Lenvatinib Combined with Tislelizumab and TACE Applied As Neoadjuvant Regimen for the Patients of CNLC Stage IB and IIA Hepatocellular Carcinoma with High-risk Recurrence Factors

Lenvatinib Combined with Tislelizumab and TACE Applied As Neoadjuvant Regimen for the Patients of CNLC Stage IB and IIA Hepatocellular Carcinoma with High Risk of Recurrence: Study Protocol of a Monocenter, Single-arm, Open Label Clincal Trail

This is a monocenter, single-arm, open-label study to evaluate the efficacy and safety of Lenvatinib combined with Tislelizumab and TACE applied as neoadjuvant regimen for the patients of CNLC stage IB and IIA hepatocellular carcinoma with high risk of recurrence Primary outcome: Major pathological response (MPR) Secondary outcomes: pathological complete response (pCR), R0 resection rate, objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAE)

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Oxaliplatin; TACE; Lenvatinib; Tislelizumab; Pharmorubicin
• Intervention / Treatment: Procedure: TACE; Drug: Tislelizumab, Lenvatinib

Detailed Description

Surgical treatment is dominant in the treatment of liver cancer, however, its postoperative recurrence rate is high, and the recurrence and metastasis rate in 5 years is as high as 70%. In particular, surgical resection for some large hepatocellular carcinoma adjacent to large vessels or located in middle areas always induces narrow and even no surgical margin, which may increase the risk of postoperative recurrence and decrease the overall survival rate. Preoperative neoadjuvant therapy for resectable hepatocellular carcinoma with high risk of recurrence is still controversial nationally and internationally, none consensus have been reached about neoadjuvant therapy.

As a classical treatment for liver cancer, TACE can induce tumor ischemia and necrosis through the infusion of chemotherapy drugs and embolic materials into target areas. However, TACE as neoadjuvant therapy alone has no improvement in tumor recurrence-free survival time and overall survival rate. Lenvatinib is a multi-target tyrosine kinase inhibitor and inhibits neovascularization and lymphangiogenesis by targeting VEGF1-3 and FGFR. moreover, lenvatinib also has immunomodulatory effects. A number of studies have shown that a variety of combination therapies have been carried out on the basis of Lenvatinib, and exciting outcome has been achieved by combined therapy regimens, including local therapy combined with systemic therapy and multi-drugs systemic therapy.

Neoadjuvant therapy will performe on CNLC stage IB and Stage IIA HCC patients with high risk of recurrence (patients with narrow or no surgical margin and preoperative tumor marker AFP+PIVKA≥1600). MPR, pCR,1-year recurrence-free survival (RFS), and treatment-related adverse reactions (TRAE) were evaluated.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yuhua Zhang, MD; Phone Number: +86-0571-88128058; Email: drzhangyuhua@126.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Recruiting
      • 1# Banshan East Rd. Zhejiang cancer hospital
      • Contact: Yuhua - Zhang, M.D.; Phone Number: +86-0571-88128058; Email: drzhangyuhua@126.com
      • Contact: Jia - Wu; Phone Number: +86-0571-88128052; Email: tkds123@qq.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Aged 18-75 years old (inclusive);
2. HCC is confirmed by preoperative pathological examination or meet the criterion of diagnosis and treatment norms of primary HCC issued by health commission, PRC. No prior systemic chemotherapy, immunotherapy, targeted therapy, or other anti-tumor treatments for HCC;
3. Patients with CNLC IB or IIA stage tumors before surgery and meeting the following conditions: radiological evaluation shows narrow or none surgical margins, and preoperative tumor markers AFP+PIVKA is greater than 1600.
4. ECOG score of 0 before the first administration of the study drug;
5. Child-Pugh scores is 5-6 points and liver function is grade A;
6. Expected survival time of at least 16 weeks;
7. Pre-administration organ function levels meet the requirements and are tolerant of surgery. The functional indicators of important organs meet the following requirements: hemoglobin ≥90g/L, neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L; aspartate aminotransferase or alanine aminotransferase ≤5 times the upper limit of normal (ULN), alkaline phosphatase ≤2.5 ULN, serum albumin ≥30g/L; serum creatinine <1.5 ULN; international normalized ratio (INR) ≤2 or prothrombin time (PT) within the upper limit of normal range ≤6 seconds; serum creatinine ≤1.5 ULN, creatinine clearance rate ≥60 mL/min.
8. Male and female participants of childbearing potential must agree to use effective contraception throughout the study period;
9. Sign an informed consent form and agree to provide previously stored tumor tissue specimens or fresh biopsy specimens of the tumor lesion.

Exclusion Criteria:

1. Pathologically diagnosed as non-hepatocellular carcinoma;
2. Previously received anti-tumor treatments such as chemotherapy, radiotherapy, radiofrequency ablation, intervention, targeted therapy, immunotherapy or surgical treatment for liver cancer (excluding previous non-tumor-related surgery or diagnostic biopsy);
3. CNLC stage is IA, IIB or worse.
4. Viral load limited to hepatitis B virus (HBV) DNA>2000 copies/ml, hepatitis C virus (HCV) RNA>1000;
5. Long-term steroid users who require long-term systemic steroid therapy (equivalent to >10 mg of prednisone per day) or any other form of immunosuppressive treatment;
6. Significant clinical bleeding or bleeding tendency within 3 months before enrollment or currently undergoing thrombolysis or anticoagulation treatment;
7. Complete intestinal obstruction and incomplete intestinal obstruction requiring treatment, but patients who have had obstruction relieved by fistula or stent placement can be enrolled;
8. Active severe clinical infection (> grade 2, NCI-CTCAE version 5.0), including active tuberculosis; history of active tuberculosis infection for more than 1 year before enrollment, not treated with regular anti-tuberculosis treatment or tuberculosis still in the active period; active known or suspected autoimmune disease;
9. Uncontrolled diabetes (fasting blood glucose ≥10 mmol/L), severe lung disease (such as acute pulmonary disease, pulmonary fibrosis that affects lung function, interstitial lung disease. Excluding recovered radiation pneumonitis);
10. Clinically significant cardiovascular disease; hypertension which cannot be well controlled by anti-hypertensive drugs (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg);
11. Patients undergoing renal replacement therapy;
12. History of other malignant tumors within the past 5 years. Excluding cured basal cell carcinoma or cervical intraepithelial neoplasia;
13. Other patients who are expected to be unable to tolerate surgical treatment;
14. Patients who have had allergic reactions to any component of the study drug;
15. Presence of alcohol dependence, mental illness, pregnancy (or lactation) or other conditions that are not suitable for clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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; TACE: pharmorubicin 30mg, oxaliplatin 50mg, cycle 4-5 week.; Tislelizumab: 200mg, cycle 3 week.; Lenvatinib: weight <60kg, 8mg/day; weight ≥60kg, 12mg/day.	Procedure: TACE; TACE: pharmorubicin 30mg, oxaliplatin 50mg, cycle 4-5 week.; Drug: Tislelizumab, Lenvatinib; Tislelizumab: 200mg, cycle 3 week. Lenvatinib: weight <60kg, 8mg/day; weight ≥60kg, 12mg/day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major pathological response	Proportion of residual tumor ingredient lesser than 30% in the postoperative pathological result.	Up to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response	None residual tumor ingredient detected in the postoperative pathological result.	Up to 16 weeks
R0 resection rate	The proportion of patients achieved a complete resection with negative margin.	Up to 16 weeks
Objective response rate (ORR)	he proportion of participants with a documented, confirmed complete response or partial response per RECIST v1.1	Up to 4 cycle treatment (each cycle is 4 weeks), an average of 16 weeks.
disease control rate (DCR)	The percentage of patients who have achieved either a complete response (CR), a partial response (PR), or stable disease (SD) after undergoing treatment for their cancer.	Up to 4 cycle treatment (each cycle is 4 weeks), an average of 16 weeks.
treatment-related adverse events (TRAE)	Adverse event that occurs during or after treatment	Up to 4 cycle treatment (each cycle is 4 weeks), an average of 16 weeks.
Recurrence-free survival (RFS)	The length of time after cancer treatment during which a patient remains free from any signs or symptoms of cancer recurrence.	Up to 4 cycle treatment (each cycle is 4 weeks), an average of 16 weeks.

Collaborators and Investigators

• Sponsor: Zhejiang Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 17, 2023
• First Submitted That Met QC Criteria: June 17, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 9, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Recurrence; Carcinoma; Carcinoma, Hepatocellular; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tislelizumab; Lenvatinib
• Other Study ID Numbers: 20230408 (Other Grant/Funding Number: Jordan University of Science and Technology)

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
• product manufactured in and exported from the U.S.: No