A Phase II Open Label, Randomized, 3 Arm Trial of 2 Schedules of Ixabepilone Plus Bevacizumab and Paclitaxel Plus Bevacizumab as First Line Therapy for Locally Recurrent or Metastatic Breast Cancer

Inclusion Criteria

Inclusion criteria:

- Locally recurrent or metastatic breast cancer, previously untreated with chemotherapy
for advanced disease.

- At least 1 target lesion per RECIST criteria. Locally recurrent disease must not be
amenable to resection with curative intent.

- No previous cytotoxic chemotherapy for locally recurrent/metastatic disease.

- Relapse 12 months or more after completing prior adjuvant or neoadjuvant taxane
therapy.

- No previous breast cancer known to overexpress or amplify the human epidermal growth
factor receptor 2 gene.

- Prior hormonal therapy in adjuvant, recurrent, or metastatic setting allowed but must
have been discontinued at least 2 weeks before randomization.

- Karnofsky performance status of 80 to 100 or Eastern Cooperative Oncology Group
performance status of 0 to 1.

- Estimated life expectancy of at least 12 weeks.

- Recovery from recent therapy (except for alopecia), including chemotherapy,
immunotherapy, biologic therapy, or investigational product. Any such therapy must
have been completed at least 3 weeks before randomization and at least 6 weeks from
use of nitrosourea, or mitomycin.

- Recovery from recent surgery and radiation therapy. At least 1 week since minor
surgery and/or focal/palliative radiation therapy; at least 3 weeks from radiation;
at least 4 weeks from major surgery; and at least 8 weeks from liver resection,
thoracotomy, or neurosurgery.

- Absolute neutrophil count ≥1500/mm^3.

- Hemoglobin ≥9 g/dL.

- Platelets ≥100,000/mm^3.

- Total bilirubin ≤1.5 times the upper limit of normal (ULN).

- Aspartate aminotransferase or alanine aminotransferase ≤2.5*ULN.

- Normal partial thromboplastin time and either international normalized ratio or
prothrombin time <1.5*ULN.

- Serum creatinine ≤1.5*ULN or 24-hour creatinine clearance >60 mL/min.

- Urine dipstick for proteinuria <2+ (negative, trace, or +1). Participants with ≥2+
proteinuria at baseline were to undergo 24-hour urine collection and demonstrate ≤1g
of protein in 24 hours to be eligible.

Exclusion criteria:

- Women of child-bearing potential (WOCBP) unwilling or unable to use an acceptable
method of birth control to avoid pregnancy for the entire study period and up to 6
months after treatment with bevacizumab.

- Women who were pregnant or breastfeeding.

- Women with a positive pregnancy test on enrollment or prior to study drug
administration.

- Sexually active fertile men, whose partners were WOCBP, not using an adequate method
of birth control.

- Evidence of baseline sensory or motor neuropathy.

- Serious infection or nonmalignant medical illnesses uncontrolled or the control of
which could be jeopardized by this therapy.

- History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess,
serious gastric ulcer, or bone fracture within 6 months of study entry.

- History of hypertensive crisis or hypertensive encephalopathy.

- Significant vascular disease.

- Clinically significant cardiovascular disease.

- Baseline left ventricular ejection fraction by multiple-gated acquisition scan or
echocardiogram for subjects with prior exposure to anthracyclines not within
institutional normal limits.

- Symptomatic peripheral vascular disease.

- History of high dose chemotherapy with bone marrow transplant or peripheral blood
stem cell transplant within the previous 2 years.

- Evidence of bleeding diathesis or coagulopathy.

- Prior treatment with an epothilone or any antiangiogenic agent.

- Concurrent nonhealing wound, ulcer, or fracture.

- Any current or history of brain and/or leptomeningeal metastases. Psychiatric
disorders or other conditions rendering the participant incapable of complying with
the requirements of the protocol.

- Any concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in
situ of the cervix.

- Known allergy to any of the study drugs or their excipients.