Metastatic Breast Cancer
Conditions
Brief summary
This is a Phase III, multicenter, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared with chemotherapy alone in subjects with previously untreated metastatic breast cancer.
Detailed description
This study includes a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up phase. During the blinded treatment phase, patients receive chemotherapy and study drug (bevacizumab or placebo) every 3 weeks until disease progression, treatment-limiting toxicity, or death due to any cause. The optional open-label post-progression phase consists of chemotherapy treatment (per investigator discretion) and optional treatment with open-label bevacizumab. Patients who complete the study or who discontinue from treatment (regardless of participation in the optional open-label post-progression phase) will be followed for survival and subsequent anti-cancer therapies every 4 months until death, withdrawal of consent, loss to follow-up, or study termination. Patients who discontinue from treatment during the blinded treatment phase for reasons other than disease progression will have tumor assessments every 9 weeks until documented disease progression or death.
Interventions
DRUGBevacizumab
Patients received bevacizumab until disease progression, treatment limiting toxicity, or death due to any cause up to a maximum treatment duration of 48 months. The dose of bevacizumab was based on the patient's weight at either screening or baseline and remained the same throughout the blinded treatment phase of the study. The initial dose was delivered over 90±10 minutes. If there were no infusion related adverse events (fever and/or chills), the second infusion was delivered over 60±10 minutes. If the 60 minute infusion was well tolerated, all subsequent infusions were delivered over 30±10 minutes.
DRUGPlacebo
Placebo consisted of the vehicle for bevacizumab without the antibody.
DRUGChemotherapy
The chemotherapy was selected by the investigator prior to randomization. Chemotherapy treatment continued until disease progression, unacceptable toxicity, investigator/patient decision, or death, whichever occurred first, except for the anthracycline-based regimens, which had a maximum treatment duration of 8 cycles. Taxanes - 1 of the following 2 taxanes on Day 1 of every 21-day cycle 1. Docetaxel 75-100 mg/m\^2 IV 2. Paclitaxel protein-bound particles (Abraxane®) 260 mg/m\^2 IV Anthracyclines - 1 of the following 4 anthracycline-based regimens on Day 1 of every 21-day cycle 1. 5-fluorouracil 500 mg/m\^2 IV + epirubicin 90-100 mg/m\^2 IV + cyclophosphamide 500 mg/m\^2 IV 2. 5-fluorouracil 500 mg/m\^2 IV + doxorubicin 50 mg/m\^2 IV + cyclophosphamide 500 mg/m\^2 IV 3. Doxorubicin 50-60 mg/m\^2 IV + cyclophosphamide 500-600 mg/m\^2 IV 4. Epirubicin 90-100 mg/m\^2 IV + cyclophosphamide 500-600 mg/m\^2 IV Capecitabine: 1000 mg/m\^2 orally twice daily on Days 1-14 of each 21-day cycle
Sponsors
Genentech, Inc.
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
* Histologically or cytologically confirmed adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease. * Signed Informed Consent Form. * Age ≥ 18 years. * For women of childbearing potential, use of accepted and effective method of non-hormonal contraception. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Ability and capacity to comply with study and follow-up procedures. * For anthracycline cohort only: Adequate left ventricular function at study entry, defined as a left ventricular ejection fraction (LVEF) ≥ 50% by either multigated acquisition (MUGA) scan scan or echocardiography (ECHO). * For subjects who have received recent radiation therapy, recovery prior to baseline (Day 0) from any significant (Grade ≥ 3) acute toxicity.
Exclusion criteria
* Unknown human epidermal growth factor receptor 2 (HER2) status or known HER2-positive status. * Prior chemotherapy for locally recurrent or metastatic disease. * Prior hormonal therapy less than 1 week prior to Day 0. * Prior adjuvant or neoadjuvant chemotherapy within 12 months prior to Day 0. * For anthracycline cohort only: Prior anthracycline as part of neoadjuvant or adjuvant therapy for localized breast cancer. * Investigational therapy within 28 days of Day 0. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study. * Minor surgical procedures, such as fine needle aspirations or core biopsies, within 7 days prior to Day 0. * Prior therapy with bevacizumab, sorafenib, sunitinib, or other vascular endothelial growth factor (VEGF) pathway-targeted therapy. * Known brain or other central nervous system (CNS) metastases. * Blood pressure of \> 150/100 mmHg. * Unstable angina. * New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF). * History of myocardial infarction within 6 months prior to Day 0. * History of stroke or transient ischemic attack within 6 months prior to Day 0. * Clinically significant peripheral vascular disease. * Evidence of bleeding diathesis or coagulopathy. * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0. * Serious non-healing wound, ulcer, or bone fracture. * Pregnancy (positive serum pregnancy test) or lactation. * Inadequate organ function, as evidenced by any of the following laboratory values: Absolute neutrophil count \< 1500/uL; platelet count \< 100,000/uL; total bilirubin \> 1.5 mg/dL; alkaline phosphatase, AST, and/or ALT \> 2x upper limit of normal (ULN) (\> 5x ULN in subjects with known liver or, for alkaline phosphatase elevations, bone involvement); alkaline phosphatase \> 2x ULN (\> 7x ULN in subjects with known bone involvement); serum creatinine \> 2.0 mg/dL; partial thromboplastin time (PTT) and/or either international normalized ratio (INR) or prothrombin time (PT) \> 1.5x upper limit of normal (except for subjects receiving anti-coagulation therapy); urine protein/creatinine ratio \> 1.0 at screening for U.S. subjects, or urine dipstick for proteinuria \>/= 1+ at screening followed by 24-hour urine collection demonstrating \> 1 g protein/24 hr for ex-U.S. subjects. * Uncontrolled serious medical or psychiatric illness. * Active infection requiring intravenous (iv) antibiotics at Day 0. * History of other malignancies within 5 years of Day 0 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix (subjects with a history of bilateral breast cancer will be eligible).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months) | PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months) | An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions. |
| Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months) | Duration of objective response was defined as the time from the first tumor assessment that led to a determination of an objective response to the time of disease progression or death due to any cause, whichever occurred first. |
| Overall Survival | Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months) | Overall survival was defined as the time from randomization until death from any cause. |
| 1-year Survival | Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months) | 1-year survival was defined as the percentage of patients who were alive 1 year after randomization. The percentage of patients alive at 1 year was determined using Kaplan-Meier analyses and the 95% confidence intervals were computed using the Brookmeyer-Crowley method. |
| Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) | Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months) | PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the Independent Review Committee using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. |
Countries
Australia, Brazil, Canada, France, Greece, Guatemala, Mexico, Netherlands, Norway, Panama, Peru, Philippines, Russia, Singapore, South Korea, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States, Uruguay
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer. | 415 |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer. | 207 |
| Bevacizumab 15 mg/kg + Capecitabine Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer. | 409 |
| Placebo to Bevacizumab + Capecitabine Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer. | 206 |
| Total | 1,237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 190 | 89 | 186 | 99 |
| Overall Study | Lost to Follow-up | 5 | 4 | 7 | 5 |
| Overall Study | Patient Withdrew for Survival Follow-up | 23 | 7 | 23 | 9 |
| Overall Study | Sponsor's Decision to Terminate Study | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Bevacizumab 15 mg/kg + Capecitabine | Placebo to Bevacizumab + Capecitabine |
|---|---|---|---|---|---|
| Age, Customized 40-64 years | 881 Participants | 295 Participants | 160 Participants | 289 Participants | 137 Participants |
| Age, Customized < 40 years | 79 Participants | 29 Participants | 14 Participants | 21 Participants | 15 Participants |
| Age, Customized ≥ 65 years | 277 Participants | 91 Participants | 33 Participants | 99 Participants | 54 Participants |
| Sex: Female, Male Female | 1232 Participants | 413 Participants | 207 Participants | 408 Participants | 204 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 413 | 19 / 202 | 72 / 404 | 15 / 201 |
| serious Total, serious adverse events | 156 / 413 | 59 / 202 | 140 / 404 | 72 / 201 |
Outcome results
Primary
Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.
Time frame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 9.2 Months |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 8.0 Months |
| Bevacizumab 15 mg/kg + Capecitabine | Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 8.6 Months |
| Placebo to Bevacizumab + Capecitabine | Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 5.7 Months |
Secondary
1-year Survival
1-year survival was defined as the percentage of patients who were alive 1 year after randomization. The percentage of patients alive at 1 year was determined using Kaplan-Meier analyses and the 95% confidence intervals were computed using the Brookmeyer-Crowley method.
Time frame: Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | 1-year Survival | 80.7 Percentage of participants |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | 1-year Survival | 83.2 Percentage of participants |
| Bevacizumab 15 mg/kg + Capecitabine | 1-year Survival | 81.0 Percentage of participants |
| Placebo to Bevacizumab + Capecitabine | 1-year Survival | 74.8 Percentage of participants |
Secondary
Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Duration of objective response was defined as the time from the first tumor assessment that led to a determination of an objective response to the time of disease progression or death due to any cause, whichever occurred first.
Time frame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment. Only patients with measurable disease at baseline and who had an objective response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 8.3 Months |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 7.1 Months |
| Bevacizumab 15 mg/kg + Capecitabine | Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 9.2 Months |
| Placebo to Bevacizumab + Capecitabine | Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 7.2 Months |
Secondary
Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
Time frame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment. Only patients with measurable disease at baseline were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 51.3 Percentage of participants |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 37.9 Percentage of participants |
| Bevacizumab 15 mg/kg + Capecitabine | Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 35.4 Percentage of participants |
| Placebo to Bevacizumab + Capecitabine | Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) | 23.6 Percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the time from randomization until death from any cause.
Time frame: Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Overall Survival | 27.5 Months |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Overall Survival | NA Months |
| Bevacizumab 15 mg/kg + Capecitabine | Overall Survival | 25.7 Months |
| Placebo to Bevacizumab + Capecitabine | Overall Survival | 22.8 Months |
Secondary
Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST)
PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the Independent Review Committee using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first.
Time frame: Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)
Population: Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen | Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) | 10.7 Months |
| Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen | Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) | 8.3 Months |
| Bevacizumab 15 mg/kg + Capecitabine | Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) | 9.8 Months |
| Placebo to Bevacizumab + Capecitabine | Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) | 6.2 Months |