjuvant therapy. The investigators aim to comprehensively assess the efficacy and safety of neoadjuvant HAIC plus PD-1 and adjuvant PD-1 in the perioperative treatment of HCC.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma; Beyond Milan Criteria
• Intervention / Treatment: Drug: Neoadjuvant HAIC and PD-1 Plus Adjuvant PD-1

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yaojun Zhang, MD, PHD; Phone Number: +8613719433968; Email: zhangyuj@sysucc.org.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Newly diagnosed and untreated hepatocellular carcinoma (clinical diagnostic criteria based on the " Chinese Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2024 Edition) " formulated by the National Health Commission of China and the Barcelona Clinic Liver Cancer (BCLC) strategy for prognosis prediction and treatment recommendation of the European Association for the Study of the Liver (EASL));
2. Tumor staging: beyond Milan criteria (single tumor >5 cm, or 2-3 tumors with the largest diameter >3 cm), resectable CNLC stage Ib/IIa hepatocellular carcinoma;
3. No tumor thrombus, distant metastasis, or lymph node metastasis;
4. Normal liver volume ≥ 700 cc, estimated residual liver volume >40% after resection;
5. Patient KPS ≥ 90;
6. Liver function Child-Pugh class A;
7. Estimated survival of more than 6 months;
8. Function of important organs meets the following requirements: white blood cells ≥ 4.0×10^9/l, neutrophils ≥ 1.5×10^9/l, platelets ≥ 80.0×10^9/l, hemoglobin ≥ 90 g/l; serum albumin ≥ 2.8 g/dl; total bilirubin ≤ 1.5 × ULN, ALT/AST/ALP ≤ 2.5 × ULN; serum creatinine ≤ 1.5 × ULN or creatinine clearance rate > 60 mL/min; no severe organic diseases;
9. The subject must be able to understand and voluntarily sign a written informed consent form, and must sign the informed consent form prior to any specific procedure of the study, agreeing to comply with the medication and postoperative follow-up requirements as designed in this study.

Exclusion Criteria:

1. Combined with severe impairment of functions of other important organs such as heart, lungs, and kidneys; active infections other than viral hepatitis or other serious comorbid conditions, making the patient unable to tolerate treatment;
2. Contraindications to surgical resection and immunotherapy;
3. History of other malignant tumors;
4. Combined with immunological diseases or other conditions requiring long-term steroid treatment;
5. Known or suspected allergy to the study drug or any drugs administered in connection with this trial;
6. History of organ transplantation;
7. Pregnant or breastfeeding women;
8. Other factors that may affect patient enrollment and assessment outcomes;
9. Refusal to follow-up according to the requirements set by the study protocol, and refusal to sign the informed consent form.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental arm; Two cycles of FOLFOX-HAIC combined with tislelizumab as neoadjuvant therapy, followed by surgical resection and four cycles of adjuvant tislelizumab.

Drug: Neoadjuvant HAIC and PD-1 Plus Adjuvant PD-1; Patients will first receive two cycles of FOLFOX-HAIC combined with tislelizumab as neoadjuvant therapy, with a 3-week interval between cycles. Two weeks after completing the neoadjuvant therapy, imaging assessments will be conducted to evaluate treatment efficacy and surgical feasibility. Surgical resection should be performed within two weeks following the imaging assessment. Four weeks post-resection, patients will undergo a follow-up evaluation to assess postoperative recovery and determine the presence of any residual tumor. If no residual or recurrent tumor is detected, adjuvant therapy with tislelizumab will commence (every three weeks, for a total of four cycles).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
recurrence free survival, RFS	RFS is defined as the time from treatment to post-resection tumor recurrence or death from any cause.	From date of treatment beginning until the date of first documented tumor recurrence or date of death from any cause, whichever came first, assessed up to 1 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate，ORR	The ratio of patients achieving the best efficacy of neoadjuvant therapy, including complete response (CR) and partial response (PR), to all patients.	From date of neoadjuvant treatment beginning until the date of neoadjuvant treatment completion, up to 1 year.
pathological complete response，pCR	The ratio of patients with no viable tumor cells in the pathology after resection to all patients undergoing surgical resection.	From date of neoadjuvant treatment beginning until the date of surgical resection completion, , up to 1 year.
overall survival, OS	OS is defined as the time from randomization to death from any cause.	From date of treatment beginning until the date of death from any cause, assessed up to 1 years.
perioperative complication rate	Perioperative complication includes intraoperative complications such as bleeding and transfusion, extensive adhesions, diaphragm resection, prolonged surgery time, etc., as well as postoperative complications such as bleeding, infection, bile leakage, liver dysfunction, etc.	The period from the start of surgery to the patient's discharge from hospital, up to 1 year.
Incidence of adverse events (safety )	Treatment-related adverse events are evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0).	From date of neoadjuvant treatment beginning until the date of adjuvant treatment completion, up to 2 year.

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Yaojun Zhang, MD, PHD, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: June 13, 2024
• First Submitted That Met QC Criteria: June 20, 2024
• First Posted (Actual): June 21, 2024

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 20, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: B2024-211-01

Drug and device information, study documents

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