HAIC Combined With Second-line "Target Immunity" for HCC With TACE Standard Treatment Low Response or Failure

HAIC Combined With Second-line "Target Immunity" for Advanced Hepatocellular Carcinoma With Low Response or Failure of TACE Combined With First-line "Target Immunity": A Prospective, Randomized- Control, Multicenter Clinical Trial

This study is a prospective, randomized controlled, multicenter clinical study. The purpose of this study is to explore the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with second-line regorafenib and immune checkpoint inhibitors in the treatment of transarterial chemoembolization (TACE) combined with first-line molecular targeted drugs and immune checkpoint inhibitors with low response or failure in advanced hepatocellular carcinoma.

This is a randomized, open, parallel-controlled, multi-center clinical trial with a type of comparison using a merit test. This study will recruit 176 patients with advanced liver cancer who have received TACE combined with first-line "target immune" therapy and were rated as low response or treatment failure according to mRECIST criteria in multiple research centers across the country. Subjects randomly assigned to the experimental group will receive HAIC in combination with regorafenib and immune checkpoint inhibitors, and subjects randomly assigned to the control group will receive TACE in combination with regorafenib and immune checkpoint inhibitors.

Inclusion Criteria:

• Voluntarily participate in this study and sign the informed consent;
• Age ≥18 years old to 70 years old;
• Patients diagnosed with primary liver cancer by histopathology, cytology or imaging;
• The China liver cancer staging is IIb-IIIa;
• Patients with intermediate and advanced liver cancer who must receive at least one cycle of TACE combined with first-line "target immune" therapy and are assessed as partial remission (PR), stable disease (SD）(low response), and progressive disease (PD) (failure) according to mRECIST criteria;
• At least one measurable (based on RECIST 1.1 criteria and mRECIST criteria) lesions, tumor lesions located at the local treatment site, if progressed, considered measurable;
• Local treatment (surgery, radiotherapy, radiofrequency/microwave ablation, cryoablation, percutaneous ethanol injection) can be used in the past, but it must be completed before 3 months;
• ECOG PS score ≤ 2;
• Child-Pugh liver function classification: grade A/B (≤9 points);
• Expected survival > 3 months;
• Patients with active hepatitis B virus (HBV) infection: HBV DNA ≤2000 IU/mL (104 cps/ml) obtained within 28 days prior to initiation of study treatment, and receiving anti-HBV treatment for at least 14 days prior to study entry (based on local standard treatment) and willing to continue to receive treatment during the study;

Exclusion Criteria:

• Have received HAIC treatment in the past;
• Known allergy to possible therapeutic drugs;
• Previously received regorafenib treatment;
• According to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), the toxicity grade caused by TACE combined with first-line "target immunity" treatment is > grade 3;
• Patients with liver decompensation, including esophageal or gastric variceal bleeding or hepatic encephalopathy, pregnancy or breastfeeding and other aggressive malignant diseases;
• Use immunosuppressive drugs and high-dose hormone therapy within 2 weeks before randomization to achieve the purpose of immunosuppression (dose>10mg/day prednisone or other hormones with equivalent efficacy);
• CART treatment within 3 months before randomization;
• Laboratory test values 1 week before randomization: blood routine: ① leukocyte <3.0×109/L; ② absolute neutrophil count <1.5×109/L; ③ platelets <75×109/L; ④ hemoglobin < 90g/L; liver function: ①serum albumin<30g/L; ②ALT and AST>5×ULN; renal function: ①serum creatinine>1.5×ULN; ②Cr clearance rate<50ml/min; ③estimated renal small Globular filtration rate (eGFR) <30 mL/min/1.73 m2; coagulation function: ① international normalized ratio (INR)> 2; ② prothrombin time (PT) exceeding the range of normal control> 6 seconds;
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg, diastolic blood pressure > 110 mmHg);
• Uncontrollable diabetes;
• Active heart disease, including myocardial infarction, unstable angina pectoris, NYHA class II and above heart failure, and poorly controlled arrhythmias (including QTcF interval >450 ms in men and >470 ms in women);
• Women are pregnant or breastfeeding;
• History of any active autoimmune disease or autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, vasculitis, glomerulonephritis, hyperthyroidism, or hypothyroidism, asthma requiring bronchodilator treatment, etc;
• Uncontrolled clinically significant ascites (uncontrolled with diuretics or paracentesis);
• Combined with active infection, except HBV and HCV;
• Arterial or venous thrombosis or embolic events, such as cerebrovascular accident (including transient ischemic attack), deep venous thrombosis or pulmonary embolism, occurred 6 months before starting drug treatment;
• Known central nervous system (CNS) metastasis or meningeal metastasis;
• The patient cannot receive follow-up or is participating in other clinical trials;
• The investigator believes that the patient has other conditions that make it inappropriate to participate in this study.