Hepatocellular Carcinoma, Unresectable Hepatocellular Carcinoma
Conditions
Brief summary
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
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.
Interventions
DRUGCisplatin
Undergo TACE
PROCEDUREComputed Tomography
Undergo CT scan
DRUGDoxorubicin Hydrochloride
Undergo TACE
Undergo TACE
OTHERLaboratory Biomarker Analysis
Correlative studies
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
DRUGMitomycin
Undergo TACE
OTHERPharmacological Study
Correlative studies
OTHERPlacebo Administration
Given PO
DRUGSorafenib Tosylate
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Assessed every 3 months for 2 years and then every 6 months for 2 years | 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. |
| 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 | 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. |
| 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacogenetic and Pharmacokinetic Properties of Sorafenib Including Angiogenesis, Monooxygenases, Polymorphisms and Multidrug Resistance Mutation (MDR) | Assessed at baseline, days 1, 8 and 15 of cycle 1 sorafenib, 3-5 days prior to 2nd and 3rd TACE | This analysis will be performed across a few ECOG-ACRIN studies of sorafenib to evaluate the association between genotypes that are related with sorafenib activity and clinical outcomes. |
| Inter-reader Concordance for Response by EASL (European Association for the Study of the Liver) Criteria | at 4 months and 8 months Assessed at 4 months and 8 months following initial chemoembolization | Response was determined using the European Association for the Study of the Liver (EASL) criteria, which was recommended as an alternative to RECIST for grading therapeutic response of advanced hepatocellular carcinoma (HCC). The EASL criteria use the longest dimension of enhancing tumor as the primary metric for gauging tumor response. The Kappa statistics will be applied to assess agreement between readers. |
| Association Between Objective Tumor Response by EASL Criteria and PFS as Well as OS | 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. OS is defined as time from randomization to death or date last known alive. Response is assessed at 4 and 8 months by EASL criteria. |
| To Evaluate the Effects of Intra-hepatic vs. Extra-hepatic Progression on OS. | Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years | 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. OS is defined as the time from randomization to death or date last known alive. |
Countries
United States
Participant flow
Recruitment details
This study activated on October 28, 2009 and closed to accrual on November 19, 2014 due to poor enrollment. A total of 235 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Sorafenib and TACE) Patients receive sorafenib tosylate at 400mg 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 (this option may only be utilized for patients registered prior to addendum #3); conventional chemoembolization comprising doxorubicin hydrochloride only; or chemoembolization comprising LC bead and doxorubicin. Treatment with TACE repeats approximately every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. | 118 |
| Arm B (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 A. | 117 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 42 | 22 |
| Overall Study | Alternative therapy | 4 | 8 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Disease progression | 31 | 48 |
| Overall Study | Ineligible | 1 | 0 |
| Overall Study | Never started treatment | 8 | 9 |
| Overall Study | Non-compliance | 3 | 2 |
| Overall Study | Other complicating disease | 2 | 2 |
| Overall Study | Performance status worsening | 0 | 1 |
| Overall Study | Physician Decision | 6 | 3 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Unblinded | 0 | 1 |
| Overall Study | Withdrawal by Subject | 16 | 16 |
Baseline characteristics
| Characteristic | Arm B (Placebo and TACE) | Total | Arm A (Sorafenib and TACE) |
|---|---|---|---|
| Age, Continuous | 64.1 years | 62.8 years | 62.1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 30 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 98 Participants | 197 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 27 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 51 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 78 Participants | 149 Participants | 71 Participants |
| Sex: Female, Male Female | 16 Participants | 30 Participants | 14 Participants |
| Sex: Female, Male Male | 101 Participants | 205 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 85 / 118 | 88 / 117 |
| other Total, other adverse events | 22 / 110 | 21 / 108 |
| serious Total, serious adverse events | 65 / 110 | 41 / 108 |
Outcome results
Primary
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
Population: All randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Sorafenib and TACE) | Progression-free Survival (PFS) | 9.3 months |
| Arm B (Placebo and TACE) | Progression-free Survival (PFS) | 8.4 months |
p-value: 0.4Cochran-Mantel-Haenszel
Secondary
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
Population: All randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Sorafenib and TACE) | Overall Survival (OS) | 19.8 months |
| Arm B (Placebo and TACE) | Overall Survival (OS) | 19.9 months |
p-value: 0.76Log Rank
Secondary
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
Population: Only patients with extra-hepatic progression (as well as those with both intra- and extra-hepatic progression) are included in this analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Sorafenib and TACE) | Progression-free Survival (PFS) Among Patients With Extra-hepatic Progression | 6.83 months |
| Arm B (Placebo and TACE) | Progression-free Survival (PFS) Among Patients With Extra-hepatic Progression | 5.6 months |
Secondary
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
Population: Only patients with intra-hepatic progression are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Sorafenib and TACE) | Progression-free Survival (PFS) Among Patients With Intra-hepatic Progression | 8.5 months |
| Arm B (Placebo and TACE) | Progression-free Survival (PFS) Among Patients With Intra-hepatic Progression | 7.8 months |
Other Pre-specified
Association Between Objective Tumor Response by EASL Criteria and PFS as Well as OS
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. OS is defined as time from randomization to death or date last known alive. Response is assessed at 4 and 8 months by EASL criteria.
Time frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years
Other Pre-specified
Inter-reader Concordance for Response by EASL (European Association for the Study of the Liver) Criteria
Response was determined using the European Association for the Study of the Liver (EASL) criteria, which was recommended as an alternative to RECIST for grading therapeutic response of advanced hepatocellular carcinoma (HCC). The EASL criteria use the longest dimension of enhancing tumor as the primary metric for gauging tumor response. The Kappa statistics will be applied to assess agreement between readers.
Time frame: at 4 months and 8 months Assessed at 4 months and 8 months following initial chemoembolization
Other Pre-specified
Pharmacogenetic and Pharmacokinetic Properties of Sorafenib Including Angiogenesis, Monooxygenases, Polymorphisms and Multidrug Resistance Mutation (MDR)
This analysis will be performed across a few ECOG-ACRIN studies of sorafenib to evaluate the association between genotypes that are related with sorafenib activity and clinical outcomes.
Time frame: Assessed at baseline, days 1, 8 and 15 of cycle 1 sorafenib, 3-5 days prior to 2nd and 3rd TACE
Other Pre-specified
To Evaluate the Effects of Intra-hepatic vs. Extra-hepatic Progression on OS.
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. OS is defined as the time from randomization to death or date last known alive.
Time frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years