Combination Chemotherapy and Bevacizumab in Treating Women With HER2/Neu-Negative Stage II or Stage III Breast Cancer

PRIMARY OBJECTIVES:

I. To assess the feasibility of administering two sequential chemotherapy doublets with
Avastin in the adjuvant setting.

II. To assess the safety of Avastin in the adjuvant setting particularly regarding cardiac
function, wound healing and toxicity of radiation.

SECONDARY OBJECTIVES:

I. To determine the effect of Avastin on immunity, especially VEGF-A upregulation of MDSC and
suppression of T-Cells.

II. To determine the effect of therapy on numbers of myeloid derived suppressor cells and
compare the humoral and cellular response to p53 in breast cancer patients treated with the
same chemotherapy.

III. Patients will be followed for freedom from tumor progression and survival.

OUTLINE:

COURSES 1-4: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1
and pegfilgrastim subcutaneously (SC) on day 1. Treatment repeats every 2 weeks for 4 courses
in the absence of unacceptable toxicity or disease progression.

COURSES 5-7: Patients receive paclitaxel IV and gemcitabine hydrochloride IV on day 1 and
pegfilgrastim SC on day 1. Patients also receive bevacizumab IV on day 1 in courses 5-7.
Treatment repeats every 2 weeks for 4 courses in the absence of unacceptable toxicity or
disease progression.

COURSES 8-16: Patients receive bevacizumab IV alone on day 1. Treatment repeats every 3 weeks
for 8 courses in the absence of unacceptable toxicity or disease progression.

After course 8, patients may undergo radiotherapy and hormone therapy, if clinically
indicated.

After completion of study treatment, patients are followed every 3 months for 2 years and
then every 6 months for 5 years.

Inclusion Criteria:

- Histological diagnosis of invasive breast cancer: By pathologic evaluation, primary
tumor must be T1-4N1-3M0 or T3-4N 0M0 that is ER/PR positive or negative and HER-2/neu
negative (1+) immunocytochemistry or not amplified by FISH

- OR By pathologic evaluation, primary tumor must be T2N0 that is ER, PR and HER-2neu
negative

- Women of reproductive potential must be non-pregnant and non-nursing and must agree to
employ an effective barrier method of birth control throughout the study and for up to
6 months following treatment

- Women of child-bearing potential, must have a negative pregnancy test within 7 days of
initiating study (no childbearing potential is defined as age 55 years or older and no
menses for two years or any age with surgical removal of the uterus and/or both
ovaries)

- ECOG performance status of 0 or 1

- Definitive surgery, lumpectomy and axillary sampling or modified radical mastectomy

- Three weeks since last surgery other than port or right atrial catheter placement

- No significant cardiac disease and a normal left ventricular ejection fraction

- No significant open wounds, uncontrolled hypertension, history of venous or arterial
clotting

- Adequate laboratory parameters within 30 days prior to enrollment defined as:

- Absolute neutrophil count greater than or equal to 1,500/mcl

- Platelet count equal to or greater than 150,000/mcl

- Hemoglobin >11gm/dl

- Alkaline phosphatase equal or less than 1.5 times the ULN

- Total bilirubin equal to or less than 1.5 times the ULN

- AST and ALT no greater than 1.5 times the ULN

- Creatinine less than 1.5 times the ULN

- Urine protein < 2+ on urinalysis, UPC 1.0 or 24 hour urine < 1 g protein

- No active serious infections or other condition precluding chemotherapy

- Able to give informed consent

- Able to return for treatment and follow-up on the specified days

Exclusion Criteria:

- Prior malignancy; except for adequately treated basal cell or squamous cell skin
cancer or noninvasive carcinomas, or other cancer from which the patient has been
disease free for 5 years

- Prior chemotherapy or radiation therapy

- Breast cancer that over expresses Her-2/neu

- Stage IV or metastatic breast cancer

- Inability to cooperate with treatment protocol

- Any comorbidity or condition which, in the opinion of the investigator, may interfere
with the assessments and procedures of this protocol

- Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 12 months of study
enrollment

- Any history of stroke or transient ischemic attack at any time

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment

- Serious, non-healing wound, ulcer, or bone fracture

- Proteinuria at screening as demonstrated by either urine protein/creatinine (UPC)
ratio >= 1.0 at screening OR urinalysis for proteinuria >= 2+ (patients discovered to
have >= 2+ proteinuria on urinalysis at baseline and undergo a 24 hour urine
collection and demonstrate > 1g of protein in 24 hours are ineligible)

- Known hypersensitivity to any component of Avastin or gemcitabine or other required
drugs in the study

- History of venous or arterial thrombosis

- Current, ongoing treatment with full-dose warfarin or its equivalent (i.e.,
unfractionated and/or low molecular weight heparin) for any reason (ASA okay)