Breast Cancer
Conditions
Brief summary
This study will evaluate the efficacy and safety of 2 doses of Avastin in combination with docetaxel, versus docetaxel plus placebo, in patients with metastatic HER2 negative breast cancer who are candidates for taxane-based chemotherapy but who have not received prior chemotherapy for metastatic disease. The anticipated time on treatment is 1-2 years and the target sample size is 500+ individuals.
Detailed description
Five participants randomized to the docetaxel 100 mg/m\^2 plus placebo group actually received docetaxel 100 mg/m\^2 plus bevacizumab 7.5 mg/kg and are included in the docetaxel 100 mg/m\^2 plus bevacizumab 7.5 mg/kg group for the adverse event results. Sixteen participants randomized to the docetaxel 100 mg/m\^2 plus placebo group actually received docetaxel 100 mg/m\^2 plus bevacizumab 15.0 mg/kg and are included in the docetaxel 100 mg/m\^2 plus bevacizumab 15.0 mg/kg group for the adverse event results.
Interventions
DRUGDocetaxel
Docetaxel was supplied in 2 vials, 1 containing docetaxel and 1 containing a solvent, for intravenous infusion.
DRUGPlacebo to bevacizumab
Placebo to bevacizumab was supplied as a sterile liquid for intravenous infusion in single-use vials.
DRUGBevacizumab
Bevacizumab was supplied as a sterile liquid for intravenous infusion in single-use vials.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients ≥ 18 years of age. * Human epidermal growth factor receptor 2 (HER2)-negative cancer of the breast with locally recurrent or metastatic disease, suitable for chemotherapy. * No adjuvant chemotherapy within 6 months before randomization, and no taxane-based chemotherapy within 12 months before randomization. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Exclusion criteria
* Previous chemotherapy for metastatic or locally recurrent breast cancer. * Radiotherapy for treatment of metastatic disease. * Other primary tumors within last 5 years, except for controlled limited basal cell or squamous cancer of the skin, or cancer in situ of the cervix. * Spinal cord compression or brain metastases. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization. * Inadequate bone marrow, liver, or renal function. * Uncontrolled hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months) | Progression-free survival was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST 1.0). Progression-free survival was defined as the time from randomization to the time of the first documented disease progression or death, whichever occurred first. Disease progression was defined as ≥ 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the unequivocal progression of existing non-target lesions, or appearance of new lesion(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response or a Partial Response | Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months) | Responses were evaluated using the Response Evaluation Criteria in Solid Tumors. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. 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. |
| Duration of Response | Baseline to the 15 September 2008 cut-off date (up to 2 years, 6 months) | Duration of response was defined as the time from the first documented complete response or partial response to disease progression or death. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. 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. Responses were evaluated using the Response Evaluation Criteria in Solid Tumors. |
| Time to Treatment Failure | Baseline to the 15 September 2008 cut-off date (up to 2 years, 6 months) | Time to treatment failure was defined as time from randomization to the date of disease progression, death, or withdrawal of treatment due to an adverse event, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first. |
| Overall Survival | Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months) | Overall survival was defined as the time from randomization to death from any cause. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, France, Germany, Italy, Lithuania, Mexico, Netherlands, Panama, Poland, Portugal, Romania, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom
Participant flow
Pre-assignment details
21 participants randomized to the placebo group received bevacizumab 7.5 mg/kg (n=5) or 15.0 mg/kg (n=16). Please see the Detailed Description for an explanation of the differences in the number of participants in the treatment groups in Participant Flow and Adverse Events.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo Participants received docetaxel 100 mg/m\^2 intravenously on Day 1 of each 3 week cycle for a maximum of 27 weeks (9 cycles). In addition, participants received placebo to bevacizumab intravenously on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, or participant withdrawal. | 241 |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg Participants received docetaxel 100 mg/m\^2 intravenously on Day 1 of each 3 week cycle for a maximum of 27 weeks (9 cycles). In addition, participants received bevacizumab 7.5 mg/kg intravenously on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, or participant withdrawal. | 248 |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg Participants received docetaxel 100 mg/m\^2 intravenously on Day 1 of each 3 week cycle for a maximum of 27 weeks (9 cycles). In addition, participants received bevacizumab 15.0 mg/kg intravenously on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, or participant withdrawal. | 247 |
| Total | 736 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 144 | 149 | 143 |
| Overall Study | In Follow-up When Study Stopped | 87 | 92 | 96 |
| Overall Study | Lost to Follow-up | 10 | 7 | 8 |
Baseline characteristics
| Characteristic | Total | Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Docetaxel 100 mg/m^2 Plus Placebo |
|---|---|---|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 10.61 | 53.6 years STANDARD_DEVIATION 10.78 | 53.9 years STANDARD_DEVIATION 10.61 | 53.5 years STANDARD_DEVIATION 10.47 |
| Sex: Female, Male Female | 736 Participants | 247 Participants | 248 Participants | 241 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 216 / 217 | 251 / 252 | 260 / 261 |
| serious Total, serious adverse events | 82 / 217 | 106 / 252 | 120 / 261 |
Outcome results
Primary
Progression-free Survival
Progression-free survival was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST 1.0). Progression-free survival was defined as the time from randomization to the time of the first documented disease progression or death, whichever occurred first. Disease progression was defined as ≥ 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the unequivocal progression of existing non-target lesions, or appearance of new lesion(s).
Time frame: Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether they received study drug or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo | Progression-free Survival | 8.0 Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Progression-free Survival | 8.7 Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Progression-free Survival | 8.8 Months |
p-value: 0.031895% CI: [0.63, 0.98]Log Rank
p-value: 0.003695% CI: [0.57, 0.9]Log Rank
Secondary
Duration of Response
Duration of response was defined as the time from the first documented complete response or partial response to disease progression or death. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. 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. Responses were evaluated using the Response Evaluation Criteria in Solid Tumors.
Time frame: Baseline to the 15 September 2008 cut-off date (up to 2 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether they received study drug or not. Only participants with measurable disease at Baseline who had a complete response or a partial response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo | Duration of Response | 6.4 Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Duration of Response | 7.2 Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Duration of Response | 7.0 Months |
Secondary
Overall Survival
Overall survival was defined as the time from randomization to death from any cause.
Time frame: Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether they received study drug or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo | Overall Survival | NA Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Overall Survival | NA Months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Overall Survival | NA Months |
p-value: 0.696295% CI: [0.62, 1.37]Log Rank
p-value: 0.076595% CI: [0.45, 1.04]Log Rank
Secondary
Percentage of Participants With a Complete Response or a Partial Response
Responses were evaluated using the Response Evaluation Criteria in Solid Tumors. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. 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.
Time frame: Baseline to the 15 Sep 2008 cut-off date (up to 2 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether they received study drug or not. Only participants with measurable disease at Baseline were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo | Percentage of Participants With a Complete Response or a Partial Response | Complete response | 1.0 Percentage of participants |
| Docetaxel 100 mg/m^2 Plus Placebo | Percentage of Participants With a Complete Response or a Partial Response | Partial response | 43.5 Percentage of participants |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Percentage of Participants With a Complete Response or a Partial Response | Complete response | 3.0 Percentage of participants |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Percentage of Participants With a Complete Response or a Partial Response | Partial response | 52.2 Percentage of participants |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Percentage of Participants With a Complete Response or a Partial Response | Complete response | 1.0 Percentage of participants |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Percentage of Participants With a Complete Response or a Partial Response | Partial response | 62.1 Percentage of participants |
Secondary
Time to Treatment Failure
Time to treatment failure was defined as time from randomization to the date of disease progression, death, or withdrawal of treatment due to an adverse event, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first.
Time frame: Baseline to the 15 September 2008 cut-off date (up to 2 years, 6 months)
Population: Intent-to-treat population: All randomized participants, regardless of whether they received study drug or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel 100 mg/m^2 Plus Placebo | Time to Treatment Failure | 6.1 months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 7.5 mg/kg | Time to Treatment Failure | 7.0 months |
| Docetaxel 100 mg/m^2 Plus Bevacizumab 15.0 mg/kg | Time to Treatment Failure | 7.7 months |
p-value: 0.110595% CI: [0.69, 1.04]Log Rank
p-value: 0.024195% CI: [0.65, 0.97]Log Rank