Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil/Leucovorin Versus Sorafenib in Advanced Hepatocellular Carcinoma

Inclusion Criteria:

• Written informed consent must be obtained prior to any screening procedures.
• Cytohistological confirmation is required for diagnosis of HCC.
• Patients with advanced (unresectable and/or metastatic, stage C based onBarcelona-Clinic Liver Cancer [BCLC] staging classification) hepatocellular carcinomawhich would not be suitable for treatment with loco-regional therapies or haveprogressed following locoregional therapy such as surgical resection, percutaneoushepatic arterial embolization, radiofrequency ablation, and percutaneousinterventional therapy.
• At least one tumor lesion meeting measurable disease criteria as determined by RECISTv1.1. Lesions previously treated with local therapy, such as radiation therapy,hepatic arterial embolization, radiofrequency ablation, and percutaneousinterventional therapy should not be selected unless progression is noted at baseline,in which case, these lesions would be considered as non-target lesions.
• Current cirrhotic status of Child-Pugh class A-B, with no encephalopathy. Ascitescontrolled by diuretics is permitted in this study.
• Availability of a representative tumor tissue specimen (archival tumor tissue isallowed) at pre-screening.
• Eastern Cooperative Oncology Group Scale for Assessment of Patient Performance Status ≤ 2.
• Both men and women enrolled in this trial must use adequate barrier birth controlmeasures during the course of the trial and 4 weeks after the completion of trial.
• Adequate bone marrow, liver and renal function as assessed by central lab by means ofthe following laboratory requirements from samples within 7 days prior to procedure:
• Hemoglobin > 100g/L
• Absolute neutrophil count >3.0 ×109/L
• Neutrophil count > 1.5 ×109/L
• Platelet count ≥ 50.0 ×109/L
• Total bilirubin < 51 μmol/L
• Alanine transaminase (ALT) and aminotransferase (AST) < 5 x upper limit of normal
• Albumin > 28 g/L
• Prothrombin time (PT)-international normalized ratio (INR) < 2.3, or PT < 6seconds above control
• Serum creatinine < 110 μmol/L
• Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

• Received any prior systemic chemotherapy or molecular-targeted therapy for HCC such assorafenib.
• Previous local therapy completed less than 4 weeks prior to the dosing and, if presentany related acute toxicity > grade 1.
• Any contraindications for hepatic arterial infusion procedure:
• Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%).
• Renal failure / insufficiency requiring hemo-or peritoneal dialysis.
• Known severe atheromatosis.
• Known uncontrolled blood hypertension (> 160/100 mm/Hg).
• Patients with any other malignancies within the last 3 years before study start.
• History of HCC tumor rupture.
• Patients with severe encephalopathy.
• Patients with known active bleeding (e.g. from GI ulcers, esophageal varices) within 2months prior to baseline/screening visit or with history or evidence of inheritedbleeding diathesis or coagulopathy.
• Clinically significant (CTC grade 3 or 4) venous or arterial thrombotic disease withinpast 6 months.
• History of cardiac disease:
• Congestive heart failure >New York Heart Association (NYHA) class 2 (refer toAppendix 13.9).
• Active coronary artery disease (CAD) (myocardial infarction more than 6 monthsprior to study entry is allowed).
• Cardiac arrhythmias (>Grade 2 NCI-CTCAE Version 4.0) which are poorly controlledwith anti-arrhythmic therapy or requiring pace maker.
• Uncontrolled blood hypertension (> 160/100 mm/Hg).
• Serious, non-healing wound, ulcer, or bone fracture.
• History of abdominal fistula, GI perforation, or intra-abdominal abscess within past 6months prior to study treatment.
• Clinically significant third space fluid accumulation (i.e., ascites requiring tappingdespite use of diuretic or pleural effusion that either required tapping or isassociated with shortness of breath).
• Patients who have undergone major surgical procedure, open biopsy, or significanttraumatic injury within 4 weeks of the start of protocol treatment.
• History of a bone marrow or solid organ transplant.
• Use of biologic response modifiers, such as G-colony stimulating factor (CSF), within 3 weeks prior to start of study drug. (G-CSF and other hematopoietic growth factorsmay be used in the management of acute toxicity such as febrile neutropenia whenclinically indicated or at the discretion of the investigator; however, they may notbe substituted for a required dose reduction). Subjects taking chronic erythropoietinare permitted provided no dose adjustment is undertaken within 1 month prior to thestudy or during the study.
• Any other condition that would, in the Investigator's judgment, contraindicatepatient's participation in the clinical study due to safety concerns or compliancewith clinical study procedures, e.g., infection/inflammation, intestinal obstruction,unable or unwilling to swallow medication, social/ psychological issues, etc.
• Unable to undergo either contrast-enhanced magnetic resonance imaging (MRI) orcontrast-enhanced computed tomography (CT).
• Known history of human immunodeficiency virus (HIV) seropositivity. HIV testing is notrequired as part of this study.
• Patients who have received any other investigational agents within a period of timethat is less than the cycle length used for that treatment or equal to 4 weeks (whichever is shorter) prior to starting study drug and recovered from any sideeffects to grade 1 or less.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive human chorionic gonadotropin (hCG) laboratory test.
• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring dosing and for 7 days after permanently discontinuing HAIF and/or sorafenibtreatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle ofthe patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.
• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy) or tubal ligation at least six weeks before taking study treatment.In case of oophorectomy alone, only when the reproductive status of the woman hasbeen confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female patients onthe study the vasectomized male partner should be the sole partner for thatpatient.
• Combination of any two of the following (a+b or a+c, or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception.
2. Placement of an intrauterine device or intrauterine system
3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm orcervical/vault caps) with spermicidal foam/gel/film/cream/vaginalsuppository. In case of use of oral contraception women should have been stable on the same pill for aminimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. ageappropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case ofoophorectomy alone, only when the reproductive status of the woman has been confirmed byfollow up hormone level assessment is she considered not of child bearing potential.

• Sexually active males unless they use a condom during intercourse while receivingtreatment and for 7 days after stopping study treatment and should not father a childin this period. A condom is required to be used also by vasectomized men in order toprevent delivery of the drug via seminal fluid.
• Subjects unable to suffer the discomfort of the HAI procedure (e.g. pain,claustrophobia, noise).
• Any contraindication for sorafenib, oxaliplatin, leucovorin, or fluorouraciladministration.
• Any agents which could affect the absorption or pharmacokinetics of the study drugs.
• Known or suspected allergy to the investigational agents or any agent given inassociation with this study.