Concurrently vs Sequentially Combined HAIC With Targeted and Immunotherapy in Potentially Resectable HCC

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare HAIC concurrently with sequentially combined with targeted and immunotherapies in terms of efficacy and safety in patients with potentially resectable intermediate and advanced HCC (CNLC stage IIa IIIa). The main questions it aims to answer are: Does a strong combination regimen of three simultaneous treatments (HAIC, targeted agents and immunotherapy) definitely result in a higher surgical conversion rate and better survival benefit? Can the combination of targeted and immunotherapies based on patients' response to HAIC therapy avoid over-treatment of some patients without affecting the surgical conversion rate and overall survival? Participants will be randomly assigned to receive either HAIC concurrently or sequentially combined with targeted and immunotherapies. Researchers will compare concurrent treatment group with sequential treatment group to see if there are different in terms of the conversion resection rate, long-term survival, and safety.

Detailed Description
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Participants in the concurrent treatment group will receive two cycles of HAIC (the drugs are oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and frequency according to instructions), then evaluate the response of tumor, those who achieve complete response (CR) will receive surgical resection or follow-up, those with partial response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments. After four cycles of combined therapy, second evaluation of efficacy will be performed, those who achieve CR will receive surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment. Participants in the sequential treatment group will receive two cycles of HAIC (drugs of oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200 mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4 weeks), then evaluate the response of tumor, and those who achieve complete response (CR ) will receive surgical resection or follow-up, while other patients continue to receive two cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four cycles, a second efficacy assessment will be performed, and patients who achieve CR will undergo surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.

Official Title
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A Randomized Controlled Study of the Efficacy of Hepatic Arterial Perfusion Chemotherapy Concurrently Compared to Sequentially Combined With Targeted and Immunotherapy in Potentially Resectable Intermediate and Advanced HCC

Conditions
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Hepatocellular Carcinoma, Chemotherapy Effect, Chemotherapeutic Toxicity

Intervention / Treatment
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* Drug: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU
* Drug: Concurrent Lenvatinib
* Drug: Concurrent PD-1 antibody
* Drug: Sequential Lenvatinib
* Drug: Sequential PD-1 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 and ≤75 years; ECOG PS score of 0 1; Clinical or pathological diagnosis of hepatocellular carcinoma and meeting the stage IIa-IIIa of CNLC staging according to the relevant definitions in the 2015 edition of the Guidelines for Standardized Pathological Diagnosis of Primary Liver Cancer; Not having received previous treatment against hepatocellular carcinoma; Those who cannot be surgically resected after discussion by the multidisciplinary team of the participating centers , but have a potential chance of resection after conversion therapy, including: multiple tumors located in one lobe of the liver; portal vein cancer thrombus not reaching the main trunk, which can be resected together with the primary focus; Laboratory tests meet the following conditions, or the following conditions can be achieved with short-term treatment: Neutrophil count ≥2.0×109/L; Hemoglobin ≥ 100 g/L; Platelet count ≥ 75 × 109/L; Plasma albumin level ≥ 35 g/L; Plasma total bilirubin less than 2 times the upper limit of normal; Plasma alanine aminotransferase (ALT) less than 3 times the upper limit of normal; Plasma aspartate aminotransferase (AST) less than 3 times the upper limit of normal; Plasma creatinine less than 1.5 times the upper limit of normal; Plasma prothrombin time is normal or exceeds the upper limit of normal value by ≤ 4 seconds; Prothrombinogen international normalized ratio (INR) ≤ 2.2; Patients were fully informed about the study and signed an informed consent form. Exclusion Criteria: Those with severe comorbidity including cardiac, cerebral, pulmonary, renal, and other vital organ function damage, combined with severe infections or other serious concomitant diseases (> grade 2 CTCAE Version 5.0 adverse events), who cannot tolerate the treatment; Those with a history of other malignant tumors; Those with a history of related drug allergy; Those with known hypersensitivity to any component of the targeted and immunologic drugs to be applied; Those with a history of organ transplantation; Those who have received previous treatment targeting hepatocellular carcinoma (including interferon); Those with co-infection with HIV; Those with drugs abuse; Those who have had gastrointestinal bleeding or cardiovascular events within the last 30 days; Pregnant or breastfeeding women, or women of childbearing age who do not wish to use contraception; Persons with concomitant psychiatric disorders that preclude informed consent or affect acceptance of treatment; Other factors that may affect patient enrollment and assessment results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: concurrent treatment group<br>Participants receive two cycles of HAIC (the drugs are oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and frequency according to instructions), then evaluate the response of tumor, those who achieve complete response (CR) will receive surgical resection or follow-up, those with partial response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments. After four cycles of combined therapy, second evaluation of efficacy will be performed, those who achieve CR will receive surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment. | Drug: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU<br>* Hepatic arterial infusion chemotherapy with (oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks)<br>* Other names: Hepatic arterial infusion chemotherapy (HAIC);Drug: Concurrent Lenvatinib<br>* Lenvatinib 8mg/day combined with the HAIC from the first cycle<br>* Other names: Concurrent targeted therapy;Drug: Concurrent PD-1 antibody<br>* PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the first cycle (dosage and frequency according to instructions)<br>* Other names: Concurrent immunotherapy;|
| Active Comparator: sequential treatment group<br>Participants receive two cycles of HAIC (drugs of oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200 mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4 weeks), then evaluate the response of tumor, and those who achieve complete response (CR ) will receive surgical resection or follow-up, while other patients continue to receive two cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four cycles, a second efficacy assessment will be performed, and patients who achieve CR will undergo surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment. | Drug: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU<br>* Hepatic arterial infusion chemotherapy with (oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks)<br>* Other names: Hepatic arterial infusion chemotherapy (HAIC);Drug: Sequential Lenvatinib<br>* Lenvatinib 8mg/day combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR)<br>* Other names: Sequential targeted therapy;Drug: Sequential PD-1 antibody<br>* PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR) (dosage and frequency according to instructions)<br>* Other names: Sequential immunotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival of the participants | From date of randomization until the date of death from any cause, assessed at least 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-free survival of the participants | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed at least 36 months | 
| ORR | Objective response rates, which means the proportion of patients with efficacy assessment of complete response and partial response for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively. | Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days) | 
| DCR | Disease control rates, which means the proportion of patients with efficacy assessment of complete response, partial response and stable disease for the size of intrahepatic target lesions according to mRECIST criteria and RECIST v1.1 criteria respectively. | Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days) | 
| CRR | Conversion resection rate refer to the proportion of patients in both groups who actually underwent subsequent surgical resection. | This outcome measure will be assessed at the end of Cycle 4 (each cycle is 28 days) | 
| Safety profiles of all participants | Adverse Events and Severe Adverse Events evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | This outcome measure will be assessed at the end of Cycle 1 to 4(each cycle is 28 days), and every 3 months through study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic artery infusion chemotherapy, Tyrosine kinase inhibitors, Immune checkpoint inhibitors, Intermediate and advanced stage hepatocellular carcinoma, combined therapy, conversion resection