A Study of Neoadjuvant Tislelizumab Plus Lenvatinib in Resectable HCC at High Risk of Recurrence

Official title

Tislelizumab Plus Lenvatinib as Neoadjuvant Therapy for Patients With Resectable HCC at High Risk of Recurrence: a Prospective, Multicenter, Randomized Controlled Phase III Study

Overview

This is a prospective, multicenter, randomized controlled, phase 3 study to explore the efficacy and safety of neoadjuvant tislelizumab plus lenvatinib in patients with resectable HCC at high risk of recurrence.

Detailed description

Hepatectomy remains the primary curative treatment for HCC. However, the high rate of postoperative recurrence significantly limits long-term survival. For patients with resectable HCC at high risk of recurrence, strategies to reduce postoperative recurrence and prolong overall survival are needed. Previous studies have reported that combination regimens of immune checkpoint inhibitors plus antiangiogenic agents show promising efficacy and safety in the perioperative setting for HCC. This prospective, multicenter, randomized controlled phase 3 study aims to evaluate the efficacy and safety of neoadjuvant tislelizumab plus lenvatinib in patients with resectable HCC at high risk of recurrence.

Interventions

• Drug Tislelizumab
  Tislelizumab, 200mg, IV, q3w. Treatment will be given in 3-week cycles for a total of 2 cycles.
• Drug Lenvatinib
  Lenvatinib, 8mg for BW\<60kg or 12mg for BW≥60kg, PO, qd. Treatment will be given in 3-week cycles for a total of 2 cycles.

Primary outcome measures

• 1-year event-free survival rate [Time frame: 1 year after randomization]

Secondary outcome measures (10)

• Objective response rate [Time frame: 6 weeks after randomization]
• Disease control rate [Time frame: 6 weeks after randomization]
• Major pathologic response rate [Time frame: 10 weeks after randomization]
• 1-year recurrence-free survival rate [Time frame: 1 year after randomization]
• 2-year recurrence-free survival rate [Time frame: 2 year after randomization]
• Recurrence-free survival [Time frame: 36 months after randomization]
• Event-free survival [Time frame: 36 months after randomization]
• Overall survival [Time frame: 48 months after randomization]
• Incidence of surgery delay [Time frame: 10 weeks after randomization]
• Incidence of treatment-related adverse events(graded per CTCAE v5.0) [Time frame: 10 weeks after randomization]

Eligibility criteria

Inclusion criteria

• Voluntarily participates in this study and provides written informed consent.
• Aged 18 to 75 years, inclusive; male or female.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
• Child-Pugh class A liver function.
• China Liver Cancer (CNLC) stage Ib to IIa.
• Histologically/cytologically confirmed HCC, or clinically diagnosed primary hepatocellular carcinoma according to accepted diagnostic criteria, with lesions meeting the criteria for surgical resection as defined in the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 edition).
• At least one measurable lesion per RECIST v1.1.
• Estimated life expectancy ≥ 6 months.
• Adequate major organ function as defined below, without transfusion of any blood components or use of hematopoietic growth factors within 14 days prior to assessment:

• Hematology

• Absolute neutrophil count (ANC) ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 5.6 mmol/L (9 g/dL)
• Hepatic and renal function

• Serum creatinine (SCr) ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula)
• Total bilirubin (TBIL) ≤ 1.5 × ULN
• AST and/or ALT ≤ 2.5 × ULN
• Urine protein < 2+; if urine protein is ≥ 2+, 24-hour urine protein must be ≤ 1 g.
• Adequate coagulation function, with no active bleeding and no thrombotic disease:

• International normalized ratio (INR) ≤ 1.5 × ULN
• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
• Prothrombin time (PT) ≤ 1.5 × ULN
• Contraception requirements:

• Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during study treatment and for 6 months after the last dose; must have a negative serum or urine pregnancy test within 7 days prior to enrollment and must not be breastfeeding.
• Men with partners of childbearing potential must agree to use effective contraception during the study and for 6 months after the end of study treatment.
• Demonstrates good compliance and is able/willing to complete required follow-up.

Exclusion criteria

• Prior antitumor therapy for the current HCC, including radiotherapy, chemotherapy, concurrent chemoradiotherapy, other locoregional therapies (e.g., TACE, HAIC), or prior immunotherapy or targeted therapy.

Note: Patients who developed recurrence after prior surgery may be enrolled; if prior postoperative adjuvant therapy was given, enrollment is allowed only if ≥6 months have elapsed since completion of adjuvant therapy.

• Known cholangiocarcinoma, sarcomatoid HCC, mixed hepatocellular-cholangiocarcinoma, or fibrolamellar carcinoma; or any other active malignancy besides HCC within the past 5 years or concurrently (except cured basal cell carcinoma of the skin and cervical carcinoma in situ).
• Hypertension inadequately controlled with antihypertensive therapy (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg); or history of hypertensive crisis or hypertensive encephalopathy.
• Known hypersensitivity to macromolecular protein preparations, or known allergy to tislelizumab, lenvatinib, or any of their excipients.
• Any active autoimmune disease or history of autoimmune disease (including but not limited to autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis/colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism). Patients with vitiligo, or asthma that completely resolved in childhood and requires no intervention in adulthood, may be eligible. Patients with asthma requiring medical intervention with bronchodilators are not eligible.
• Use of immunosuppressive agents or systemic, or absorbable topical, corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) within 2 weeks prior to enrollment.
• Symptomatic ascites or pleural effusion requiring therapeutic paracentesis or drainage.
• Uncontrolled clinically significant cardiac symptoms or disease, including any of the following:

• New York Heart Association (NYHA) class > II heart failure
• Unstable angina
• Myocardial infarction within 1 year
• Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention
• Within the past 3 months, presence of gastrointestinal conditions such as esophageal varices, active gastric or duodenal ulcer, ulcerative colitis, portal hypertension, or active bleeding from an unresected tumor; or any other condition judged by the investigator to confer a risk of gastrointestinal bleeding or perforation.
• History of or current severe bleeding (within 3 months, bleeding volume >30 mL), hemoptysis (within 4 weeks, >5 mL fresh blood), or thromboembolic events within 12 months (including stroke and/or transient ischemic attack).
• Active infection, or unexplained fever >38.5°C during screening or prior to first dose (fever judged by the investigator to be tumor-related is allowed).
• Objective evidence of prior or current pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function.
• Congenital or acquired immunodeficiency, such as HIV infection.
• Receipt of a live vaccine within 4 weeks prior to study drug administration, or anticipated need for live vaccination during the study.
• Known history of psychotropic drug abuse, alcoholism, or illicit drug use.
• Anticipated inability or unwillingness to comply with required study procedures, assessments, and follow-up (including completion of standard-of-care evaluations not covered by the study), as judged by the investigator.
• Any other condition that, in the investigator's judgment, makes the subject unsuitable for the study, including factors that may lead to premature study discontinuation (e.g., other serious diseases \[including psychiatric disorders\] requiring concomitant treatment, severe laboratory abnormalities, or family/social factors that may compromise subject safety or the collection of data and specimens).

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

• Tianjin Medical University Cancer Institute & Hospital — Tianjin

Identifiers

NCT: NCT07475026 · 2512012685

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗