Trial Information

A Phase III Randomized, Double-Blind Trial of Chemoembolization With or Without Sorafenib in Unresectable Hepatocellular Carcinoma (HCC) in Patients With and Without Vascular Invasion

PRIMARY OBJECTIVE:

I. To compare Progression-Free Survival (PFS) of chemoembolization alone to sorafenib 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 MDR.

II. ECOG secondary imaging objective: Site 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 RECIST) and OS.

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

OUTLINE: This is a multicenter study. Patients are stratified according to macrovascular
intrahepatic portal vein invasion (present vs absent), Child Pugh score (A vs B7), and
chemoembolization method (doxorubicin-eluting bead vs conventional). Patients are randomized
to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily 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 twice daily 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. Patients undergo chest, abdomen, and/or pelvis CT scans or MRI at baseline, at 4
and 8 months, and every 2 months thereafter.

Blood and tissue samples may be collected at baseline and periodically during study for
pharmacogenetic and pharmacokinetic studies. After completion of study therapy, patients are
followed up periodically for 4 years.