Bevacizumab to Treat Inflammatory Breast Cancer or Locally Advanced Breast Cancer

This is a pilot study in patients with previously untreated inflammatory breast cancer (IBC)
or locally advanced breast cancer (LABC) to evaluate angiogenesis parameters after treatment
with rhuMAb VEGF - recombinant humanized monoclonal antibody vascular endothelial growth
factor (bevacizumab). The challenge for new molecular-targeted anti-angiogenesis therapy is
to devise appropriate and reliable markers to monitor efficacy. This may be achieved
directly by evaluating changes in angiogenesis parameters in tumor samples. The use of less
invasive surrogate markers to assess the efficacy of anti-angiogenic therapy is preferable.
This may include functional changes in tumor vasculature assessed using non-invasive methods
such as magnetic resonance imaging (MRI) or determination of changes in circulating soluble
markers of angiogenesis.

Most breast cancers over express VEGF thus making it an ideal disease for treatment with
anti-angiogenesis therapy. This study will evaluate the effects of bevacizumab on
angiogenesis parameters both molecular and functional. The first cycle will consist of
bevacizumab alone followed by six cycles of bevacizumab in combination with doxorubicin and
docetaxel (AT). Loco-regional therapy will follow and bevacizumab will be recommenced for
eight cycles.

Changes in pre-designated angiogenesis parameters will be assessed at baseline, three weeks
after bevacizumab and after three cycles of AT/bevacizumab. The first three molecular
parameters: endothelial cell proliferation, endothelial cell apoptosis and tissue VEGF
require multiple tumor core biopsies obtained using a mammotome. The fourth parameter k(ep),
the redistribution constant is obtained using dynamic MRI. To determine the variability of
the values of the three molecular primary angiogenesis parameters, multiple biopsies will be
sampled at the same time points. An attempt will be made to correlate each of the four
primary angiogenesis parameters with time to progression/recurrence. The effects of
bevacizumab alone and AT/bevacizumab directly on tumor vasculature using dynamic MRI imaging
and on the circulating angiogenesis marker, serum vascular cell adhesion molecule-1 (VCAM-1)
at the same three time points and prior to surgery and will be undertaken in an exploratory
manner. An attempt will be made to correlate changes in these parameters with clinical
findings and changes in tissue angiogenesis parameters. Additionally, other angiogenesis
biomarkers will also be studied in an exploratory manner.

Thrombosis factors will be monitored given the increased incidence of venous and arterial
thrombosis seen in previous clinical trials using bevacizumab. An increase in the incidence
of hypertension has also been seen. A subset of patients in this study will undergo frequent
blood pressure monitoring to obtain a profile of the effect of bevacizumab on blood
pressure.

- INCLUSION CRITERIA:

Patients must have inflammatory breast cancer or locally advanced breast cancer previously
untreated with chemotherapy and/or radiation therapy. Inflammatory breast cancer is
defined as histologically proven invasive adenocarcinoma of one breast with clinical
inflammatory signs including onset of erythema and brawny induration or edema of the skin
with an erysipeloid edge with or without an underlying tumor mass. Dermal lymphatic
involvement by tumor cells is not a requirement for diagnosis. We will define locally
advanced breast cancer as stage IIB, IIIA, or IIIC breast cancer according to the 2002
AJCC staging guidelines. Patients must have tissue accessible for serial biopsies.

Age greater than or equal to 18 years.

ECOG performance status of 0, 1, or 2.

Patients must have a left ventricular ejection fraction of greater than or equal to 50%
without clinical symptoms or signs of heart failure.

Patients must have adequate bone marrow, hepatic and renal function as defined by the
following:

Absolute neutrophil count greater than or equal to 1500/mL; Platelets greater than or
equal to 100,000/mL; Serum creatinine less than or equal to 1.5 mg/dL; AST, ALT less than
or equal to 1.5 times the upper limit of normal; Alkaline phosphatase less than or equal
to 2.5 times the upper limit of normal; Total bilirubin less than or equal to the upper
limit of normal for institution. In patients with evidence of Gilbert's disease, elevated
bilirubin should not be related to tumor or other liver diseases, and should be less than
or equal to 2 times the upper limit of normal.

Women of childbearing potential must agree to use an accepted and effective method of
contraception during their participation on the trial.

Patients must be able to provide informed consent.

EXCLUSION CRITERIA:

Evidence of carcinomatous meningitis or brain metastases or other CNS disease including
history of stroke, primary brain tumor or seizures not controlled by standard medical
therapy.

History of an active malignancy other than in situ carcinoma of the cervix, or
non-melanomatous skin cancers in the last five years prior to Day 1 on study.

Patients with non-healing wounds, bone fractures, or major surgery within the previous 28
days..

Uncontrolled hypertension (sustained systolic blood pressure greater than 160 mmHg or
diastolic blood pressure of greater than 100 mmHg).

Clinically significant cardiovascular disease (e.g., myocardial infarction, unstable
angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure,
serious cardiac arrhythmia requiring medication, or Grade II or greater peripheral
vascular disease within 12 months prior to Day 1 on study.

INR greater than 1.50. Prior history of bleeding diathesis or coagulopathy including deep
venous thrombosis or pulmonary embolism. Recent (within last six months) or current
history of gastrointestinal bleeding.

Current use of full-dose or parenteral anticoagulants or chronic daily treatment with
aspirin (greater than 325 mg/day) within 10 days prior to Day 1 on study.

Active infection requiring intravenous antibiotics on Day 1 on study.

Patients with 24 hour urine protein greater than or equal to 500 mg or a history of a
primary renal disease (excluding infection).

Clinical grade greater than or equal to 2 peripheral neuropathy.

History of other disease, metabolic dysfunction, physical examination finding or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that might affect the interpretation
of the results of the study or render the subject at high risk from treatment
complications.

Pregnant or lactating women.

Patients who are receiving other investigational drugs.

Patients with a history of hypersensitivity reaction to products containing Polysorbate 80
(Tween 80).

Patients with a known hypersensitivity to E. coli derived products.

Patients with an arterial thromboembolic event (including transient ischemic attack,
cerebrovascular accident, unstable angina, or myocardial infarction) within 6 months.

Patients with clinically significant peripheral artery disease.