Treatment of HER2-Positive Metastatic Breast Cancer With Herceptin and Bevacizumab (Antibodies Against HER2 and VEGF)

Based on preclinical experiments conducted in our laboratories, we hypothesize that the
aggressive behavior of HER2-overexpressing breast cancers is due in part to increased
angiogenesis resulting from HER2-induced increases in vascular endothelial growth factor
(VEGF) expression. In vivo experiments suggest that combined blockade of the HER2 receptor
and VEGF results in superior anti-tumor efficacy compared with either treatment alone.

The current clinical trial, for which the phase I portion has been completed, will examine
the efficacy and safety of trastuzumab (Herceptin) and bevacizumab (anti-VEGF antibody) in
the treatment of HER2-overexpressing metastatic breast cancer.

Inclusion Criteria:

- Metastatic or relapsed locally advanced breast cancer

- HER2-positive by FISH

- No prior chemotherapy for metastatic disease

- ECOG performance status 0-2

- Normal left ventricular ejection fraction

- Bidimensionally measurable disease

- Oxygen saturation > 90% on room air

Exclusion Criteria:

- Other invasive malignancy within 5 years

- More than 3 different metastatic sites

- >50% liver involvement by metastasis

- Newly diagnosed untreated Stage IIIB breast cancer

- Prior chemotherapy for metastatic disease

- Clinically significant cardiovascular disease

- History or evidence of CNS disease

- Major surgery within 28 days prior to day 0

- Current or recent use of parenteral anticoagulants

- WBC < 3,000/uL

- Platelet count < 75,000/uL

- Hemoglobin < 9.0 g/dL

- Total Bilirubin > 2.0 mg/dL

- AST or ALT > 5 time upper limit of normal for subjects with documented liver
metastases; > 2.5 times upper limit of normal for subjects without evidence of liver
metastases

- Proteinuria (> 1g protein/24 hours at baseline)

- Prior therapy with Herceptin or rhuMAb VEGF (bevacizumab)