Carboplatin, Paclitaxel, and Bevacizumab in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

OBJECTIVES:

Primary

• To determine the progression-free survival of patients with locally recurrent or metastatic breast cancer treated with carboplatin, paclitaxel albumin-stabilized nanoparticle formulation, and bevacizumab as first-line therapy.

Secondary

• To determine the response rate in these patients.
• To determine the overall survival of these patients.
• To evaluate the toxicity profile of this regimen in these patients.

OUTLINE: Patients receive carboplatin IV over 1 hour and bevacizumab IV on days 1, 22 and 43. Patients also receive paclitaxel albumin-bound nanoparticle formulation IV over 30 minutes on days 1, 8 ,15, 22, 29, 36, 43, and 50. Treatment continues in the absence of disease progression or unacceptable toxicity.

Formalin-fixed paraffin-embedded archived tumor tissue samples are assessed by immunohistochemistry (IHC) for various biomarkers. Levels of Notch-1, Notch-4, cyclin A, cyclin B, Jagged-1, and DLL4 in tumor-associated endothelial cells are correlated with response in both estrogen- and progesterone-positive and negative tumors, and independently of p53 status.

After completion of study treatment, patients are followed for up to 2 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed primary adenocarcinoma of the breast

• Locally recurrent or metastatic disease
• Must have HER-2-negative breast cancer or, if HER-2-positive, must be unable to receive trastuzumab (Herceptin®) or have previously received trastuzumab in the past
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by conventional techniques or as > 10 mm by spiral CT scan.
• No known CNS disease
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria

• Postmenopausal status not specified
• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
• Life expectancy > 12 weeks
• WBC ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN (unless bone metastasis is present in the absence of liver metastasis)
• Creatinine ≤ 1.5 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other concurrent malignancies within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

Exclusion criteria

• Pre-existing neuropathy ≥ grade 1
• Uncontrolled intercurrent illness including, but not limited to, any of the following:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Serious, non-healing wound, ulcer, or bone fracture
• Psychiatric illness/social situations that would limit compliance with study requirements
• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications)
• History of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association class II-IV congestive heart failure
• History of myocardial infarction or unstable angina within the past 6 months
• History of stroke or transient ischemic attack within the past 6 months
• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
• Symptomatic peripheral vascular disease
• Evidence of bleeding diathesis or coagulopathy
• Significant traumatic injury within the past 28 days
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• Proteinuria, as demonstrated by either urine protein:creatinine ratio ≥ 1.0 OR urine dipstick for proteinuria ≥ 2+

• Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline must demonstrate 24-hour urine protein ≤ 1g
• History of allergy or hypersensitivity to paclitaxel albumin-stabilized nanoparticle formulation, paclitaxel, bevacizumab, carboplatin, albumin, drug product excipients, or chemically similar agents

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from all prior therapy
• No prior chemotherapy for locally recurrent or metastatic disease
• Prior neoadjuvant or adjuvant chemotherapy allowed
• More than 1 week since prior core biopsy or other minor surgical procedure, excluding placement of a vascular access device
• More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy
• More than 4 weeks since prior radiotherapy
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• At least 1 year since prior taxane regimen
• No other concurrent investigational agents
• Concurrent anticoagulation allowed, provided the following criteria are met:

• Stable dose of warfarin or low molecular weight heparin
• INR within desired range (2-3)
• No evidence of active bleeding or coagulopathy
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent radiotherapy, chemotherapy, immunotherapy, or antitumor hormonal therapy