Phase III Randomized Study of Sorafenib Plus Doxorubicin Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

Inclusion Criteria:

- Patients must have pathologically or cytologically proven hepatocelluar carcinoma;
Known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or
fibrolamellar variant is not allowed

- Patients must have locally advanced or metastatic disease; Locally advanced disease
is defined as disease deemed to be unresectable or non-eligible for transplant
without distant metastases

- Lesions must be accurately measurable in at least one dimension (longest diameter to
be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral CT
scan

- No prior adjuvant sorafenib or other Raf/VEGF inhibitors; Other prior adjuvant
therapy is allowed if completed >6 months prior to registration with documented
recurrence of HCC

- Patients may have been treated with loco regional therapies provided that they either
have:

- 1) a target lesion that has not been subjected to local therapy or

- 2) the target lesion(s) within the field of the local therapy has shown an
increase of >= 20% in the size since last treatment.

- Such therapy must be completed at least 4 weeks prior to registration;
Patients that have received palliative radiation therapy to the bone need
not wait 4 weeks to begin protocol therapy

- Prior therapies allowed include the following:

- A) bland embolization, radiation, radioactive microspheres, etc

- B) chemoembolization using any chemotherapy (except, see "D", below)

- C) chemoembolization drug-eluting beads using doxorubicin

- D) prior therapy with chemoembolization using doxorubicin in the non drug
eluting beads form is NOT allowed

- No prior systemic therapy for metastatic disease

- No prior exposure to systemic doxorubicin administered intravenously

- Antiviral treatment is allowed, however interferon therapy must be stopped at least 4
weeks prior to registration

- Allografts are not allowed: No prior history of any allograft, including but not
limited to liver and bone marrow transplants

- No known CNS tumors including brain metastases

- No clinically significant gastrointestinal bleeding events requiring intervention,
transfusion, or admission to hospital within 30 days prior to registration

- Patients must have completed any major surgery >= 4 weeks from registration

- Concomitant treatment with Rifampin or St John's Wort is not allowed; Patients should
discontinue these drugs at least 4 weeks prior to registration

- Patients with a history of hypertension should be well controlled (< 140/90 mmHg) on
a regimen of anti-hypertensive therapy

- Significant history of cardiac disease is not allowed:

- Congestive heart failure > Class II New York Heart Assocation (NYHA)

- Myocardial infarction within 6 months prior to registration

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
or digoxin

- Serious myocardial dysfunction, defined as scintigraphically (MUGA, myocardial
scintigram) determined absolute left ventricular ejection fraction (LVEF) below
45% or an LVEF below the normal limit at the individual institution

- No history of bleeding diathesis

- Patients receiving combination anti-retroviral therapy for human immunodeficiency
virus (HIV) are excluded from the study because of possible pharmacokinetic
interactions with sorafenib

- ECOG performance status 0-2

- Pregnancy/Nursing Status: The effects of sorafenib on the developing fetus at the
recommended therapeutic dose are unknown and may be teratogenic; Thus, women who are
pregnant should not go on study. Women should not breastfeed while participating in
this study

- Granulocytes ≥ 1,500/μL

- Hemoglobin ≥ 8.5 g/dL

- Platelets ≥ 75,000/μL

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Child-Pugh score A

- Bilirubin ≤ 3 mg/dL

- ALT and AST ≤ 5 times upper limit of normal (ULN)

- PT/INR ≤ 1.7 (Patients who are being therapeutically anticoagulated with an agent
such as coumadin or heparin will be allowed to participate provided that no prior
evidence of underlying abnormality in these parameters exists)