Breast Cancer
Conditions
Keywords
Metastatic Breast Cancer, Advanced Breast Cancer, Hormone Receptor AND Her2/neu Negative, Triple Negative, Triple Negative Breast Cancer, Stage IV or Inoperable Stage III Breast Cancer
Brief summary
Taxanes (such as paclitaxel) are highly active to treat breast cancer. Abraxane® (nanoparticle albumin-bound paclitaxel) compared to standard paclitaxel improves efficacy and tolerability. When combined with a taxane, platinum agents improve response in metastatic breast cancer, with carboplatin conferring less toxicity than cisplatin. Monoclonal antibodies including bevacizumab target vascular endothelial growth factor (VEGF) to reduce angiogenesis. We hypothesize that the previously-untested combination of weekly Abraxane® and carboplatin plus biweekly bevacizumab will lengthen time to progression without producing intolerable toxicity.
Detailed description
Anthracycline-based chemotherapy is widely used as adjuvant treatment for breast cancer. In addition to the challenge posed by anthracycline-induced cardiotoxicity, there are issues surrounding previous treatment with anthracyclines which limit its utility in the metastatic disease setting. Many patients with advanced disease will have had prior anthracycline-based adjuvant therapy, may have reached a maximum cumulative lifetime dose, or developed refractory disease, creating an obvious need for non-anthracycline treatment strategies.3 Platinum- and taxane-based chemotherapies as first-line therapy for metastatic breast cancer have demonstrated significant activity, producing single-agent response rates \> 50%; in combination these rates increased to \> 60% in both previously untreated and in patients who previously received anthracyclines.3 However, overall survival has remained relatively unchanged.4 As there is currently no standard of care for patients with metastatic breast cancer, various physical and psychological factors must be considered when evaluating chemotherapy treatment options, including the patient's tumor biology and growth rate, presence and extent of metastases, history of prior treatment and response, sensitivity and tolerance to therapy, and quality of life.2 Strategies to develop combination, higher dose, or sequential regimens using these active agents, while improving response rates and/or time to progression, may produce increased toxicity without increased survival.2 Because metastatic breast cancer remains essentially incurable using cytotoxic therapy alone, the study of targeted biologics offers new opportunities to enhance drug delivery via their ability to regulate specific receptors that are associated with clinically aggressive disease processes.
Interventions
DRUGAbraxane
100 mg/m2 IV over 30 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death..
DRUGBevacizumab
10 mg/kg IV days 1,15 Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria,intolerable toxicity, or death.
DRUGCarboplatin
area under curve (AUC)=2 IV over 15 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death.
Sponsors
Genentech, Inc.
Celgene Corporation
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Tissue block containing tumor to confirm metastatic breast cancer is required; * Measurable disease according to RECIST criteria * Triple negative disease defined as tumor demonstrating no expression for estrogen, progesterone or human epidermal growth factor receptor 2(HER2)receptors. No expression is categorized as ≤ 10% of cells staining or Allred ≤ 2; * Aged 18 years or older; * Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of 0 or 1; life expectancy ≥ 3 months; * Patients may have received 0 - 1 prior therapies (except taxanes in the metastatic setting). An interval of at least 1 week must have elapsed since prior chemotherapy or hormonal therapy for metastatic disease; at least 6 months must have elapsed since prior adjuvant therapy; * ≥ 2 weeks between surgery and study enrollment (≥ 4 weeks between major surgery (defined as open abdominal/thoracic/cardiac) and study enrollment; * Laboratory tests performed within 14 days of study entry: * Granulocytes ≥ 1,500/µL; * Platelets ≥ 100,000/µL; * Hemoglobin ≥ 9 gm/dL; * Total bilirubin ≤ institutional upper limit of normal (ULN); * Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 5 times ULN; * Alkaline phosphatase ≤ 2.5 times ULN; * Estimated creatinine clearance ≥ 60 mL/min. * left ventricular ejection fraction (LVEF)≥ 50% by multigated acquisition (MUGA)/Echocardiogram; * Informed consent to receive protocol treatment, to provide biologic specimens, and to complete neurotoxicity questionnaires; * Cognitive and communication skills to comply with study and/or follow-up procedures; * No reproductive potential: * If pre-menopausal: Negative serum pregnancy test and patient agreement to use adequate contraceptive method (abstinence, intrauterine device, barrier device with spermicide or surgical sterilization) during and for 3 months after completion of treatment. * If post-menopausal: Amenorrhea for ≥ 12 months.
Exclusion criteria
* Pregnant or breast feeding; * Prior treatment with Abraxane®, carboplatin or bevacizumab, or any taxane for metastatic breast cancer; * Known hypersensitivity to any component of any study drug; * Active infection; * Current neuropathy ≥ grade 2; * central nervous system (CNS) metastases as determined by head CT with contrast; * History of bleeding within the past 6 months or active bleeding disorder; * Serious non-healing wound, ulcer or bone fracture; * Uncontrolled congestive heart failure (CHF), or history of myocardial infarction(MI), unstable angina, stroke, or transient ischemia within previous 6 months; * Inadequately controlled hypertension (defined as systolic blood pressure \< 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications; prior history of hypertensive crisis or hypertensive encephalopathy; * Proteinuria (defined as urine protein: creatinine (UPC) ratio ≥ 1.0 or urine dipstick ≥ 2+. * Significant vascular disease (aortic aneurysm, aortic dissection) or symptomatic peripheral vascular disease; * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within previous 6 months; * Uncontrolled serious contraindicated medical condition or psychiatric illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer. | 5 years | Best clinical response is based on RECIST criteria, the proportion in each response category along with the exact binomial confidence intervals are estimated. Toxicity summaries are also provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Proportion Progression-free as Estimated by Kaplan-Meier Methods | 5 years | PFS was defined as time from trial enrollment to disease progression or death, whichever occurred first. |
| To Evaluate Sequential Plasma Samples for Presence of Selected Angiogenic Markers | 18 months | — |
| to Determine if Apolipoprotein Alleles (Apo-E) Correlate With Treatment-related Neuropathy | 18 months | — |
| to Determine if SPARC Expression in Breast Tumors Predicts Progression-free Survival (PFS) | 18 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abraxane, Carboplatin, Bevacizumab Abraxane 100 mg/m2 IV over 30 min days 1,8,15.; Carboplatin AUC=2 IV over 15 min days 1,8,15., Bevacizumab 10 mg/kg IV days 1,15
Abraxane: 100 mg/m2 IV over 30 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death..
Bevacizumab: 10 mg/kg IV days 1,15 Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria,intolerable toxicity, or death.
Carboplatin: area under curve (AUC)=2 IV over 15 min days 1,8,15. Cycles Repeated Every 28 days until documented evidence of disease progression by RECIST criteria, intolerable toxicity, or death. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | none provided | 3 |
| Overall Study | Physician Decision | 14 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Abraxane, Carboplatin, Bevacizumab |
|---|---|
| Age, Continuous | 50 years STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 41 participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 22 / 41 |
Outcome results
Primary
Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer.
Best clinical response is based on RECIST criteria, the proportion in each response category along with the exact binomial confidence intervals are estimated. Toxicity summaries are also provided.
Time frame: 5 years
Population: 2 subjects withdrew and were not assessed for response
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Abraxane, Carboplatin, Bevacizumab | Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer. | Complete Response | 18 percentage of participants |
| Abraxane, Carboplatin, Bevacizumab | Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer. | Partial Response | 69 percentage of participants |
| Abraxane, Carboplatin, Bevacizumab | Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer. | Stable Disease | 8 percentage of participants |
| Abraxane, Carboplatin, Bevacizumab | Best Clinical Response Expressed as Percentage of Participants Treated With Combination Regimen of Weekly Abraxane® and Carboplatin Plus Biweekly Bevacizumab to Treat Women With Stage IV or Inoperable Stage III Triple Negative Metastatic Breast Cancer. | Progressive Disease | 5 percentage of participants |
Secondary
Median Proportion Progression-free as Estimated by Kaplan-Meier Methods
PFS was defined as time from trial enrollment to disease progression or death, whichever occurred first.
Time frame: 5 years
Population: One subject lost to follow up and not included in analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abraxane, Carboplatin, Bevacizumab | Median Proportion Progression-free as Estimated by Kaplan-Meier Methods | 15 months |
Secondary
to Determine if Apolipoprotein Alleles (Apo-E) Correlate With Treatment-related Neuropathy
Time frame: 18 months
Population: Samples were collected, but analysis was not performed as there was inadequate funding to support the testing and analysis of samples.
Secondary
to Determine if SPARC Expression in Breast Tumors Predicts Progression-free Survival (PFS)
Time frame: 18 months
Population: Study plan stipulated that tissue samples would not be assessed for quantitatively if no difference in SPARC expression was observed between tumor and non-tumor cells was observed qualitatively.
Secondary
To Evaluate Sequential Plasma Samples for Presence of Selected Angiogenic Markers
Time frame: 18 months
Population: Analysis of samples was not performed, as there was inadequate funding to support the testing and analysis of the samples.