Safety and Efficacy of Lenvatinib and Anti-PD1 Antibody Combined With Radiotherapy Neoadjuvant Treatment for Resectable Hepatocellular Carcinoma With PVTT

Study Overview
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Brief Summary
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Patients with hepatocellular carcinoma with PVTT can benefit from surgical resection and radiotherapy. As the rapid development of systematic treatment in hepatocellular carcinoma, ICIs neoadjuvant therapy is being actively explored .But there is no evidence to prove the safety and efficacy of lenvatinib and anti-PD1 antibody combined with radiotherapy neoadjuvant treatment for resectable hepatocellular carcinoma with PVTT. This study intends to supplement the evidence of benefit in such patients.

Official Title
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Safety and Efficacy of Lenvatinib and Anti-PD1 Antibody Combined With Radiotherapy Neoadjuvant Treatment for Resectable Hepatocellular Carcinoma With PVTT,Prospective, Multicenter, Single-arm Study

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sintilimab
* Drug: Lenvatinib
* Radiation: radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-70, with no gender limitation; HCC patients who strictly met the clinical diagnostic criteria of The Code for The Diagnosis and Treatment of Primary Liver Cancer (2019 edition) or were confirmed by histopathological or cytological examination; BCLC stage C, no distant metastasis; Patients with PVTT of type VP1-2-3-4 according to Japanese VP Classification; The primary tumor can be resected (the remaining liver has complete vascular structure and sufficient liver volume, in line with the decision-making system of safe liver resection) ECOG score 0-1; Child-Pugh score ≤7; If the patient is HBV antigen positive, HBV DNA < 500 IU/ mL, conventional antiviral treatment; The major organs meeting the following criteria: Adequate bone marrow function, defined as: Absolute neutrophil count (ANC ≥ or equal to 1.5 X 10 ^ 9 per liter (/ L)) Hemoglobin (Hb ≥ 8.5 g/dL) Platelet count ≥ 75×10 ^ 9 / L. Adequate liver function, defined as: Albumin > 2.8 g/dL Bilirubin is 3.0 mg/dL or less Aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) are less than or equal to 5 ULN. Adequate coagulation function, defined as an international standardized ratio ( (INR) of 2.3 or less. Adequate renal function was defined as creatinine clearance greater than 40 mL/min (mL/min), calculated according to the Cockcroft and Gault formulas. Adequate pancreatic function, defined as amylase and lipase. = 1.5 x ULN. Adequate control of blood pressure (BP) with up to 3 antihypertensive drugs, defined as BP-lt at screening time; = 150/90 mmHg (mmHg), and there was no change in antihypertensive therapy 1 week prior to cycle 1 / day 1. Patients are expected to survive longer than 3 months. No pregnancy or pregnancy plan. Subjects voluntarily joined the study and signed informed consent with good compliance and follow-up. Exclusion Criteria: Extrahepatic metastasis of primary hepatocellular carcinoma; Diffuse liver cancer; Patients who had previously received targeted drugs or immune checkpoint inhibitors; allergic to Lenvatinib or PD-1 inhibitor ingredients; Patients with grade II or higher myocardial ischemia or myocardial infarction and poorly controlled arrhythmias (including QTc interval ≥470 ms); Patients with grade III   IV cardiac insufficiency according to NYHA standard, or left ventricular ejection fraction (LVEF) < 50% as indicated by color doppler echocardiography; abnormal coagulation function (INR > 1.5 or prothrombin time (PT) > ULN+4 seconds or APTT &gt; 1.5ULN), with bleeding tendency or receiving thrombolytic or anticoagulant therapy; pregnant or breast-feeding women; Fertile patients unwilling or unable to take effective contraceptive measures; have a history of mental illness or abuse of psychotropic drugs; patients with co-HIV infection; a history of liver resection, liver transplantation, interventional therapy, and other malignant tumors; patients with active infection; contraindications to radiotherapy; Patients with poor compliance such as floating population; participants in clinical trials of other experimental drugs or devices within 4 weeks; those considered unsuitable for inclusion by the researcher.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sintilimab+Lenvatinib+Radiotherapy<br> | Drug: Sintilimab<br>* Sintilimab will be at a dose of 200mg,Q3W<br>Drug: Lenvatinib<br>* On the first day of the trial, Lenvatinib will be taken orally once daily （8mg/day ≤ 60kg or 12mg/day ≥60kg).<br>Radiation: radiotherapy<br>* Radiotherapy will be completed within two weeks at a dose of 300cGy× 10 fraction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety(CTCAE v5.0) | Number of patients who reported incidence of grade ≥3 treatment related adverse events. | up to 5 years | 
| Number of patients who complete pre-op treatment and proceed to surgery | Number of patients who complete pre-op treatment and proceed to surgery | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response(MPR) | Survival tumor ≤10% during surgery | Within 3 months after surgery | 
| Objective Response Rate(ORR) | Efficacy included objective response (includes complete and partial response) according to modified RECIST 1.1 for HCC | within 1 week before surgery | 
| Imaging-pathology Concordance Rate | Imaging-pathology Concordance Rate | Within 3 months after surgery | 
| PVTT regression rate | The fading rate of PVTT | Within 3 months after surgery | 
| Median Overall survival(mOS) | mOS is defined as the median difference (in months) between the date of study enrollment to the date death due to any cause | up to 5 years | 
| Recurrence free survival(RFS) | From radical resection to the date of the first documented tumor into recurrence or death from any cause, whichever occurred first | 1 year after surgery |