CS1008- in Combination With Sorafenib Compared to Sorafenib Alone in Subjects With Advanced Liver Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed HCC or clinical diagnosis of HCC when the following criteria are all met:

  • History of chronic hepatitis and/or cirrhosis of liver;
  • Typical features of HCC demonstrated in dynamic imaging studies, such as three-phase computed tomography (CT); AND
  • AFP level > 200 ng/mL

• Advanced diseases

  • Extrahepatic metastasis, OR
  • Locally advanced diseases which are not amendable for surgical resection or other loco-regional therapies including transhepatic arterial (chemo)embolization (TACE or TAE) and local ablative therapy
• Measurable disease based on RECIST criteria (version 1.0) of at least 1 untreated target lesion that can be measured in 1 dimension
• At least 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Child-Pugh class A
• Life expectancy of at least 12 weeks

• Adequate organ and bone marrow function as assessed by clinical laboratory evaluations:

  • Hemoglobin ≥ 8.5 g/dL (transfusion and/or growth factor support allowed)
  • Absolute neutrophil count (ANC) ??? 1.0 x 109/L
  • Platelet count ≥ 75 x 109/L
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/min
  • AST and alkaline phosphatase ??? 5.0 x ULN
  • Total bilirubin ≤ 1.5 x ULN
• Serum amylase and lipase ≤ 1.5 x ULN
• Women of childbearing potential must be willing to consent to using effective contraception (eg, abstinence, hormonal contraceptives, bilateral tubal ligation, barrier with spermicide, intrauterine device) while on treatment and for 3 months thereafter. Men who are the partner of a woman of childbearing potential must be willing to consent to using effective contraception (eg, vasectomy or barrier with spermicide) while on treatment and for 3 months thereafter
• All female subjects of childbearing potential must have a negative pregnancy test (serum or urine) result
• Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an IRB/IEC approved ICF before performance of any study specific procedures or tests
• Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

• Any prior systemic therapy for HCC, including systemic chemotherapy (prior exposure to chemotherapy by TACE is allowed), immunotherapy, sorafenib or other Raf kinase inhibitors, VEGF/VEGFR-inhibitors, epidermal growth factor receptor inhibitors or mTOR inhibitors
• Radiotherapy or major surgical procedure within 4 weeks of the screening/baseline visit or minor surgical procedures (eg, core biopsy or fine needle aspiration) within 2 weeks of the screening/baseline visit
• Anticipation of need for RT or a major surgical procedure during the study
• Any investigational agent within 4 weeks before the screening/baseline visit

• History of any of the following conditions within 6 months before the screening/baseline visit:

  • Myocardial infarction with significant impairment of cardiac function (eg, ejection fraction ≤ 30%)
  • Severe/unstable angina pectoris
  • New York Heart Association (NYHA) class III or IV congestive heart failure (Section 17.2)
  • Clinically significant pulmonary disease (eg, severe chronic obstructive pulmonary disease or asthma)
• Clinically active brain metastases (defined as untreated, symptomatic or requiring steroids or anticonvulsants medications to control associated symptoms), uncontrolled seizure disorder; spinal cord compression; or carcinomatous meningitis. Subjects with treated brain metastasis will be included in the study if they have recovered from the acute, toxic effects of radiotherapy. A minimum of 15 days must have elapsed between the end of RT and the screening/baseline visit
• History of organ transplantation
• Clinically significant, severe, active infection requiring IV antibiotics
• Known history of human immunodeficiency virus (HIV) infection
• History of prior sensitivity reaction to any components of CS-1008 or sorafenib formulations
• History of a second malignancy, with the exception of in situ cervical cancer or adequately treated basal cell or squamous cell carcinoma of the skin
• Pregnant or breast feeding
• Serious intercurrent medical illnesses that, in the opinion of the Investigator, would impair the subject's ability to provide informed consent or unacceptably reduce the safety of the proposed treatment
• Clinically significant (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade ≥ 3) gastrointestinal bleeding in the past 12 months or current active gastrointestinal bleeding
• Presence of esophageal varices at risk of bleeding, such as large esophageal/gastric varices or those with red sign, or active peptic ulcer with or without exposed vessels at risk of bleeding (as documented by endoscopy)
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within past 6 months