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
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
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.
Inclusion Criteria:
Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below:
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:
Patients must have an Eastern Cooperative Oncology Group (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
Patients must not be taking cytochrome P450 enzyme inducing drugs
Age >= 18 years
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
Washington D.C., District of Columbia 20422, United States
Highland Park, Illinois 60035, United States
Pekin, Illinois 61554, United States
Saint Louis Park, Minnesota 55416, United States
Lebanon, New Hampshire 03756, United States
Brooklyn, New York 11209, United States
New York, New York 10010, United States
Winston-Salem, North Carolina 27104, United States