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

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.

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(PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments.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.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 and ≤75 years;
2. ECOG PS score of 0\~1;
3. 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;
4. Not having received previous treatment against hepatocellular carcinoma;
5. 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;
6. 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;
7. Patients were fully informed about the study and signed an informed consent form.

Exclusion Criteria:

1. 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;
2. Those with a history of other malignant tumors;
3. Those with a history of related drug allergy;
4. Those with known hypersensitivity to any component of the targeted and immunologic drugs to be applied;
5. Those with a history of organ transplantation;
6. Those who have received previous treatment targeting hepatocellular carcinoma (including interferon);
7. Those with co-infection with HIV;
8. Those with drugs abuse;
9. Those who have had gastrointestinal bleeding or cardiovascular events within the last 30 days;
10. Pregnant or breastfeeding women, or women of childbearing age who do not wish to use contraception;
11. Persons with concomitant psychiatric disorders that preclude informed consent or affect acceptance of treatment;
12. Other factors that may affect patient enrollment and assessment results.