The purpose of this study is to evaluate the safety and effectiveness of combined treatment with trastuzumab (Herceptin) and bevacizumab (anti-VEGF antibody) in patients with HER2-positive metastatic breast cancer.

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)