• 1. To evaluate the anti-cancer activity (e.g. proportion of patients with confirmed complete responses and partial responses as per the WHO criteria) in patients with advanced inoperable biopsy-proven hepatocellular carcinoma [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  

• 1. To determine duration of response, time to response, time to progression, duration of stable disease and survival. [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  
• 2. To evaluate proportion of patients with stable disease. [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  
• 3. To determine the toxicities of this treatment regimen, [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  
• 4. Pharmacokinetic profiles of sorafenib will be determined in approximately 20-23 patients enrolled in selected sites, to receive all requested plasma samples from 16 patients with valid pharmacokinetic data. [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  
• 5. To evaluate pERK concentration in the original tumor biopsy, when possible, and correlate it with measures of clinical benefit (e.g. response, time to progression and survival). [ Time Frame: Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria. ] [ Designated as safety issue: No ]
  

TIME FRAME Secondary outcomes:

Tumor response measurements will be made at baseline and every 8 weeks, within the last 10 days of each dual cycle during the treatment period, according to WHO criteria.

Pharmacokinetic profiles will be determinate in the first 20 patients enrolled in selected sites, on day 28 of the first dosing cycle (one day prior or after day 28 is allowed). Alpha-fetoprotein (AFP), Serum Her-2 status and plasma adrenomedullin levels will be measured every 8 weeks (2 cycles). Serum protein pattern and blood cell RNA expression pattern will be measured on day 15 of the first cycle and on day 1 of every second cycle starting at cycle 3 (cycle 5, 7 etc). Plasma samples for viral load will also be measured at these time points for selected patients. Viral serology: Hepatitis C virus antibody (HCV Ab) and Hepatitis B surface antigen (HBsAg) will be analyzed by local laboratory in each site on day 15 of the first cycle and on day 1 of every second cycle starting at cycle 3 (cycle 5, 7 etc). pERK concentration will be measured in the tumor biopsy, (but not from cytology specimens), taken during cycle 2 if possible, according to the investigators discretion

Inclusion Criteria:

• Histologically or cytologically confirmed primary hepatocellular carcinoma (HCC)
• Inoperable disease (T2-T4, any N, M0 or M1) or refused surgery
• Measurable disease
• At least 1 bidimensionally measurable lesion at least 2 cm by CT scan or MRI
• Presence of at least 1 of the following:
• Alpha-fetoprotein greater than the upper limit of normal (ULN)
• Hepatitis C antibody positive
• Hepatitis B surface antigen positive
• Child's Pugh class A or B
• Candidate for systemic therapy

Exclusion Criteria:

• Fibrolamellar disease mixed histology
• Metastatic brain or meningeal tumors