Carcinoma, Hepatocellular
Conditions
Keywords
Sorafenib (Nexavar), Erlotinib (Tarceva), First Line, HCC
Brief summary
This is a randomized trial to evaluate the clinical benefit of sorafenib 400 mg twice daily and erlotinib 150 mg once a day versus sorafenib 400 mg twice daily and placebo erlotinib once daily in subjects with unresectable advanced or metastatic Child-Pugh A HCC. Patients who are candidates for potentially curative intervention (i.e. surgical resection or local ablation) are not eligible for this study.
Detailed description
European quality of life scale (5 dimensions) (EQ-5D)
Interventions
DRUGSorafenib (Nexavar, BAY43-9006)
Sorafenib 400 mg twice daily
Erlotinib 150 mg once daily
DRUGPlacebo
Matching erlotinib placebo 150 mg once daily
Sponsors
Bayer
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 \> 18 years of age * Patients who have a life expectancy of at least 12 weeks * Patients with histological or cytologically documented HCC * Patients must have at least one tumor lesion that meets both of the following criteria: * The lesion can be accurately measured in at least one dimension according to response evaluation criteria in solid tumors (RECIST) * The lesion has not been previously treated with local therapy * Patients who have an ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 0 or 1 * Cirrhotic status of Child-Pugh class A. * Patients who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time.
Exclusion criteria
* History of cardiac disease: congestive heart failure \> New York Heart Association (NYHA) class 2; active coronary artery disease (CAD); cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin), or uncontrolled hypertension. Myocardial infarction more than 6 months prior to study entry is permitted. * Abnormalities of the cornea based on history (e.g. dry eye syndrome, Sogren's syndrome) including congenital abnormality (e.g. Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g. fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test). * History of interstitial lung disease (ILD). * Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry. * Previous treatment with yttrium-90 spheres * Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study. * Uncontrolled ascites (defined as not easily controlled with diuretic treatment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization of the first patient until 34 months or date of death of any cause whichever came first | Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control | From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks | Disease control was defined as the number of participants who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST assessed by magnetic resonance imaging (MRI) that was confirmed at least 28 days from the first demonstration of that rating. CR: disappearance of all clinical and radiological evidence of target and non-target tumors. PR: at least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. SD: steady state of disease. Neither sufficient shrinkage for PR nor sufficient increase for PD. |
| Time to Radiological Tumor Progression (TTP) | From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks | TTP was the time from randomization to radiological tumor progression. Participants without radiological tumor progression at the time of analysis were censored at their last date of tumor evaluation. Progressive disease (PD) was defined using Response Evaluation Criteria in Solid Tumors (RECIST version 1.0), as at least a 20% increase in the sum of longest diameter (LD) of measured lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Appearance of new lesions also constituted PD. |
| Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | The EQ-5D was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit. | The European quality of life scale (5 dimensions) (EQ-5D) questionnaire was given to the participants at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems'). The 5 health dimensions are summarized into a single score, the EQ-5D index score. The EQ-5D index score has a range of 0 and 1 with 0 representing death and 1 representing perfect health. |
| Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | The EQ-5D VAS was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit. | Participants indicated on a scale of 0 (worst) to 100 (best) how good or bad their health state was on that particular day. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response | From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks | Tumor response was the proportion of participants with the best tumor response (ie, achieving either a confirmed complete response \[CR\] or partial response \[PR\], according to Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria). |
| Time to Response | From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks | Time to response was the number of days from randomization to the date the CR or PR was documented (with confirmation) (Note: the relevant date is that of the first documentation, not the confirmation date). |
| Duration of Response | From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks | Duration of response - RECIST: number of days from the date that CR or PR is first documented to date that PD is first objectively documented or to death before progression. Note: the relevant date is that of the first documentation, not the confirmation date (if participant progressed or died then censored=no) or to last observation if participant did not progress or die then censored=yes note: this last observation date should be the same as that used for time to progression. |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, France, Germany, Greece, Hong Kong, Israel, Italy, New Zealand, Peru, Poland, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 128 study centers in 26 countries in North America, South America, Europe, Africa, and Asia.
Pre-assignment details
Of the 962 screened participants, 242 were screen failures and were excluded from participated in the study. A total of 720 participants were randomized to study arms: 358 participants in the sorafenib + placebo group and 362 participants in the sorafenib + erlotinib group.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) Participants received sorafenib 400 mg twice daily (bid) and erlotinib 150 mg tablet once daily (qd) | 362 |
| Sorafenib (Nexavar, BAY43-9006) + Placebo Participants received sorafenib 400 mg twice daily (bid) and matching erlotinib placebo 150 mg tablet once daily (qd) | 358 |
| Total | 720 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Death | 181 | 208 |
| Follow-up Period | Lost to Follow-up | 12 | 8 |
| Follow-up Period | Missing | 94 | 80 |
| Follow-up Period | Protocol driven decision point | 47 | 36 |
| Follow-up Period | Withdrawal by Subject | 6 | 9 |
| Treatment Period | Adverse Event | 120 | 128 |
| Treatment Period | Lost to Follow-up | 3 | 5 |
| Treatment Period | Missing | 1 | 0 |
| Treatment Period | Never treated | 0 | 3 |
| Treatment Period | Noncompliance with study medication | 4 | 1 |
| Treatment Period | Physician Decision | 2 | 2 |
| Treatment Period | Protocol driven decision point | 0 | 2 |
| Treatment Period | Protocol Violation | 5 | 9 |
| Treatment Period | Study terminated by sponsor | 2 | 0 |
| Treatment Period | Switch to commercial drug | 1 | 1 |
| Treatment Period | Transfer to treatment continuation study | 5 | 2 |
| Treatment Period | Withdrawal by Subject | 26 | 24 |
Baseline characteristics
| Characteristic | Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Sorafenib (Nexavar, BAY43-9006) + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.3 Years STANDARD_DEVIATION 11.8 | 59.5 Years STANDARD_DEVIATION 13 | 59.9 Years STANDARD_DEVIATION 12.4 |
| ECOG stratification group 0 | 222 Participants | 216 Participants | 438 Participants |
| ECOG stratification group 1 | 140 Participants | 142 Participants | 282 Participants |
| Extrahepatic spread No | 157 Participants | 139 Participants | 296 Participants |
| Extrahepatic spread Yes | 205 Participants | 219 Participants | 424 Participants |
| Macroscopic vascular invasion No | 224 Participants | 205 Participants | 429 Participants |
| Macroscopic vascular invasion Yes | 138 Participants | 153 Participants | 291 Participants |
| Sex: Female, Male Female | 67 Participants | 72 Participants | 139 Participants |
| Sex: Female, Male Male | 295 Participants | 286 Participants | 581 Participants |
| Smoking status current smoker | 118 Participants | 123 Participants | 241 Participants |
| Smoking status former smoker | 132 Participants | 128 Participants | 260 Participants |
| Smoking status non-smoker | 112 Participants | 107 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 353 / 362 | 349 / 355 |
| serious Total, serious adverse events | 214 / 362 | 198 / 355 |
Outcome results
Primary
Overall Survival
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause.
Time frame: From randomization of the first patient until 34 months or date of death of any cause whichever came first
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Overall Survival | 289 Days |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Overall Survival | 259 Days |
Secondary
Disease Control
Disease control was defined as the number of participants who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST assessed by magnetic resonance imaging (MRI) that was confirmed at least 28 days from the first demonstration of that rating. CR: disappearance of all clinical and radiological evidence of target and non-target tumors. PR: at least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. SD: steady state of disease. Neither sufficient shrinkage for PR nor sufficient increase for PD.
Time frame: From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Disease Control | 159 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Disease Control | 188 Participants |
Secondary
Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index
The European quality of life scale (5 dimensions) (EQ-5D) questionnaire was given to the participants at each visit. The EQ-5D questionnaire consisted of 5 ordinal categorical responses (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The scores for the EQ-5D dimensions are assigned according to the level of problems reported (1 'no problems'; 2 'some problems'; 3 'extreme problems'). The 5 health dimensions are summarized into a single score, the EQ-5D index score. The EQ-5D index score has a range of 0 and 1 with 0 representing death and 1 representing perfect health.
Time frame: The EQ-5D was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit.
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle2 | 0.753 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle4 | 0.704 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle1 | 0.777 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle5 | 0.679 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle3 | 0.728 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle6 | 0.654 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle3 | 0.724 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle1 | 0.774 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle2 | 0.749 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle6 | 0.651 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle4 | 0.700 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - Index | cycle5 | 0.675 Scores on a scale |
Secondary
Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS
Participants indicated on a scale of 0 (worst) to 100 (best) how good or bad their health state was on that particular day.
Time frame: The EQ-5D VAS was administered at the beginning of the visit prior to seeing the investigator. Questionnaires were to be completed every 6 weeks (Day 1 of each cycle) for subsequent cycles and at the end of treatment visit.
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle1 | 74.397 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle2 | 72.649 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle3 | 70.900 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle4 | 69.151 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle5 | 67.402 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle6 | 65.653 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle5 | 67.660 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle1 | 74.656 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle4 | 69.409 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle2 | 72.907 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle6 | 65.911 Scores on a scale |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Health-related Quality of Life and Utility Values as Measured by EQ-5D - VAS | cycle3 | 71.158 Scores on a scale |
Secondary
Time to Radiological Tumor Progression (TTP)
TTP was the time from randomization to radiological tumor progression. Participants without radiological tumor progression at the time of analysis were censored at their last date of tumor evaluation. Progressive disease (PD) was defined using Response Evaluation Criteria in Solid Tumors (RECIST version 1.0), as at least a 20% increase in the sum of longest diameter (LD) of measured lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. Appearance of new lesions also constituted PD.
Time frame: From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Time to Radiological Tumor Progression (TTP) | 97 Days |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Time to Radiological Tumor Progression (TTP) | 122 Days |
Other Pre-specified
Duration of Response
Duration of response - RECIST: number of days from the date that CR or PR is first documented to date that PD is first objectively documented or to death before progression. Note: the relevant date is that of the first documentation, not the confirmation date (if participant progressed or died then censored=no) or to last observation if participant did not progress or die then censored=yes note: this last observation date should be the same as that used for time to progression.
Time frame: From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
Population: The full analysis set (FAS), which was defined as all randomized participants. Duration of response was evaluated in the 14 participants in the sorafenib + placebo group and 24 participants in the sorafenib + erlotinib group who achieved their confirmed best response as CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Duration of Response | 297 Days |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Duration of Response | 168 Days |
Other Pre-specified
Time to Response
Time to response was the number of days from randomization to the date the CR or PR was documented (with confirmation) (Note: the relevant date is that of the first documentation, not the confirmation date).
Time frame: From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
Population: The full analysis set (FAS), which was defined as all randomized participants. Time to response was evaluated in the 14 participants in the sorafenib + placebo group and 24 participants in the sorafenib + erlotinib group who achieved their confirmed best response as CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Time to Response | 84.5 Days |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Time to Response | 83.5 Days |
Other Pre-specified
Tumor Response
Tumor response was the proportion of participants with the best tumor response (ie, achieving either a confirmed complete response \[CR\] or partial response \[PR\], according to Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria).
Time frame: From randomization of the first participant until 34 months later (cut-off date), assessed every 6 weeks
Population: The full analysis set (FAS), which was defined as all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + Erlotinib (Tarceva) | Tumor Response | 24 Participants |
| Sorafenib (Nexavar, BAY43-9006) + Placebo | Tumor Response | 14 Participants |