This randomized phase III trial studies the side effects and how well different chemotherapy regimens with or without bevacizumab work in treating patients with stage IIIC or stage IV breast cancer. Drugs used in chemotherapy, such as paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may block tumor growth by targeting certain cells and slowing the growth of blood vessels to the tumor. It is not yet known which treatment regimen is more effective in treating patients with breast cancer.
PRIMARY OBJECTIVES: I. To compare the progression-free survival (PFS) in patients with metastatic breast cancer receiving nab-paclitaxel versus paclitaxel (control arm). II. To compare PFS in patients receiving ixabepilone versus paclitaxel. SECONDARY OBJECTIVES: I. To compare the objective response rate, duration of response, and time to treatment failure in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare these endpoints in patients receiving ixabepilone versus paclitaxel. II. To compare the 12-month rate of progression in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare this endpoint in patients receiving ixabepilone versus paclitaxel. III. To determine toxicities in patients receiving nab-paclitaxel as compared to paclitaxel, and in patients receiving ixabepilone as compared to paclitaxel. IV. To compare overall survival in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare overall survival in patients receiving ixabepilone versus paclitaxel. V. To evaluate the relationships between secreted protein, acidic, cysteine-rich (SPARC) overexpression and changes in blood levels of caveolin-1 (Cav-1) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel. VI. To evaluate the relationships between changes in blood levels of circulating tumor cells (CTCs) and circulating endothelial cells (CECs) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel. VII. To evaluate the association of expression levels of the microtubule associated proteins tau and beta-tubulin isotype composition with PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel. VIII. To investigate a potential cytochrome P450, family 2, subfamily C polypeptide 8, 2, 3 (CYP2C8\*2/\*3) by paclitaxel interaction with respect to progression-free survival (PFS). IX. To determine if CYP2C8\*2 and CPY2C8\*3 are associated with paclitaxel-induced peripheral neuropathy. X. To perform exploratory analysis of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) and ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2) polymorphisms with response and toxicity profiles. XI. To prospectively collect data on sociodemographics, non-cancer morbidities, and receipt of post-trial therapy to evaluate the role of potential disparities on survival from cancer. XII. To evaluate the relationship between physical activity behaviors at the time of enrollment in the protocol and progression-free and overall survival. XIII. To identify baseline factors that predict the risk of grade 3, 4, or 5 toxicity in patients receiving treatment with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab. XIV. To perform an exploratory analysis of whether other factors included in patient assessments (either individually or in combination) predict the risk of grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab, with a specific focus on the relationship between pre-existing hypertension or neuropathy. XV. To compare the associations of baseline factors to grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab. XVI. To explore whether longitudinal changes in factors are in association with the occurrence of grade 3, 4, or 5 toxicities in patients with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab. XVII. To explore the association between grade 2-4 neuropathy and longitudinal changes in the following functional status measures: a) Older Americans Resources and Services (OARS) Multidimensional Functional Assessment Questionnaire (MFAQ) (Instrumental Activities of Daily Living \[IADL\]); b) Medical Outcomes Study (MOS) Physical Functioning; c) Karnofsky Performance Status Rated Healthcare Professional; d) Timed "Up and Go"; e) OARS Physical Health Section. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A (WEEKLY PACLITAXEL): Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15. Patients may also receive bevacizumab IV over 30-90 minutes on days 1 and 15. ARM B (WEEKLY NAB-PACLITAXEL): Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A. ARM C (WEEKLY IXABEPILONE): Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A. (closed to accrual as of 7/18/11) In all arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 6 months for 2 years and then annually for up to 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
799
Given IV
Given IV
Correlative studies
Given IV
Given IV
Ancillary studies
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Sparks Regional Medical Center
Fort Smith, Arkansas, United States
Mercy Hospital Fort Smith
Fort Smith, Arkansas, United States
NEA Baptist Memorial Hospital
Jonesboro, Arkansas, United States
Kaiser Permanente-Anaheim
Anaheim, California, United States
Progression Free Survival
Progression-free survival (PFS) is defined as the interval from registration until first disease progression, regardless of site, or death resulting from any cause, which ever occurred first. Distribution was estimated using the Kaplan Meier product-limit method. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria).
Time frame: Time from randomization to progression or death due to any cause, whichever occurs first (up to 5 years)
Objective Tumor Response Rate
Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions).
Time frame: Up to 5 years
Time to Treatment Failure
Time from registration until treatment failure, defined as early termination of protocol therapy for any reason, first disease progression or death without progression. Surviving participants who were failure free were censored as date last known alive and failure free. Distribution was estimated using the Kaplan Meier product-limit method.
Time frame: Time from randomization until progression, death, or yearly termination of protocol therapy (up to 5 years)
12 Month Progression Free Survival
Percentage of participants who were alive and progression free at 12 months. The 12 month progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
Time frame: 12 months
Overall Survival
Overall survival was measured as the interval from study entry until death, from any cause, or last contact. Distribution was estimated using the Kaplan Meier product-limit method.
Time frame: Time from randomization to death or last follow-up (up to 5 years)
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