Hepatic Arterial Infusion of Raltetrexed With Oxaliplatin(SALOX) Versus FOLFOX in Advanced Hepatocellular Carcinoma

Inclusion Criteria:

• Provision of signed and dated, written informed consent form (ICF) and any locallyrequired authorization obtained from the patient prior to any mandatory study specificprocedures, sampling, and analyses.
• Provision of signed and dated written genetic informed consent prior to optionalcollection of sample for genetic analysis.
• Patients with BCLC stage C hepatocellular carcinoma confirmed by pathology orclinically diagnosed
• Age ≥18 years and < 75 years at the time of screening.
• Portal vein invasion or extrahepatic oligosaccharides were detected by baselineimaging. Oligosaccharides were defined as no more than two extrahepatic organs and nomore than three tumors.
• Child-Pugh score class A to B
• No local antitumor therapy for hepatocellular carcinoma was received within 4 weeksprior to enrollment
• No previous systemic antitumor therapy for hepatocellular carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment
• The expected survival time is no less than 3 months
• Patients with HBV infection, which is characterized by positive hepatitis B surfaceantigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBVDNA (≥10 IU/ml or above the limit of detection per local lab standard), must betreated with antiviral therapy, as per institutional practice. HBV antiviral therapymust be initiated prior to randomization and patients must remain on antiviral therapyfor the study duration and for 6 months after the last dose of study medication.Patients must show evidence HBV stabilization or signs of viral response (e.g.,reduction HBV DNA levels) prior to starting IP. Patients who test positive foranti-hepatitis B core (HBc) with undetectable HBV DNA (<10 IU/ml or under the limit ofdetection per local lab standard) do not require anti-viral therapy prior torandomization. These subjects will be tested at every cycle to monitor HBV DNA levelsand initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit ofdetection per local lab standard). HBV DNA detectable subjects must initiate andremain on antiviral therapy for the study duration and for 6 months after the lastdose of study medication.
• Patients with HCV infection must have management of this disease per localinstitutional practice throughout the study. HCV diagnosis is characterized by thepresence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody uponenrollment.
• At least 1 measurable intrahepatic lesion suitable for repeat assessments according tothe following mRECIST criteria: （1）Liver lesions that show typical features of HCC onIV contrast-enhanced CT or MRI scans, ie, hypervascularity in the arterial phase withwashout in the portal or the late venous phase；（2）Viable, non-necrotic portion (arterial phase IV contrast-enhancing) that can be accurately measured at baseline as ≥10 mm in the longest diameter.
• Adequate organ and marrow function as defined below. Criteria "a," "b," "c," and "f"may not be met with transfusions, infusions, or growth factor support administeredwithin 14 days of starting the first dose. Hemoglobin ≥9.0 g/dL、Absolute neutrophil count ≥1000/µL、Platelet count ≥50000/µL、Totalbilirubin ≤2.0 × the upper limit of normal (ULN)、alanine aminotransferase (ALT) andaspartate aminotransferase (AST) ≤5 × ULN、Albumin ≥2.8 g/dL、International normalized ratio ≤1.6、2+ proteinuria or less urine dipstick reading、Calculated creatinine clearance (CL) ≥30mL/min as determined by Cockcroft-Gault (using actual body weight) or 24hour urinecreatinine CL Males: Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL) Females: Creatinine CL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)
• Must have a life expectancy of at least 12 weeks.
• Body weight >30 kg

Exclusion Criteria:

• A history of liver decompensation, such as refractory ascites, gastrointestinalbleeding, or hepatic encephalopathy; Uncontrolled complications, including but notlimited to: Persistent or activity (except the HBV and HCV) infection, symptoms ofcongestive heart failure and uncontrolled diabetes, uncontrolled hypertension,unstable angina, uncontrolled arrhythmias, active ILD, severe chronic GI diseaseaccompanied by diarrhea, or compliance with requirements may limit the research,resulted in significant increase risk of AE or influence Subjects providedpsychiatric/social problem status on their ability to provide written informedconsent.A history of active primary immunodeficiency or human immunodeficiency virus;Active or previous records of autoimmune disease or inflammatory diseases, includinginflammatory bowel disease (e.g., colitis or crohn's disease], diverticulitis, except [diverticulosis], systemic lupus erythematosus (sle), sarcoidosis syndrome or wegenersyndrome (e.g., granulomatous vasculitis, gray's disease, rheumatoid arthritis, thepituitary gland inflammation and uveitis]).
• Known to produce allergic or hypersensitive reactions to any study drug or anyexcipient thereof;
• Significant clinical gastrointestinal bleeding or a potential risk of bleeding wasidentified by the investigator during the 30 days prior to study entry.
• Tumors of the central nervous system, including metastatic brain tumors;
• Pregnant women or breast-feeding patients;
• Complicated with other malignant tumors:
• Malignant tumors that have been treated for therapeutic purposes, have no knownactive disease for ≥5 years prior to the first administration of the study drug,and have a low potential risk of recurrence
• Fully treated non-melanoma skin cancer or malignant freckle moles with noevidence of disease
• Fully treated carcinoma in situ without evidence of disease
• Prior to the initial dosing of the study drug, they had received anti-PD-1,anti-PD-L1, or anti-CTLA-4 therapy
• HAIC treatment was received prior to initial dosing of the study drug
• Has received anti-tumor system therapy for HCC. Non-anti-tumor purpose combinedhormone therapy (e.g., hormone replacement therapy) is excluded.
• Is currently using, or has used an immunosuppressive drug within 14 days prior to thefirst dose of the investigational drug. This standard has the following exceptions:
• intranasal, inhaled, topical or topical steroids (e.g., intraarticular)
• Systemic corticosteroid therapy not exceeding 10 mg/ day of prednisone or itsphysiological equivalent as a prophylactic use of steroids for hypersensitivity (e.g., CT scan pretherapy medication)
• Steroids as a prophylactic for allergic reactions.
• A live attenuated vaccine was administered within 30 days prior to the firstadministration of the study drug. Note: If enrolled, patients shall not receive liveattenuated vaccine within 30 days of receiving study drug therapy and after the lastadministration of study drug.
• Pregnant or lactating women, or fertile men or women who do not want to usehigh-efficiency contraceptives, 6 months after the last dosing of study treatment,from screening to study treatment. Based on the patient's preferred and customarylifestyle, abstinence during treatment and washout is an acceptable contraceptivemethod.