Chemoembolization With or Without Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVE:

I. To compare progression-free survival (PFS) of chemoembolization alone to sorafenib
(sorafenib tosylate) in combination with chemoembolization.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) of chemoembolization alone to sorafenib in combination
with chemoembolization.

II. To evaluate extra-hepatic versus intra-hepatic patterns of failure. III. To determine the
rates of toxicity related to sorafenib in combination with chemoembolization.

TERTIARY OBJECTIVES:

I. To analyze the pharmacogenetic and pharmacokinetic properties of sorafenib including
angiogenesis, monooxygenases, polymorphisms and multidrug resistance (MDR).

II. Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network
(ACRIN) secondary imaging objective: site versus (vs.) central evaluation of PFS.

III. To determine the inter-reader concordance for response characterization at four and
eight months by the European Association for the Study of Liver (EASL) criteria.

IV. To determine the value of objective tumor response at four and eight months by the EASL
criteria to predict PFS (by Response Evaluation Criteria in Solid Tumors [RECIST]) and OS.

V. To evaluate the effects of intra-hepatic vs. extra-hepatic progression on OS.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily (BID) in the absence of
disease progression or unacceptable toxicity. Beginning within 2 weeks after a stable dose of
sorafenib tosylate is reached, patients undergo transarterial chemoembolization (TACE)
comprising doxorubicin hydrochloride, mitomycin C, and cisplatin (closed to accrual as of
10/1/2010); conventional chemoembolization comprising doxorubicin hydrochloride only; or
chemoembolization comprising doxorubicin-eluting beads. Treatment with TACE repeats
approximately every 4 weeks for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive placebo PO BID in the absence of disease progression or unacceptable
toxicity. Beginning within 2 weeks after a stable dose of placebo is reached, patients
undergo TACE as in Arm I.

MAINTENANCE THERAPY: After completion of chemoembolization, patients receive sorafenib
tosylate or placebo as in Arm I and II in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 4 years.

Inclusion Criteria:

- Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion
listed below:

- Histologically confirmed

- Magnetic resonance imaging (MRI) or computerized tomography (CT) consistent with
liver cirrhosis AND at least one solid liver lesion > 2 cm with early enhancement
and delayed enhancement washout regardless of alpha-feto protein levels (AFP)

- AFP > 400 ng/mL AND evidence of at least one solid liver lesion > 2 cm regardless
of specific imaging characteristics on CT or MRI

- Patients must have hepatocellular carcinoma (HCC) limited to the liver; there must be
no clinical or radiographic evidence of extrahepatic HCC

- Portal lymphadenopathy IS permitted for patients with hepatitis B virus (HBV) or
hepatitis C virus (HCV) - as lymphadenopathy is commonly associated with hepatitis
unrelated to malignancy

- Staging CT of the chest and CT or MRI of the abdomen and pelvis must have been
completed within 4 weeks of study registration

- Patients must have measurable disease constituting < 50% of liver parenchyma within 4
weeks of registration

- Patients may not have ascites detectable on physical examination

- Patients must not be candidates for curative resection, orthotopic liver
transplantation, or radiofrequency ablation (RFA)

- Patients may have been treated with RFA in the past, but no sooner than 4 weeks before
study registration

- Patients may have undergone previously attempted curative liver resection

- Patients may NOT have been previously treated with brachytherapy such as yttrium-90
microsphere

- Patients may NOT have been previously treated with sorafenib, chemoembolization, or
systemic chemotherapy including cytotoxic agents or molecularly targeted agents

- Branch portal vein invasion by tumor is permitted but patients with main portal vein
invasion by tumor are not eligible

- Patients must have Child-Pugh score of A or B7 within 4 weeks prior to study
registration

- Serum total bilirubin =< 2.0 mg/dL

- Alkaline phosphatase < 5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 5 x ULN

- Serum creatinine =< 1.5 mg/dL

- Platelet count >= 50,000/mm^3

- Patients must not have any evidence of bleeding diathesis or active gastrointestinal
bleeding

- Patients must have no clinical signs of heart failure and meet New York Heart
Association functional classification I or II defined as:

- Class I - patients with no limitation of activities; they suffer no symptoms from
ordinary activities

- Class II - patients with slight, mild limitation of activity; they are
comfortable with rest or with mild exertion

- Patients must have an ECOG performance status of 0 or 1

- Patients must have a life expectancy of at least 3 months

- Patients must not be known to be human immunodeficiency virus (HIV) positive

- Patients must not have other uncontrolled intercurrent illnesses excluding HBV or HCV,
including, but not limited to: uncontrolled hypertension, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/addictive
disorders that would limit compliance with study requirements

- Uncontrolled hypertension is defined as optimally treated baseline blood pressure
that exceeds 150/90 mm Hg

- Patients must not be taking cytochrome P450 enzyme inducing drugs

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception

- Patients must not have an allergy to iodine or gadolinium contrast that cannot be
safely controlled with premedication

- Patient must be able to swallow pills, as study medications cannot be crushed