Trial of Chemotherapy and Avastin as Treatment for Women With Breast Cancer at High Risk for Relapse

For patients with locally advanced breast cancers (LABC) primary or neoadjuvant chemotherapy
(NAC) has become accepted as standard treatment. Advantages of NAC include shrinking the
primary tumor, often rendering an unresectable cancer resectable, and the theoretically
concurrent treatment of occult metastatic disease prior to definitive local therapy (surgery
+/- radiation therapy). NAC can reduce the extent of surgery required for the management of
local breast cancer from mastectomy to lump- or segmentectomy, without compromising major
outcome measures, such as overall and disease free survival. At this time, the current
standard of care for women felt to be candidates for NAC is an anthracycline + taxane
regimen. The intent is to induce a pCR which as noted above is a strong indicator of
survival. Yet, in both large NSABP studies, the proportion of women achieving this is less
than 20% with these regimens raising a major challenge in clinical practice: what is the
appropriate treatment for women with persistent disease after NAC? Given that gemcitabine and
capecitabine are non-cross-resistant to anthracyclines and taxanes and use a different
mechanism of action, have an acceptable toxicity profile, and in the absence of standard
options for therapy we are interested in utilizing these agents coupled with bevacizumab as
adjuvant treatment in women with residual breast cancer following primary chemotherapy.

Inclusion Criteria:

General health

- Women Age >18.

- ECOG Performance status 0-1

- Life expectancy must be 3 months. Clinical stage

- Histologically or cytologically adenocarcinoma of breast

- Pre-operative stage II-III per AJCC 6th edition, based on baseline evaluation by
clinical examination, breast imaging, and/or preoperative work-up.

- Evidence of residual invasive breast cancer or node positive disease following
neoadjuvant chemotherapy.

Prior Therapy

- Patients must have received primary (neoadjuvant) chemotherapy for local or
locoregional breast cancer containing an anthracycline and a taxane.

- Patients must have completed definitive resection of primary tumor with adequate
excision of gross disease.

- Patients must have residual invasive carcinoma in the breast and/or residual carcinoma
in one or more regional nodes following preoperative chemotherapy.

Adequate hematologic and metabolic parameters within four weeks of study entry defined as:

- Absolute neutrophil count ≥1,500/mm3 Platelets ≥ 150,000/mm3

- Total bilirubin ≤ 2.0 mg/dL

- Serum creatinine ≤ 2x upper limit of normal

- Serum calcium ≤1.5x upper normal limit Concurrent treatments

- Current use of anti-coagulants is allowed as long as patients have been on a stable
dose for more than 2 weeks with stable INR.

- Chronic therapy with full dose aspirin up to 325 mg/day or standard non-steroidal
anti-inflammatory agents is allowed.

Informed consent

- Provision of signed informed consent.

Exclusion Criteria:

Prior therapy

- No prior gemcitabine, continuous infusion 5-FU, or oral fluoropyrimidine
(capecitabine, UFT, S-1, 5-FU/eniluracil, etc.)

- No known hypersensitivity to capecitabine or prior unanticipated severe reaction to
(capecitabine, UFT, S-1, 5-FU/eniluracil, etc.) therapy or known hypersensitivity to
5-fluorouracil.

- No concurrent or prior endocrine therapy as adjuvant treatment.

- No prior breast radiation

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in another experimental drug study

- Stage IV breast cancer

- Patients must not have evidence of metastatic disease at enrollment. Women of
child-bearing potential.

- Nonpregnant and nonlactating.

- Women of child-bearing potential must have a negative serum pregnancy test and must
agree to an effective means of contraception during the entire study period.

Concurrent medical conditions:

- No other active cancers, except non-melanoma skin cancers.

- No serious infection or other serious underlying medical condition that would
otherwise impair their ability to receive protocol treatment.

- Patients with clinically significant medical or psychiatric problems which may
interfere with treatment on study.

Avastin-specific exclusions:

- 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

- Known CNS disease

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

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

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

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment

- 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 urine dipstick for proteinuria ≥ 2+
(patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should
undergo a 24 hour

- urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

- Known hypersensitivity to any component of bevacizumab any history of stroke or
transient ischemic attack at any time

- History of myocardial infarction or unstable angina within 12 months of study
enrollment Inability to comply with study and/or follow-up procedures