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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Procedure: Hepatic Artery Infusion Chemotherapy
* Procedure: Transarterial Chemoembolization
* Drug: Regorafenib
* Drug: Immune Checkpoint Inhibitors


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HAIC combined with regorafenib and immune checkpoint inhibitors<br>Subjects received FOLFOX regimen HAIC treatment, within 2 weeks of regorafenib (28 days as a cycle, 80-160 mg qd regorafenib orally on days 1-21) and immune checkpoint inhibitors (continue treatment according to the original plan, 1 cycle every 3 weeks) treatment. HAIC treatment was repeated every 3 weeks for a maximum of six cycles. | Procedure: Hepatic Artery Infusion Chemotherapy<br>* HAIC adopts FOLFOX chemotherapy regimen, hepatic arteriography through a radial artery or femoral artery cannulation, routine hepatic artery cannulation, imaging, infusion of chemotherapy drugs into hepatic artery: oxaliplatin 85 mg/m2 on the first day for 0-3 hours, folinic acid 400 mg/m2 for 3-4.5 hours on day 1, fluorouracil 400 mg/m2 for 4.5-6.5 hours on day 1, and fluorouracil 2500 mg/m2 for 46 hours on days 1-3.<br>* Other names: HAIC;Drug: Regorafenib<br>* Regorafenib is administered for 28 days per treatment cycle, with oral regorafenib on days 1-21, 80-160 mg once daily. The dose is adjusted according to adverse reactions, with a minimum of 80 mg.<br>* Other names: second-line target drug;Drug: Immune Checkpoint Inhibitors<br>* Optional immune checkpoint inhibitors include Camrelizumab, Sintilimab, Nivolumab, Pembrolizumab, and Toripalimab. Treatment is based on the immune checkpoint inhibitor before the patients are randomized into the group, and it is not recommended to replace the immune checkpoint inhibitor. The dosage is 200 mg, intravenous infusion, D1, once every 21 days (Q3W). Dosing interruption or dose reduction may be necessary based on individual safety and tolerability considerations; dosing with immune checkpoint inhibitors should not be suspended for more than 4 weeks.<br>* Other names: Camrelizumab, Sintilimab, Nivolumab, Pembrolizumab, Toripalimab;|
| Active Comparator: TACE combined with regorafenib and immune checkpoint inhibitors<br>Choose traditional precise cTACE or dTACE treatment, and receive regorafenib within 2 weeks (28 days as a cycle, 80-160mg qd regorafenib orally on d1-21) and immune checkpoint inhibitors (continue treatment according to the original plan, every 3 weeks as a cycle) treatment. CT or MRI examination was repeated 4-6 weeks after the operation to evaluate whether there were active lesions. If there were still active lesions, one repeat TACE could be performed, and the number of TACE was less than 3 times. | Procedure: Transarterial Chemoembolization<br>* Treatment regimens have chosen lipiodol-based hepatic arterial chemoembolization, with lipiodol dosage varying from 5-20ml depending on tumor size. The chemotherapy drug is gemcitabine 1.0 combined with 100mg oxaliplatin, combined with 1/3 to 1 dose of solid embolic agent (the dosage is determined by the investigator based on the tumor size). After uniform emulsification, the drug is injected into the supplying blood vessels and stops when the intravascular blood flow is slow. Later, angiography is performed again, and the tumor staining disappears and the supplying artery is occlusions. CT or MRI scans are performed 4 to 6 weeks postoperatively to assess the presence of active lesions. Repeat TACE if active lesions are still present. The frequency of TACE treatment is determined by the investigator and is given according to the patient's condition, generally 2-4 times. The interval between TACE treatments is 30-45 days, with a maximum of six cycles.<br>* Other names: TACE;Drug: Regorafenib<br>* Regorafenib is administered for 28 days per treatment cycle, with oral regorafenib on days 1-21, 80-160 mg once daily. The dose is adjusted according to adverse reactions, with a minimum of 80 mg.<br>* Other names: second-line target drug;Drug: Immune Checkpoint Inhibitors<br>* Optional immune checkpoint inhibitors include Camrelizumab, Sintilimab, Nivolumab, Pembrolizumab, and Toripalimab. Treatment is based on the immune checkpoint inhibitor before the patients are randomized into the group, and it is not recommended to replace the immune checkpoint inhibitor. The dosage is 200 mg, intravenous infusion, D1, once every 21 days (Q3W). Dosing interruption or dose reduction may be necessary based on individual safety and tolerability considerations; dosing with immune checkpoint inhibitors should not be suspended for more than 4 weeks.<br>* Other names: Camrelizumab, Sintilimab, Nivolumab, Pembrolizumab, Toripalimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | The 6-month, 1-year and 2-year progression-free survival rates were evaluated. | The time from enrollment to tumor progression or death from any cause, whichever came first, measured in months, assessed up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The survival rates were evaluated. | Time from enrollment to death from any cause, in months, assessed up to 2 years. For patients who are still alive at the time of data analysis, overall survival is calculated based on the date when the patient is last known to be alive. | 
| To Tumor Untreatable Progression | End point of antitumor drug trial. | The time interval between receiving HAIC or TACE and the patient's inability to receive further intra-arterial treatment, assessed up to 12 months. | 
| Objective Response Rate | The 1-, 3-, 6-, and 12 months ORR were evaluated. | Proportion of patients who achieved complete remission (CR) or partial remission (PR) according to mRECIST criteria, assessed up to 12 months. | 
| Disease Control Rate | The 1-, 3-, 6-, and 12 months DCR were evaluated. | Proportion of patients with complete remission (CR), partial remission (PR), and stable disease (SD) according to mRECIST criteria, assessed up to 12 months. | 
| Duration of Overall Response | Evaluation index of clinical efficacy of anticancer drugs. | The time from the first assessment of the tumor as complete remission or partial remission to the first assessment as disease progression or death from any cause, assessed up to 12 months. | 
| The incidence of adverse events and serious adverse events | Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. | Every follow-up time, assessed up to 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, Hepatic Artery Infusion Chemotherapy, Transarterial Chemoembolization, Target Immunity, Advanced