CVM-1118 and Sorafenib Combination in Subjects With Advanced Hepatocellular Carcinoma

Inclusion Criteria:

1. Signed, informed consent
2. Age 18 or older (for all treatment locations with exception of Taiwan), or age 20 or older (Taiwan only)
3. Pathologically or cytologically-confirmed, advanced-stage hepatocellular carcinoma without prior systemic treatment except for prior immunotherapy and Child-Pugh liver function class A appropriate for treatment with sorafenib
4. Measurable disease according to modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST)
5. Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1
6. Adequate laboratory parameters including:

   1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), or AST and ALT ≤ 5.0 x ULN if liver function abnormalities are due to underlying malignancy
   2. Total serum bilirubin ≤ 2.0 x ULN (except for subjects with documented Gilbert's syndrome who have a limit of ≤ 3.0 x ULN)
   3. Absolute neutrophil count (ANC):1500/µL
   4. Platelets: 90,000/µL
   5. Hemoglobin: 9.0 g/dL
   6. Serum creatinine ≤ 2.0 x ULN or creatinine clearance of ≥ 50 mL/min
   7. Serum albumin ≥ 3.0 g/dL
   8. International normalized ratio (INR) ≤ 1.4
   9. Prothrombin Time (PT)/ Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULN
7. QTc interval (using Fridericia correction) of ≤ 470 msec (QTc interval may be derived from up to 3 separate EKGs performed at least 5 minutes apart)
8. Willingness to participate in collection of pharmacokinetic and other exploratory blood collection as defined in the protocol
9. Willingness to use adequate contraception throughout study and for a period of 3 months after last dose of CVM-1118

Exclusion Criteria:

1. Major surgery (other than diagnostic surgery) or radiation therapy within 28 days of starting study treatment
2. Prior systemic immunotherapy for hepatoma within 28 days of starting study treatment
3. Systemic anticancer therapy (e.g., chemotherapy, hormonal, investigational, biological therapies) within 28 days (or fewer than 5 half-lives, whichever is shorter) of starting study treatment except for ongoing hormonal therapy administered for control of a second cancer (e.g., breast or prostate cancer)
4. Receipt of a CYP3A4 inducer less than 28 days or 5 half-lives of the CYP3A4 inducer prior to the first day of sorafenib administration
5. Other known active cancer(s) likely to require treatment in the next two (2) years or likely to impact the assessment of any study endpoints
6. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy (e.g., subjects with known HBV or HCV infections controlled on antivirals are allowed)
7. Known Central Nervous system (CNS) metastases unless appropriately treated and neurologically stable for ≥ 4 weeks off steroids
8. Pregnant or currently breast-feeding
9. Known HIV-positive
10. Patients with impaired gastrointestinal (GI) diseases that may significantly alter the absorption of oral medications
11. Psychiatric illness/social situations that would interfere with compliance with study requirements
12. History of clinically significant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure (New York Heart Association classification ≥ 2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry
13. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would impart, in the judgement of the PI and/or Sponsor, excess risk associated with study participation or study drug administration, which would make the subject inappropriate for entry into this study