Neoadjuvant SBRT Combined With Lenvatinib and Pucotenlimab for Resectable Hepatocellular Carcinoma

Phase 2Active Not RecruitingNCT06524466

Sun Yat-sen University35 enrolled

Overview

At the time of diagnosis, the majority of hepatocellular carcinoma (HCC) patients are at the intermediate to advanced stages, with a 50-70% incidence of macrovascular invasion (including portal vein, hepatic vein, inferior vena cava, or bile duct invasion). Tyrosine kinase inhibitors (TKI, including lenvatinib and sorafenib) or a combination of TKIs and immune therapy is one of the standard treatment options recommended by HCC guidelines. However, numerous retrospective studies have reported that for surgically resectable HCC with macrovascular invasion, surgical resection yields better efficacy than non-surgical treatments (including transarterial interventional therapies and/or systemic therapies). Nevertheless, the postoperative recurrence rate remains exceedingly high, exceeding 80%. Therefore, determining comprehensive approaches to enhance surgical radicality and reduce postoperative recurrence rates is a current research hotspot. Recent studies have found that neoadjuvant therapy (including immunotherapy alone or in combination with TKI) before surgery can reduce postoperative recurrence rates and extend survival rates. Moreover, SBRT combined with TKI and immunotherapy has a sensitizing effect, particularly showing good sensitivity and control rates for vascular invasion. Thus, this study aims to conduct a prospective, single-arm phase II clinical trial targeting patients with surgically resectable HCC with macrovascular invasion. The primary endpoints are objective response rate (ORR) and treatment completion rate, to evaluate the efficacy and safety of the preoperative neoadjuvant therapy with the combination of SBRT, lenvatinib, and pucotenlimab (an anti PD-1 drug). The secondary endpoints include progression-free survival (PFS), overall survival (OS), incidence of adverse events, pathological response rate, and incidence of surgical complications, to preliminarily evaluate the efficacy of the neoadjuvant therapy with this triple regimen.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Interventions

Neoadjuvant SBRT combined with Lenvatinib and PucotenlimabDRUG

SBRT: SBRT will be performed within 2-4 weeks after enrollment. The total radiation dose will be 24 Gy, delivered in 3 fractions on alternate days, to be completed within one week. Lenvatinib: 8mg/day, begin immediately after enrollment. Lenvatinib should be discontinued one week before surgery. Pucotenlimab: 200mg，3-week interval between cycles, begin immediately after enrollment, a total of four cycles of Puco treatment must be completed before surgery. Surgical resection will be performed within 10-16 weeks after the completion of SBRT.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. All patients must be pathologically confirmed to have hepatocellular carcinoma by biopsy； 2. No previous antitumor treatment; 3. Tumor number ≤ 3, diameter ≤ 10 cm, confined to one lobe of the liver or the middle lobe, evaluated by a surgeon as resectable; 4. Combined with vascular invasion, with the following extents: unilateral portal vein invasion without extending beyond the main portal vein; hepatic vein invasion not reaching the inferior vena cava; unilateral bile duct invasion not reaching the common hepatic duct; 5. No extra-hepatic metastasis or lymph node metastasis. 6. Normal liver volume ≥ 700 cc; 7. Patient KPS ≥ 90; 8. Liver function Child-Pugh class A; 9. Estimated survival of more than 6 months; 10. 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; 11. 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. Diffuse type of HCC, or tumor volume exceeding 50% of liver volume; 3. Portal vein invasion extending beyond the main tract of the portal vein, or hepatic vein invasion reaching the inferior vena cava, or bile duct invasion extending beyond the common hepatic duct; 4. Contraindications to surgical resection, SBRT and immunotherapy; 5. History of other malignant tumors; 6. Combined with immunological diseases or other conditions requiring long-term steroid treatment; 7. Known or suspected allergy to the study drug or any drugs administered in connection with this trial; 8. History of organ transplantation; 9. Pregnant or breastfeeding women; 10. Other factors that may affect patient enrollment and assessment outcomes; 11. Refusal to follow-up according to the requirements set by the study protocol, and refusal to sign the informed consent form.

Outcomes

Primary Outcomes

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.

Time frame: From date of neoadjuvant treatment beginning until the date of neoadjuvant treatment completion, up to 1 year.

treatment complete rate (TCR)

The ratio of patients completing the neoadjuvant therapy to all patients.

Time frame: From date of neoadjuvant treatment beginning until the date of neoadjuvant treatment completion, up to 1 year.

Secondary Outcomes

progression-free survival (PFS)

PFS is defined as the time from treatment to the first confirmed disease progression. For patients who undergo surgical resection, disease progression is defined as postoperative recurrence/metastasis. For patients who do not undergo surgical resection, disease progression is confirmed based on imaging assessment according to the mRECIST criteria.

Time frame: From date of neoadjuvant treatment beginning until the date of follow-up completion, up to 2 year.

overall survival (OS)

OS is defined as the time from randomization to death from any cause

Time frame: From date of neoadjuvant treatment beginning until the date of death from any cause, assessed up to 2 years.

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).

Time frame: From date of neoadjuvant treatment beginning until 3 months after treatment completion, up to 1 year.

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.

Time frame: The period from the start of surgery to the patient's discharge from hospital, 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.

Time frame: From date of neoadjuvant treatment beginning until the date of surgical resection completion, up to 1 year.