Neoadjuvant HAIC of TACE Plus Donafenib in BCLC B Stage HCC: a Multi-center Randomized Controlled Trial.

The purpose of this study is to evaluate the safety and efficacy of the combination therapy with HAIC-TACE and donafenib compared to TACE plus donafenib in patients with BCLC B stage unresectable hepatocellular carcinoma (HCC) out of up-to-seven criteria.

Trans-arterial chemoembolization (TACE) is the most widely used palliative treatment for BCLC B stage hepatocellular carcinoma (HCC) patients. While a number of studies demonstrated poor effect of TACE for patients with large hepatocellular carcinoma especially for those with tumor that out of up-to-7 criteria. Some recent studies suggested that, compared with TACE, hepatic arterial infusion chemotherapy (HAIC) may improve the survivals for HCC with large tumor. Thus, the investigators carried out this prospective randomized controlled trial to demonstrate the superiority of neoadjuvant HAIC of TACE.

Total 156 subjects will be recruited in this study, each group of 78 subjects in treatment group (HAIC-TACE-Dona group) and control group (TACE-Dona group). Primary efficacy analysis will be done in the full analysis set. PFS will be used as primary outcome measures. OS, TTP, ORR, DCR and safety will be the secondary endpoints. In addition, the safety evaluation will be carried out according to the standard of adverse reaction classification (Common Terminology Criteria for Adverse Events, CTCAE v5.0).

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must volunteer to participate in the study, signed informed consent, and were able to comply with the program requirements of visits and related procedures.
2. Age and gender: \>18 years old and≤75 years old, both men and women.
3. All subjects must have Hepatocellular Carcinoma confirmed by pathological or clinical diagnosis.
4. Subjects are not suitable for radical resection or radical ablative therapy.
5. BCLC B based on Barcelona Clinic Liver Cancer staging system, and the lesions in the liver exceed up to 7 criteria, the number of tumors + the maximum diameter of tumors \> 7.
6. Patients with viable and measurable target lesion per mRECIST.
7. Patients who are expected to live more than 3 months.
8. ECOG PS 0-1.
9. Child-Pugh class A.
10. Patients with laboratory values that meet the following criteria:

    1. Hemoglobin≥90 g/L;
    2. Neutrophile granulocytes≥1.5×109/L;
    3. Platelet count≥75×109/L;
    4. Albumin≥30 g/L;
    5. Total serum bilirubin ≤ 2 times upper limits of normal;
    6. AST and ALT ≤ 5 times upper limits of normal;
    7. Serum creatinine ≤ 1.5 times upper limits of normal;
    8. Alkaline phosphatase ≤ 5 times upper limits of normal;
    9. Prothrombin time or international normalized ratio ≤ 1.5 times upper limits of normal, activated partial thromboplastin time (APTT) ≤ 1.5×ULN;

Exclusion Criteria:

1. Fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma confirmed by histology or cytology.
2. History of malignant tumor, excluding the following cases:

   1. Malignant tumor that was curatively treated more than 5 years prior to study entry and has not recurred since then;
   2. Successful radical resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder carcinoma, preinvasive cervix carcinoma, and other preinvasive cancers.
3. Diffuse tumor lesion.
4. The lesions load in the liver exceeds 20, the number of tumors + the maximum diameter of tumors \> 20.
5. Vascular invasion or extrahepatic metastasis.
6. Preexisting or history of hepatic encephalopathy, hepatorenal syndrome or liver transplantation.
7. Clinically uncontrolled ascites or pleural effusion.
8. History of surgical excision or ablation within 4 weeks of the start of treatment.
9. History of hepatic arterial infusion, more than twice TACE therapy, or history of TACE within 6 months of the start of treatment.
10. History of systemic therapy, including but not limited to chemotherapy, targeted therapy, immunotherapy.
11. History of thrombosis and/or embolism within 6 months of the start of treatment.
12. Clinically severe gastrointestinal bleeding within 6 months of the start of treatment or any life-threatening bleeding events within 3 months of the start of treatment.
13. Clinically significant cardiovascular disease, including, but not limited to, acute myocardial infarction, severe/unstable angina or prior coronary artery bypass surgery, congestive heart failure (NYHA \>2), poorly controlled arrhythmias or arrhythmias requiring pacemaker therapy, hypertension not controlled by medication (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) within the past 6 months.
14. Other significant clinical and laboratory abnormalities, such as uncontrolled diabetes, chronic kidney disease, grade II or above peripheral neuropathy (CTCAE V5.0), and thyroid dysfunction, that may affect the safety evaluation.
15. Severe infections that are active or clinically poorly controlled.
16. If accompanied by acute or chronic active hepatitis B, unless taking antiviral drugs.
17. Female patients who are pregnant, lactating, possibly pregnant, or planning to become pregnant, and fertile female or male patient who is unwilling or unable to use effective contraception.
18. Multiple branches of hepatic artery with severe variation.
19. Any other subjects that the investigator considers ineligible.