• • Safety and Tolerability In this study, safety and tolerability will be assessed according to standard (CTCAE version 3.0) toxicity reporting criteria. Adverse events will be monitored at every patient visit and quality of life will be measured at ba [ Time Frame: May 2009 ] [ Designated as safety issue: Yes ]
  

• To estimate the activity of avastin when added to single agent chemotherapy, as measured by radiographic response rate, PFS, and OS. To assess quality of life during treatment with this therapeutic approach. [ Time Frame: 8 to 9 weeks ] [ Designated as safety issue: No ]
  

There is an unmet clinical need for effective therapy of breast cancer that has metastasized to the brain. In this scenario, median survival is around 12 months using currently available therapeutic interventions. The majority of chemotherapy-based clinical trials have considered the presence of central nervous system metastasis an exclusion criterion due to the risk of toxicities, the inability of chemotherapeutic agents to cross the blood brain barrier, and the limited overall survival within this patient population.

The preclinical data regarding the safety and activity of bevacizumab in VEGF-expressing tumors provide a good rationale for its study in patients with breast cancer with metastasis to the brain. Yano, et al. illustrated that tumor cell expression of VEGF mRNA and protein directly correlated with angiogenesis and growth of brain metastasis in a nude mouse model. Transfecting the experimental cell lines known to produce visceral metastasis with an anti-sense VEGF-gene significantly reduced the incidence of brain metastasis. Kim, et al. illustrated that a murine model specific for brain metastases originating from breast cancer showed elevated expression of the angiogenic and permeability-inducing factor VEGF-A. The growth of the brain metastases in this model was attenuated by the addition of a VEGF-tyrosine kinase inhibitor via induction of apoptosis and decreased angiogenesis. VEGF has also been implicated in the development of brain edema, a significant source of the morbidity and mortality associated with brain metastasis. Enhanced levels of VEGF and its receptors have been reported in a murine model after induction of cortical ischemia. Finally, antagonism of VEGF was demonstrated to reduce both immediate and delayed volume of infarct.

The optimal dose of bevacizumab has been extensively studied in phase I trials alone and in combination with chemotherapy. The safe and effective dose has been established as 10 mg/kg q 14 days or 15 mg/kg Q 21 days. In addition to irinotecan and paclitaxel, it has been previously used in phase II/III settings in combination with capecitabine, vinorelbine, gemcitabine, and docetaxel. Phase III studies showed an overall survival advantage when bevacizumab was added to an irinotecan/5FU-based regimen for metastatic colorectal cancer, and when added to weekly paclitaxel for metastatic breast cancer.

Inclusion Criteria:

• Female, 18+, with evaluable metastatic breast cancer and stable brain metastases
• Must have received definitive radiotherapy
• No evidence, or history of, central nervous system hemorrhage
• Adequate organ and hematological function

Exclusion Criteria:

• Active infection, non-healing wound, or history of any bleeding diathesis or coagulopathy
• Uncontrolled hypertension, congestive heart failure, peripheral vascular disease