Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
The study is being conducted to compare progression-free survival in patients treated with sorafenib and gemcitabine/capecitabine versus patients treated with placebo and gemcitabine/capecitabine for locally advanced or metastatic breast cancer that has progressed during or following treatment with a bevacizumab-containing regimen.
Interventions
DRUGGemcitabine
Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle
DRUGSorafenib
Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
DRUGPlacebo
Placebo will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
DRUGCapecitabine
Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine).
Sponsors
Amgen
Accelerated Community Oncology Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the breast. * Measurable or evaluable locally advanced or metastatic disease. * Age ≥18 years. * Disease progression during or after treatment with a bevacizumab-containing regimen in the adjuvant or first-line metastatic setting. * Patients must have discontinued chemotherapy at least 3 weeks prior to randomization. * No more than one prior chemotherapy regimen for locally advanced or metastatic disease. * Prior hormonal therapy allowed provided it has been discontinued prior to randomization. * Prior radiation therapy is allowed but must be completed at least 3 weeks prior to randomization. Previously radiated area(s) must not be the only site of disease. * ECOG Performance Status of 0 or 1. * Adequate bone marrow, liver, and renal function * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization, and must agree to use adequate contraception prior to study entry, for the duration of study participation and 28 days after the last study drug dosing. * Patients must be able and willing to sign a written informed consent. * Patients must be able to swallow and retain oral medication.
Exclusion criteria
* Patients with breast cancer over-expressing human epidermal growth factor receptor 2 (HER-2) (gene amplification by FISH or 3+ over-expression by immunohistochemistry). Patients with unknown HER-2 status are not eligible. * Patients with active brain metastases. * Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization. * Prior use of gemcitabine/capecitabine or sorafenib. * Evidence or history of bleeding diathesis or coagulopathy. * Serious, non-healing wound, ulcer, or bone fracture. * Substance abuse, or medical, psychological, or social condition that may interfere with the patient's participation in the study or evaluation of the study results. * Use of cytochrome P450 enzyme-inducing anti-epileptic drugs is not allowed. * Clinically significant cardiac disease * Uncontrolled hypertension * Thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. * Pulmonary hemorrhage/bleeding event \> NCI-CTCAE Grade 2 within 4 weeks of randomization. * Any other hemorrhage/bleeding event ≥ NCI-CTCAE Grade 3 within 4 weeks of randomization. * Active clinically serious infection \> NCI-CTCAE Grade 2. * Known HIV infection or chronic hepatitis B or C (the safety and effectiveness of sorafenib in this patient population have not been studied). * Previous or concurrent cancer that is distinct in primary site or histology from breast cancer EXCEPT cervical cancer in-situ, treated basal cell carcinoma, superficial bladder tumors \[Ta and Tis\] or any cancer curatively treated \> 5 years prior to randomization. * Known or suspected allergy to sorafenib or gemcitabine/capecitabine. * Prior or concurrent use of St. John's Wort or rifampin (rifampicin) within 3 weeks of randomization. * Concurrent anti-cancer therapy other than gemcitabine/capecitabine and sorafenib/placebo. * Prior treatment with any agent that targets VEGF or VEGFR (licensed or investigational), except bevacizumab. * Women who are pregnant or breast-feeding. * Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding randomization. * Inability to comply with protocol and/or not willing or not available for follow-up assessments. * Any condition which in the investigator's opinion makes the patient unsuitable for the study participation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression Free Survival | From the date of randomization to date of first documented disease progression (i.e., the date on which a radiologic procedure or clinical evaluation was performed) or the date of death due to any cause, if before progression, assessed up to 39 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of randomization to date of death due to any cause, assessed up to 56 months. | — |
| Time to Progression | Calculated as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical, whichever is earlier), assessed up to 39 months. | — |
| Overall Response Rate | The overall tumor burden at baseline will be compared with subsequent measurements up to the date of first documented disease progression or the date of death due to any cause, if before progression, assessed up to 39 months. | Overall response rate was defined as the proportion of participants experiencing complete response (CR) and partial response (PR) as best overall response. Response was evaluated via changes from baseline in radiological tumor measurements using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions. |
| Duration of Overall Response | Period measured from the first documentation of complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease or death is objectively documented. | Duration of overall response was calculated as the time (days) from first documentation of CR or PR (whichever status is recorded first) until the first date that recurrent or progressive disease (PD) or death is objectively documented. Response was evaluated via changes from baseline in radiological tumor measurements using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions. |
Countries
United States
Participant flow
Recruitment details
The period of study was 28 Jun 2007 (first subject randomized) to 29 Feb 2012 (overall survival data cutoff date). There were 40 centers in the United States that participated in this trial.
Pre-assignment details
181 patients were assessed for eligiblity. Of these, 21 patients were excluded from the trial due to not meeting the eligibility criteria, leaving 160 patients who were randomized.
Participants by arm
| Arm | Count |
|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours); Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine)
Gemcitabine: Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle
Sorafenib: Sorafenib will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
Capecitabine: Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine). | 81 |
| B (Placebo + Gemcitabine or Capecitabine) Placebo will be administered ( 2 tablets ) orally twice daily (approximately every 12 hours); Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle; Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine)
Gemcitabine: Gemcitabine will be administered 1000 mg/m2 pm Days 1 and 8 of a 21 day cycle
Placebo: Placebo will be administered (400 mg; 2 tablets x 200 mg) orally twice daily (approximately every 12 hours)
Capecitabine: Capecitabine will be administered orally at a dose of 1,000 mg/m2 twice daily, within 30 minutes after a meal, for 14 days followed by a 7 day rest period (without capecitabine). | 79 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression/recurrence/relapse | 0 | 1 |
| Overall Study | Mis-randomization | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | A (Sorafenib + Gemcitabine or Capecitabine) | B (Placebo + Gemcitabine or Capecitabine) | Total |
|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 10.6 | 54.2 years STANDARD_DEVIATION 11 | 53.8 years STANDARD_DEVIATION 10.8 |
| Region of Enrollment United States | 81 participants | 79 participants | 160 participants |
| Sex: Female, Male Female | 81 Participants | 79 Participants | 160 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 79 | 73 / 77 |
| serious Total, serious adverse events | 32 / 79 | 28 / 77 |
Outcome results
Primary
Progression Free Survival
Time frame: From the date of randomization to date of first documented disease progression (i.e., the date on which a radiologic procedure or clinical evaluation was performed) or the date of death due to any cause, if before progression, assessed up to 39 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) | Progression Free Survival | 103 Days |
| B (Placebo + Gemcitabine or Capecitabine) | Progression Free Survival | 81 Days |
Secondary
Duration of Overall Response
Duration of overall response was calculated as the time (days) from first documentation of CR or PR (whichever status is recorded first) until the first date that recurrent or progressive disease (PD) or death is objectively documented. Response was evaluated via changes from baseline in radiological tumor measurements using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.
Time frame: Period measured from the first documentation of complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease or death is objectively documented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) | Duration of Overall Response | 94 Days |
| B (Placebo + Gemcitabine or Capecitabine) | Duration of Overall Response | 147 Days |
Secondary
Overall Response Rate
Overall response rate was defined as the proportion of participants experiencing complete response (CR) and partial response (PR) as best overall response. Response was evaluated via changes from baseline in radiological tumor measurements using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is \>=30% decrease in the sum of the longest diameter (LD) of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of \>=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.
Time frame: The overall tumor burden at baseline will be compared with subsequent measurements up to the date of first documented disease progression or the date of death due to any cause, if before progression, assessed up to 39 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) | Overall Response Rate | 19.8 percentage of participants |
| B (Placebo + Gemcitabine or Capecitabine) | Overall Response Rate | 12.7 percentage of participants |
Secondary
Overall Survival
Time frame: From the date of randomization to date of death due to any cause, assessed up to 56 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) | Overall Survival | 407 Days |
| B (Placebo + Gemcitabine or Capecitabine) | Overall Survival | 348 Days |
Secondary
Time to Progression
Time frame: Calculated as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical, whichever is earlier), assessed up to 39 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A (Sorafenib + Gemcitabine or Capecitabine) | Time to Progression | 111 Days |
| B (Placebo + Gemcitabine or Capecitabine) | Time to Progression | 82 Days |