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

This randomized phase III trial studies chemoembolization and sorafenib tosylate to see how well they work compared with chemoembolization alone in treating patients with liver cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, mitomycin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Chemoembolization kills tumor cells by carrying drugs directly into blood vessels near the tumor and then blocking the blood flow to allow a higher concentration of the drug to reach the tumor for a longer period of time. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving chemoembolization together with sorafenib tosylate is more effective than chemoembolization alone in treating patients with liver cancer.

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

1. 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:

1. 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.

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

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

ARM A: Patients receive sorafenib tosylate at 400 mg 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 B: 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 A.

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

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