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. Kinase inhibitors, such as sorafenib tosylate may stop the growth of tumor cells by blocking the action of an abnormal protein that signals cancer cells to multiply. 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: 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. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) on study. 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. Patients also undergo CT and MRI on study. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
235
Undergo TACE
Undergo CT scan
Undergo TACE
Undergo TACE
Correlative studies
Undergo MRI
Undergo TACE
Correlative studies
Given PO
Given PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
Mobile, Alabama, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
Banner University Medical Center - Tucson
Tucson, Arizona, United States
Progression-free Survival (PFS)
PFS is defined to be the time from randomization to progression or death without evidence of progression. For cases without documentation of progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within 4 months following the date last known progression-free, in which case the death will be counted as an event. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions.
Time frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years
Overall Survival (OS)
Overall survival (OS) is defined as time from randomization to death from any cause, censoring cases who had not died at the date last known alive.
Time frame: Assessed every 3 months for 2 years and then every 6 months for 2 years
Progression-free Survival (PFS) Among Patients With Extra-hepatic Progression
PFS is defined to be the time from randomization to progression or death without evidence of progression. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. For patients with progressive disease, the progression was classified as either intra- or extra-hepatic or both intra- and extra-hepatic. Patients with both intra- and extra-hepatic progression were considered as having extra-hepatic progression. This analysis was performed among patients with extra-hepatic progression.
Time frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years
Progression-free Survival (PFS) Among Patients With Intra-hepatic Progression
PFS is defined to be the time from randomization to progression or death without evidence of progression. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. For patients with progressive disease, the progression was classified as either intra- or extra-hepatic or both intra- and extra-hepatic. This analysis was performed among patients with intra-hepatic progression.
Time frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years
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University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
John L McClellan Memorial Veterans Hospital
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Marin Cancer Care Inc
Greenbrae, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
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