The purpose of this study is to evaluate the safety and efficacy of hepatic arterial infusion chemotherapy combined with Lenvatinib and PD-1 inhibitors compared to Lenvatinib plus PD-1 inhibitors for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).

Hepatic arterial infusion chemotherapy (HAIC) can significantly improve the local drug concentration in liver compared to systemic chemotherapy. The efficacy of HAIC for hepatocellular (HCC), cholangiocarcinoma, gallbladder, and colorectal carcinoma liver metastasis has been proved by many published studies. HAIC with oxaliplatin and 5-fluorouracil could significantly prolong survival time for HCC patients with portal vein tumor thrombosis (PVTT). Lenvatinib, as a new oral anti-neovascularity inhibitor, was proved to have similar efficacy in HCC patients compared to sorafenib in REFLECT study. The sub-group analysis showed that the median overall survival (OS) in Lenvatinib group was significantly longer that sorafenib group in Chinese HCC patients. Recently, the programmed death-1 (PD-1) inhibitors alone or combined with targeted therapy was explored and confirmed to be effective for advanced HCC, with the median progression-free survival (PFS) and median OS of 2.1-5.6 months and 14.4-22.1 months, resepectively. Thus, the investigators carried out this prospective controlled trial to compare the efficacy and safety of HAIC combined with Lenvatinib and PD-1 inhibitors and Lenvatinib and PD-1 inhibitors for advanced HCC with PVTT.

Total 66 subjects will be recruited in this trial, each group of 33 subjects in treatment group (HAIC-Cola group) and control group (Cola group). The primary endpoint is six-month progression-free survival rate, and the secondary endpoints are OS, overall response rate (ORR), PFS, time-to-progression (TTP) and safety. The safety evaluation will be carried out according to the standard of adverse reaction classification (Common Terminology Criteria for Adverse Events, CTCAE v5.0).

Inclusion Criteria:

1. Age and gender: >18 years old and≤75 years old, both men and women.

2. All subjects must have advanced hepatocellular carcinoma with portal vein tumor thrombosis confirmed by pathological or clinical diagnosis.

3. One measurable lesion at least.

4. ECOG PS 0-1 before 1 week of treatment begnining.

5. Child-Pugh class A; ALBI class 1-2.

6. Systemic-cheomtherapy-naive and HAIC-naive.

7. BCLC C stage with PVTT (Vp1 - Vp4).

8. Without distant metastasis.

9. Patients who are expected to live more than 3 months.

10. 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.

11. 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:

3. Allergic to contrast agent.

4. Allergic to oxaliplatin.

5. History of usage of immune inhibitor drug within 14 days before the injection of PD-1 inhibitors, except nasal spray and inhaled corticosteroids or physiological doses of systemic steroid hormones (no more than 10 mg/day of prednisolone or other corticosteroids with equivalent physiological doses).

6. Factors influenced oral Lenvatinib, such as inability to swallow, chronic diarrhea and intestinal obstruction, or other conditions that significantly affect the administration and absorption of the drug.

7. Allergic to Lenvatinib, PD-1 inhibitors, and other mono-colonal antibodies.

8. Vaccination with live attenuated vaccine within 4 weeks before the first dose or planned during the study period.

9. Peripheral neuropathy> Grade 1.

10. History of active autoimmune disease or autoimmune disease.

11. History of other malignant tumor, except for radically treated basal cell, squamous cell skin cancer, or cervical carcinoma in situ.

12. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) .

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. Abnormal coagulation function (INR>1.5 or APTT>1.5×ULN) , have bleeding tendency, or are receiving thrombolytic therapy, anticoagulation therapy or antiplatelet therapy, etc..

15. History of inherited or acquired bleeding and thrombotic tendency, such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc..

16. History of significant coughing up blood 2 months before entering the study, or the daily volume of hemoptysis reached 2.5 ml or more.

17. Patients at risk of gastrointestinal bleeding, including the following:

    1. There are active peptic ulcer lesions.
    2. Those who have a history of melena and hematemesis within 3 months.
    3. For fecal occult blood (+) or (+/-), it is necessary to recheck the stool routine within 1 week. Those who still (+) or (+/-) must undergo gastroscopy. If there is ulcer, bleeding disease, and the treating physician believes that there is a potential risk of bleeding.

18. History of thrombosis and/or embolism within 6 months of the start of treatment.

19. Complicated infections requiring drug intervention (such as intravenous infusion of antibiotics, antifungal or antiviral drugs) within 4 weeks before the first treatment, or unexplained fever >38.5°C during the screening period/before the first administration.

20. Participated in any other clinical research within 4 weeks before the first treatment.

21. History of psychotropic drug abuse or drug use.

22. Other serious physical, mental illnesses or laboratory abnormalities, which may increase the risk of participating in the research or interfere with the results of the research, and those who the researcher believes are not suitable for participating in this research.