A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Inclusion Criteria:

- Advanced-stage hepatocellular carcinoma considered non-operable that is suitable for
treatment with sorafenib. Subjects who have demonstrated progression following
initial surgical or locoregional therapy are eligible

- Confirmed hepatocellular carcinoma by pathological analysis (tissue aspirate or
biopsy)

- No previous systemic therapy for hepatocellular carcinoma

- ECOG Performance Status of 0 or 1

- Child-Pugh liver function class A

- Life expectancy of 12 weeks or more

- Adequate hematologic function (ANC ≥ 1.5 x 109/L; platelet count ≥100×109 per liter;
hemoglobin ≥8.5 g per deciliter maintained in the absence of red blood cell
transfusions; and prothrombin time international normalized ratio ≤1.7; or
prothrombin time ≤2 seconds above control)

- Adequate hepatic function (albumin ≥2.8 g per deciliter; total bilirubin ≤2 mg per
deciliter [51.3 μmol per liter]; and alanine aminotransferase and aspartate
aminotransferase ≤5 times the upper limit of the normal range)

- Adequate renal function (serum creatinine ≤1.5 times the upper limit of the normal
range or creatinine clearance ≥60 mL/min).

- At least one untreated target lesion that could be measured in one dimension,
according to the Response Evaluation Criteria in Solid Tumors (RECIST)

- Concomitant systemic antiviral therapy allowed

Exclusion Criteria:

- Previous molecularly targeted therapies or any other systemic treatment for
hepatocellular carcinoma

- Active concomitant malignancy likely to effect any of the primary or secondary
outcome measures in the current study

- Women who are pregnant, breast-feeding or planning to become pregnant during the
study

- Men or women of reproductive-potential who are unwilling to use an effective method
of contraception during the study and for 30 days following the last dose of study
medication

- Evidence of a significant medical disorder or laboratory finding that, in the opinion
of the Investigator, compromises the subject's safety during study participation such
as: uncontrolled infection or infection requiring a concomitant parenteral
antibiotic; uncontrolled diabetes; congestive heart failure; myocardial infarction
within 6 months of study; chronic renal disease; or coagulopathy (excluding
prophylactic anticoagulation)

- Active CNS metastatic disease requiring intervention

- Less than four weeks since major surgery

- Known HIV positivity