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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 235
- 试验地点
- 278
- 主要终点
- Progression-free Survival (PFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- 未提供
研究组 & 干预措施
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Cisplatin (Drug)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Computed Tomography (Procedure)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Doxorubicin-Eluting Beads (Drug)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Mitomycin (Drug)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Pharmacological Study (Other)
Arm I (sorafenib tosylate and TACE)
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.
干预措施: Sorafenib Tosylate (Drug)
Arm II (placebo and TACE)
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.
干预措施: Cisplatin (Drug)
Arm II (placebo and TACE)
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.
干预措施: Computed Tomography (Procedure)
Arm II (placebo and TACE)
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.
干预措施: Mitomycin (Drug)
Arm II (placebo and TACE)
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.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm II (placebo and TACE)
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.
干预措施: Doxorubicin-Eluting Beads (Drug)
Arm II (placebo and TACE)
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.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (placebo and TACE)
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.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (placebo and TACE)
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.
干预措施: Pharmacological Study (Other)
Arm II (placebo and TACE)
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.
干预措施: Placebo Administration (Other)
结局指标
主要结局
Progression-free Survival (PFS)
时间窗: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years
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.
次要结局
- Overall Survival (OS)(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(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(Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years)