Metastatic Breast Cancer
Conditions
Keywords
Ribbon 2, Avastin, MBC, Breast cancer
Brief summary
This phase III, multicenter, randomized, placebo-controlled, blinded trial is designed to evaluate the efficacy and safety of bevacizumab when combined with standard chemotherapy compared with chemotherapy alone in subjects with previously treated metastatic breast cancer.
Detailed description
For all Outcome Measures except Overall Survival and One-year Survival, the Time Frame was from Baseline to data cut-off for analysis of the primary Outcome Measure (up to 3 years 2 months). For the Outcome Measures Overall Survival and One-year Survival, the Time Frame was from Baseline to the end of the study (up to 6 years, 7 months).
Interventions
DRUGBevacizumab
The dose of bevacizumab was based on a patient's weight at baseline and remained the same throughout the study.
DRUGPlacebo
DRUGStandard chemotherapy
Patients received one of the following four standard chemotherapies for metastatic breast cancer. 1. Taxane - Paclitaxel (Taxol) 90 mg/m\^2 IV every week for 3 weeks followed by 1 week of rest; paclitaxel (Taxol) 175 mg/m\^2 IV every 3 weeks, or paclitaxel protein-bound particles (Abraxane) 260 mg/m\^2 IV every 3 weeks; or docetaxel (Taxotere) 75-100 mg/m\^2 IV every 3 weeks. 2. Gemcitabine (Gemzar) 1250 mg/m\^2 IV on Days 1 and 8 of each 3-week cycle. 3. Vinorelbine (Navelbine) 30 mg/m\^2 IV every week of each 3-week cycle. 4. Capecitabine (Xeloda) 1000 mg/m\^2 orally twice daily on Days 1-14 of each 3-week 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
* Signed informed consent form. * ≥ 18 years of age. * Histologically confirmed carcinoma of the breast with measurable or non-measurable metastatic disease that has progressed (patients with a history of brain metastasis are eligible for study participation \[USA only\], as long as their brain metastases have been treated and they have no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone). * Progression of disease during or following administration of one (non-investigational) chemotherapy regimen administered in the first-line setting. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * For women of childbearing potential, use of an effective means of non-hormonal contraception. * Life expectancy ≥ 3 months. * Willingness and capacity to comply with study and follow-up procedures.
Exclusion criteria
* Prior hormonal therapy only as treatment for metastatic disease without chemotherapy. Patients must have received chemotherapy for their metastatic disease in the first-line setting. Hormone therapy alone is not allowed. * For subjects who have received prior anthracycline-based therapy, documentation of left ventricular ejection fraction \< 50% by either multiple gated acquisition (MUGA) or echocardiogram (ECHO). * Treatment with more than one prior cytotoxic regimen for metastatic breast cancer (MBC). * HER2-positive status (patients who have unknown HER2 status, and for whom determination of HER2 status is not possible, are eligible for this study). * Unknown estrogen receptor (ER) and progesterone receptor (PR) status. * Radiation therapy other than for palliation or brain metastasis, biologic therapy, or chemotherapy for MBC within 21 days prior to Day 0 (Day 1 of Cycle 1 of treatment). * Prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) pathway-targeted therapy. * Untreated brain metastasis. * Inadequately controlled hypertension. * Unstable angina. * New York Heart Association Grade II or greater congestive heart failure (CHF). * History of myocardial infarction within 6 months prior to Day 0 (the day of the first bevacizumab/placebo infusion). * 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. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0; anticipation of need for major elective surgical procedure during the study. * Minor surgical procedures, fine-needle aspirations, or core biopsies within 7 days prior to Day 0. * 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. * History of anaphylactic reaction to monoclonal antibody therapy not controlled with treatment premedication. * 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. * inadequate organ function. * Pregnancy (positive serum pregnancy test) or lactation. * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the subject at high risk from treatment complications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Baseline to data cut-off for analysis of the primary Outcome Measure (up to 3 years, 2 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 |
|---|---|---|
| Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Baseline to data cut-off for analysis of the primary Outcome Measure (up to 3 years, 2 months) | Progression-free survival was defined as the time from randomization to first documented disease progression as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. Results are reported for each of the 4 standard chemotherapy cohorts used in the study. |
| Overall Survival | Baseline to the end of the study (up to 6 years, 7 months) | Overall survival was defined as the time from randomization to death from any cause. |
| One-year Survival | Baseline to the end of the study (up to 6 years, 7 months) | Percentage of patients who survived 1 year in the study. |
| Objective Response | Baseline to data cut-off for analysis of the primary Outcome Measure (up to 3 years, 2 months) | A patient had an objective response if they had 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 | Baseline to data cut-off for analysis of the primary Outcome Measure (up to 3 years, 2 months) | Duration of objective response was defined as the time from the initial response to documented disease progression or death from any cause, whichever occurred first. Duration of objective response was only analyzed in patients who achieved an objective response. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Chemotherapy + Bevacizumab Patients received one of several standard chemotherapies for metastatic breast cancer plus bevacizumab in a dose of either 10 mg/kg intravenously (IV) every 2 weeks or 15 mg/kg IV every 3 weeks depending upon the schedule of chemotherapy chosen. | 459 |
| Standard Chemotherapy + Placebo Patients received one of several standard chemotherapies for metastatic breast cancer plus placebo to bevacizumab administered IV either every 2 weeks or every 3 weeks depending upon the schedule of chemotherapy chosen. | 225 |
| Total | 684 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | > 60 days since last dose of study drug | 4 | 4 |
| Overall Study | Adverse Event | 54 | 15 |
| Overall Study | Death | 8 | 3 |
| Overall Study | Did not receive study drug | 3 | 2 |
| Overall Study | Disease progression | 279 | 149 |
| Overall Study | Other | 5 | 6 |
| Overall Study | Physician's decision to withdraw | 15 | 12 |
| Overall Study | Subject/guardian's decision to withdraw | 33 | 6 |
Baseline characteristics
| Characteristic | Standard Chemotherapy + Bevacizumab | Standard Chemotherapy + Placebo | Total |
|---|---|---|---|
| Age Continuous | 55.6 years STANDARD_DEVIATION 11 | 55.0 years STANDARD_DEVIATION 11.2 | 55.4 years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 457 Participants | 225 Participants | 682 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 125 / 458 | 39 / 221 |
| serious Total, serious adverse events | 112 / 458 | 39 / 221 |
Outcome results
Primary
Progression-free Survival
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 data cut-off for analysis of the primary Outcome Measure (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) |
|---|---|---|
| Standard Chemotherapy + Bevacizumab | Progression-free Survival | 7.2 Months |
| Standard Chemotherapy + Placebo | Progression-free Survival | 5.1 Months |
Secondary
Duration of Objective Response
Duration of objective response was defined as the time from the initial response to documented disease progression or death from any cause, whichever occurred first. Duration of objective response was only analyzed in patients who achieved an objective response.
Time frame: Baseline to data cut-off for analysis of the primary Outcome Measure (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. Only patients who had measurable disease at baseline and achieved an objective response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Chemotherapy + Bevacizumab | Duration of Objective Response | 7.3 Months |
| Standard Chemotherapy + Placebo | Duration of Objective Response | 7.5 Months |
Secondary
Objective Response
A patient had an objective response if they had 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 data cut-off for analysis of the primary Outcome Measure (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. Only patients who had measurable disease at baseline were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy + Bevacizumab | Objective Response | 39.5 Percentage of patients |
| Standard Chemotherapy + Placebo | Objective Response | 29.6 Percentage of patients |
Secondary
One-year Survival
Percentage of patients who survived 1 year in the study.
Time frame: Baseline to the end of the study (up to 6 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 (NUMBER) |
|---|---|---|
| Standard Chemotherapy + Bevacizumab | One-year Survival | 70.5 Percentage of patients |
| Standard Chemotherapy + Placebo | One-year Survival | 68.6 Percentage of patients |
Secondary
Overall Survival
Overall survival was defined as the time from randomization to death from any cause.
Time frame: Baseline to the end of the study (up to 6 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) |
|---|---|---|
| Standard Chemotherapy + Bevacizumab | Overall Survival | 18.6 Months |
| Standard Chemotherapy + Placebo | Overall Survival | 17.8 Months |
Secondary
Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine)
Progression-free survival was defined as the time from randomization to first documented disease progression as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. Results are reported for each of the 4 standard chemotherapy cohorts used in the study.
Time frame: Baseline to data cut-off for analysis of the primary Outcome Measure (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 | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard Chemotherapy + Bevacizumab | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Taxanes, n=201, 103 | 8.0 Months |
| Standard Chemotherapy + Bevacizumab | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Capecitabine, n=97, 47 | 6.9 Months |
| Standard Chemotherapy + Bevacizumab | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Gemcitabine, n=108, 52 | 6.0 Months |
| Standard Chemotherapy + Bevacizumab | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Vinorelbine, n=53, 23 | 5.7 Months |
| Standard Chemotherapy + Placebo | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Vinorelbine, n=53, 23 | 7.0 Months |
| Standard Chemotherapy + Placebo | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Taxanes, n=201, 103 | 5.8 Months |
| Standard Chemotherapy + Placebo | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Gemcitabine, n=108, 52 | 5.5 Months |
| Standard Chemotherapy + Placebo | Progression-free Survival Within Individual Standard Chemotherapy Cohorts (Taxanes, Gemcitabine, Capecitabine, and Vinorelbine) | Capecitabine, n=97, 47 | 4.1 Months |