A Randomized Phase III Trial of Weekly Paclitaxel Compared to Weekly Nanoparticle Albumin Bound Nab-paclitaxel or Ixabepilone With or Without Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer
Overview
- Phase
- Phase 3
- Intervention
- Bevacizumab
- Conditions
- Estrogen Receptor Negative
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 799
- Locations
- 697
- Primary Endpoint
- Progression Free Survival
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologic confirmation of invasive cancer of the breast
- •Stage IV disease or stage IIIC disease (using American Joint Committee on Cancer \[AJCC\] criteria, 6th edition) not amenable to local therapy
- •Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse
- •Patients with human epidermal growth factor receptor 2 (HER2) negative disease are eligible; patients with HER2+ disease are eligible providing they have previously received trastuzumab or lapatinib; documentation of progression on HER2 directed therapy is not required; Her2/neu status must be known at the time of protocol registration
- •Estrogen receptor (ER) and progesterone receptor (PgR) status must be known at the time of registration; ER and/or PgR \>= 1% cells will be considered positive
- •Prior treatment may include adjuvant or neoadjuvant taxane, however, the interval between completion of adjuvant or neoadjuvant therapy and disease recurrence must be \>= 12 months
- •No prior chemotherapy for metastatic breast cancer
- •Any number of prior hormonal therapies are allowed; the last dose should have been administered at least 7 days prior to the initiation of protocol therapy
- •Prior radiotherapy must be completed at least 2 weeks prior to study entry
- •Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (Paclitaxel)
Patients receive 90 mg/m\^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Bevacizumab
Arm A (Paclitaxel)
Patients receive 90 mg/m\^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Laboratory Biomarker Analysis
Arm A (Paclitaxel)
Patients receive 90 mg/m\^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Paclitaxel
Arm A (Paclitaxel)
Patients receive 90 mg/m\^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Questionnaire Administration
Arm B (Nab-paclitaxel)
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Bevacizumab
Arm B (Nab-paclitaxel)
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Laboratory Biomarker Analysis
Arm B (Nab-paclitaxel)
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Nab-paclitaxel
Arm B (Nab-paclitaxel)
Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
Intervention: Questionnaire Administration
Arm C (Ixabepilone)
Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual as of 7/18/11)
Intervention: Bevacizumab
Arm C (Ixabepilone)
Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual as of 7/18/11)
Intervention: Ixabepilone
Arm C (Ixabepilone)
Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual as of 7/18/11)
Intervention: Laboratory Biomarker Analysis
Arm C (Ixabepilone)
Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual as of 7/18/11)
Intervention: Questionnaire Administration
Outcomes
Primary Outcomes
Progression Free Survival
Time Frame: Time from randomization to progression or death due to any cause, whichever occurs first (up to 5 years)
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).
Secondary Outcomes
- 12 Month Progression Free Survival(12 months)
- Objective Tumor Response Rate(Up to 5 years)
- Time to Treatment Failure(Time from randomization until progression, death, or yearly termination of protocol therapy (up to 5 years))
- Overall Survival(Time from randomization to death or last follow-up (up to 5 years))