Camrelizumab, Apatinib Plus HAIC Versus Camrelizumab and Apatinib for HCC With Portal Vein Invasion: a Randomized Trial

Inclusion criteria

• volunteered with written inform consent
• unresectable HCC or progression after surgery or locoregional threapy, with the diagnosis confirmed by histologic or cytologic analysis or clinical features according to the American Association for the Study of Liver Diseases practice guidelines and the China liver cancer (CNLC) guidelines
• Patients with portal vein tumor thrombosis (PVTT) confirmed by 2 kinds of imaging examinations
• no previous systemic therapy for HCC. Herbs, Chinese medicines or proprietary Chinese medicines that contain anti-cancer active ingredients in the instructions are allowed, but such treatments need to be terminated before randomization
• at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• patients who had previously received local treatments (such as radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, trans-arterial chemoembolization, trans-arterial embolization, etc.)were allowed to be enrolled, but it was required that the target lesions were with no previous local treatment, or the target lesion had received local treatment but had progression according to the RECIST v1.1
• an Eastern Cooperative Oncology Group performance status of 0 to 1
• Child-Pugh A class liver function
• adequate organ function (absoluteneutrophil count ≥1.5 × 109/L, platelet count ≥75 × 109/L, hemoglobin ≥ 90g/L, ALB≥30g/L, TBIL ≤30 umol/L, AST ≤5×ULN, ALT ≤5×ULN, ALP ≤5×ULN, Cr ≤1.5×ULN, TSH≤1×ULN and TSH≥LLN, INR≤2.3, prolonged PT≤6s without anticoagulant therapy, urine protein <2+ or urine protein ≥2+ but 24h urine protein quantitative <1.0 g)
• patients with HBsAg (+) received anti-viral therapy, and patients with HCV-RNA (+) must received anti-viral therapy according to the guidelines and the liver function increases within CTCAE grade 1 during the study
• Female with fertility must agree to use reliable methods of contraception from the signing of the informed consent until at least 120 days after the last administration of the study drug. And the serum HCG test must be negative within 7 days before the start of the study treatment; and it must be a non-lactating period.
• For male patients whose partner is a fertile woman, they must agree to use reliable methods of contraception from the signing of the informed consent until at least 120 days after the last administration of the study drug. During the same period of time, male patients must also agree not to donate sperm.

Exclusion criteria

• intrahepatic cholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma and fibrolamellar cell carcinoma diagnosised by pathology
• patients with other malignant tumors except HCC within 5 years or at the same time, except for cured localized tumors, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, prostate carcinoma in situ, cervical carcinoma in situ, breast carcinoma in situ, etc.
• patients who are planning to undergo or have previously received organ or allogeneic bone marrow transplantation
• history of hepatic encephalopathy
• moderate and severe ascites with clinical symptoms and uncontrolled pleural effusion and pericardial effusion
• a history of gastrointestinal bleeding or a clear tendency to gastrointestinal bleeding within 6 months before the start of the study treatment
• a history of abdominal fistula, gastrointestinal perforation or abdominal abscess occurred within 6 months before the start of study treatment
• a known hereditary or acquired bleeding (such as coagulopathy) or thrombotic tendency
• currently using or recently used (within 10 days before the start of the study treatment) anticoagulant drugs
• thrombosis or embolism occurred within 6 months before the start of study treatment, such as cerebrovascular accident, pulmonary embolism
• with clinical symptoms or diseases of the heart that are not well controlled
• suffered from blood pressure that could not be well controlled by antihypertensive medication or a history of hypertensive crisis or hypertensive encephalopathy
• severe cardiovascular disease occurred within 6 months before the start of study treatment
• severe, unhealed or dehisced wounds and active ulcers or untreated fractures
• received major surgery (except for diagnosis) within 4 weeks before the start of the study treatment or is expected to undergo major surgery during the study period
• unable to swallow pills, malabsorption syndrome, or any condition that affects gastrointestinal absorption
• a history intestinal obstruction, and/or clinical signs or symptoms of gastrointestinal obstruction that were not relieved after the medical treatment within 6 months before start of the study treatment
• evidence of intra-abdominal gas that cannot be explained by puncture or recent surgery
• a history of or current central nervous system metastases
• a history of or current pulmonary fibrosis, organizing pneumonia and other active pneumonia, or severely impaired lung function, which may interfere with the detection and treatment of suspected drug-related lung toxicity
• any active autoimmune disease or a history of autoimmune disease which are expected recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, etc.), except for immune diseases that do not require medical treatment, such as vitiligo, psoriasis, asthma, and well-controlled type I diabetes, etc.
• patients undergoing immunosuppressive agents or systemic hormone therapy to achieve immunosuppressive purposes, and continues to use it within 2 weeks before signing the informed consent
• received treatment with a live attenuated vaccine within 28 days before the start of the study treatment, or expected to be vaccinated during camrelizumabtreatment or within 60 days after the last dose of camrelizumab
• active tuberculosis
• congenital or acquired immune deficiencies (such as HIV-infected)
• combined hepatitis B and hepatitis C co-infection
• patients who are known to be allergic to study drugs or excipients have a history of allergies
• palliative radiotherapy for non-target lesions for symptom control within 2 weeks before the start of study treatment, or adverse events caused by radiotherapy did not recover to ≤ CTCAE grade 1 (except for alopecia)
• perform locoreginal treatments of the liver within 28 days before start of the study treatment (such as radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.), or adverse reactions caused by previous locoreginal treatments have not recovered to ≤ CTCAE level 1 (except for alopecia etc.)
• according to the judgment of the investigator, the patients with factors that may affect the results of the study or cause the study to be terminated midway, such as alcoholism, drug abuse, other serious diseases (including mental illness) need to be treated together, severe laboratory abnormalities, accompanied by family or social factors, which will affect the safety of patients
• patients who is pregnant or breastfeeding
• other factors that the investigatior considers inappropriate to participate in the study