Paclitaxel Albumin-Stabilized Nanoparticle Formulation, Doxorubicin, Cyclophosphamide, and Pegfilgrastim With or Without Bevacizumab in Treating Women With Inflammatory or Locally Advanced Breast Cancer

OBJECTIVES:

- To compare the pathologic complete response rates in women with HER2/neu-negative
inflammatory or locally advanced breast cancer treated with paclitaxel
albumin-stabilized nanoparticle formulation, doxorubicin hydrochloride,
cyclophosphamide, and pegfilgrastim with vs without bevacizumab.

- To compare the overall survival of patients treated with these regimens.

- To assess whether there is a correlation between bevacizumab and stratification factors
(type of disease and hormone receptor status).

- To compare the toxicities of these regimens.

- To explore the molecular biomarkers related to the biology and outcome of inflammatory
breast cancer.

- To explore potential molecular biomarkers that predict response to therapy and drug
sensitivity.

- To evaluate biomarkers with respect to the sequence of paclitaxel albumin-stabilized
nanoparticle formulation and doxorubicin hydrochloride/cyclophosphamide/pegfilgrastim
administration in patients not receiving bevacizumab.

- To explore residual cancer burden and correlate it with outcome.

- To evaluate the time to treatment failure prior to surgery.

- To evaluate disease-free survival from the time of surgery in patients undergoing
definitive surgery.

OUTLINE: This is a multicenter study. Patients are stratified according to type of disease
(inflammatory vs locally advanced breast cancer) and hormone receptor status (positive
[estrogen receptor (ER)+ and/or progesterone receptor (PgR)+] vs negative [ER- and PgR-]).
Patients are randomized to 1 of 3 treatment arms.

- Arm I: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over
30 minutes on day 1 and bevacizumab IV over 30- to 90-minutes on day 1 of weeks 1-12.
Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 and
pegfilgrastim SC on day 2 of weeks 14, 16, 18, 20, 22, and 24.

- Arm II: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over
30 minutes on day 1 of weeks 1-12. Patients then receive doxorubicin hydrochloride IV
and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2 of weeks 14, 16, 18, 20,
22, and 24.

- Arm III: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1
and pegfilgrastim SC on day 2 of weeks 1, 3, 5, 7, 9, and 11. Patients then receive
paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1 of
weeks 14-25.

In all arms, patients with stable or responding disease undergo surgery 3-6 weeks after
completion of chemotherapy. Patients may then undergo radiotherapy 5 days a week for 6
weeks.

Serum, whole blood, and tissue samples are collected periodically for biomarker analysis,
circulating endothelial cell analysis, and pharmacogenomic studies, respectively.

After completion of study treatment, patients are followed every 6 months for 1 year and
then annually for 4 years.

DISEASE CHARACTERISTICS:

- Histologically or pathologically confirmed breast cancer meeting one of the following
criteria:

- Locally advanced disease (stage IIIB disease, stage IIB/IIIA, or stage IIIC
disease)

- Inflammatory disease meeting the following two clinicopathologic criteria:

- Diffuse erythema AND edema (peau d'orange) of the breast involving the
majority of the skin of the breast, i.e., more than 50%

- A biopsy demonstrating cancer either within the dermal lymphatics OR in the
breast parenchyma itself

- HER2/neu-negative tumor as demonstrated by 0 or 1+ (weak or no staining) by DAKO,
IHC, or equivalent test OR no gene amplification by FISH*

- 2+ by DAKO or IHC allowed provided FISH* negative

- NOTE: *A negative FISH test ratio is < 1.8 or FISH HER2 gene copy < 4.0; if only a
positive or negative result is available from the FISH test, a negative result is
acceptable for study entry

- Hormone receptor status known

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- Zubrod performance status 0-2

- Granulocyte count > 1,500/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count > 100,000/mm^3

- Hemoglobin 9.0 g/dL

- Serum creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 mg/dL

- ALT and AST ≤ 3 times ULN

- Alkaline phosphatase ≤ 2.5 ULN (unless bone metastasis is present in the absence of
liver metastasis)

- Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg on 24-hour urine
collection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to take oral medications (e.g., no uncontrolled nausea, vomiting, or diarrhea,
lack of physical integrity of the upper gastrointestinal tract, or malabsorption
syndrome)

- QTc < 500 msec by EKG

- LVEF normal by MUGA or ECHO (for patients with hypertension or for patients > 60
years of age)

- NYHA class II cardiac function by baseline ECHO/MUGA (for patients who have received
central thoracic radiotherapy that included the heart in the radiotherapy port, or
for patients who have a history of class II heart failure but are asymptomatic on
treatment are eligible)

- No history of stroke (cerebrovascular accident), transient ischemic attack, or
cardiac event within the past 12 months, including any of the following:

- Myocardial infarction (including severe/unstable angina)

- Coronary/peripheral artery bypass graft

- Symptomatic congestive heart failure

- Pulmonary embolism

- No poorly controlled hypertension, defined as recurrent or persistent (≥ 24 hours)
elevated blood pressure (i.e., systolic blood pressure ≥ 140 mm Hg and/or diastolic
blood pressure ≥ 90 mm Hg)

- No other malignancy within the past 5 years except for adequately treated basal cell
or squamous cell skin cancer or in situ cervical cancer

- Peripheral neuropathy < grade 2

PRIOR CONCURRENT THERAPY:

- No prior tyrosine kinase inhibitors

- More than 5 years since prior chemotherapy, radiotherapy, or biologic therapy (e.g.,
trastuzumab or bevacizumab) for invasive breast cancer

- At least 7 days since prior hormonal therapy

- At least 7 days since prior and no concurrent strong CYP3A4 inhibitors (e.g.,
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or grapefruit juice

- No concurrent CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine,
rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort)

- No other concurrent therapy for the treatment of breast cancer except for
bisphosphonates

- No concurrent brachytherapy