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

Clinical Study Protocol Phase 2, Randomized Study of CS-1008 in Combination With Sorafenib Compared to Sorafenib Alone as First-Line Systemic Therapy in Subjects With Advanced Hepatocellular Carcinoma

The purpose of this study is to determine the safety and efficacy of CS-1008 in combination with sorafenib to sorafenib alone for treating liver cancer. Approximately 160 participants will take part in this study at approximately 22 sites (4 in the US, 8 in Japan, and 10 in Asia).

Inclusion Criteria:

• Histologically or cytologically confirmed hepatocellular carcinoma (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
  • Alpha-fetoprotein (AFP) level > 200 ng/mL

• Advanced diseases

  • Extrahepatic metastasis, OR
  • Locally advanced diseases which are not amenable for surgical resection or other loco-regional therapies including transhepatic arterial (chemo) embolization (TACE or TAE) and local ablative therapy

• Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 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 10^9/L
  • Platelet count ≥ 75 x 10^9/L
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/min
  • Aspartate Aminotransferase (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 participants of childbearing potential must have a negative pregnancy test (serum or urine) result

• Participants 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 International Review Board (IRB)/ Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) before the performance of any study specific procedures or tests

• Participants 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, Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptor (VEGFR)-inhibitors, epidermal growth factor receptor inhibitors or mechanistic target of rapamycin (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 radiotherapy (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 intravenous (IV) congestive heart failure
  • 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. Participants 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 participant'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