Dose-Dense Chemotherapy Plus Bevacizumab in High Risk Lymph Node Positive Breast Cancer: A Pilot Study

Approximately 200,000 women are diagnosed with breast cancer in the United States every
year. A significant factor determining long-term survivability of breast cancer is whether
or not lymph nodes, glands which cleanse and filter the body's fluids, are involved. Despite
treatment with approved multiagent cytotoxic chemotherapy ("dose-dense chemotherapy"), women
with breast cancer involving more than 4 axillary lymph nodes still have a high risk for
recurrence.

Several dose-dense chemotherapy regimens are currently being compared in other studies,
however, at this time there is no proof that one regimen is superior to another. Therefore,
in an attempt to decrease metastases, prolong time to recurrence and improve overall
survival, it is essential to develop novel therapeutic strategies. The use of inhibitors of
angiogenesis represents a promising option.

Bevacizumab is the first angiogenesis inhibiting drug to be FDA approved, for the treatment
of colon cancer. It is has also been studied alone in progressed lymph-node positive breast
cancer and has shown moderate efficacy.

This study will observe the efficacy and tolerability of using bevacizumab in combination
with an approved dose-dense chemotherapy regimen for 8 cycles, followed by 12 of bevacizumab
alone. Patients may be on the study for up to 52 weeks if their disease has not progressed
and the regimen is tolerated.

Inclusion Criteria:

- High risk lymph node positive breast cancer defined as 5 or more involved axillary
lymph nodes

- Must have undergone surgical local therapy (modified radical mastectomy or breast
conserving surgery).

- Negative tumor margins for invasive cancer

- No evidence of distant metastasis

- Normal cardiac ejection fraction

- Adequate organ function defined as:

ANC > 1200/mm3 Platelet count > 100,000/mm Serum creatinine < 2.0 mg/dl Serum bilirubin <
1.5 x ULN

- Performance status 0-1

- Age 18 years or older

- No prior chemotherapy, hormonal therapy or radiation therapy for treatment of the
primary breast cancer

- Bilateral synchronous breast cancer is allowed if other criteria are met.

- Patients may be ER/PR+ and receive treatment with hormonal therapy (tamoxifen or
aromatase inhibitors)

- Use of effective means of contraception (men and women) in subjects of child-bearing
potential

- Signed informed consent

Exclusion Criteria:

- Evidence of distant metastases

- Inflammatory Breast Cancer

- Prior use of any chemotherapy or hormonal therapy for breast cancer

- Patients with her 2 neu positive tumors

- History of other malignancies within the last 5 years. Prior history of carcinoma in
situ of the cervix, melanoma in situ and basal cell carcinoma of the skin is allowed
within the last 5 years.

- Prior therapy with anthracyclines for any malignancy

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

- Blood pressure of equal to or higher than 150/100

- Unstable angina

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

- History of myocardial infarction within 6 months

- History of stroke within 6 months

- Clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Presence of central nervous system or brain metastases

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 0, anticipation of need for major surgical procedure during the course
of the study

- Minor surgical procedures such as fine needle aspirations or core biopsies within 7
days prior to Day 0

- Pregnant (positive pregnancy test) or lactating

- Urine protein:creatinine ratio >1.0 at screening

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to Day 0

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

- Inability to comply with study and/or follow-up procedures