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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma, Unresectable Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Cisplatin
* Procedure: Computed Tomography
* Drug: Doxorubicin Hydrochloride
* Drug: Doxorubicin-Eluting Beads
* Other: Laboratory Biomarker Analysis
* Procedure: Magnetic Resonance Imaging
* Drug: Mitomycin
* Other: Pharmacological Study
* Other: Placebo Administration
* Drug: Sorafenib Tosylate


Participation Criteria
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Eligibility Criteria
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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 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 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (sorafenib tosylate and TACE)<br>Patients receive sorafenib tosylate PO 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 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 CT and MRI on study. | Drug: Cisplatin<br>* Undergo TACE<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Doxorubicin Hydrochloride<br>* Undergo TACE<br>* Other names: Rubex;Drug: Doxorubicin-Eluting Beads<br>* Undergo TACE<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Drug: Mitomycin<br>* Undergo TACE<br>* Other names: NCI-C04706;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;|
| Active Comparator: Arm II (placebo and TACE)<br>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. | Drug: Cisplatin<br>* Undergo TACE<br>* Other names: Platosin;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Doxorubicin Hydrochloride<br>* Undergo TACE<br>* Other names: Rubex;Drug: Doxorubicin-Eluting Beads<br>* Undergo TACE<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Drug: Mitomycin<br>* Undergo TACE<br>* Other names: NCI-C04706;Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years |