A Phase I Study of ZD6474 (Zactima) and Metronomic Chemotherapy in Advanced Breast Cancer

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed Stage IV breast cancer

- Patients may have prior treatment with 0-4 prior chemotherapeutic regimens for
metastatic disease.

- 18 years of age and older

- Life expectancy of greater than 3 months as assessed by patient's primary oncologist

- ECOG Performance Status of 0-2.

- LVEF > 45%, as assessed by echocardiogram or nuclear medicine gate study within 30
days prior to initiating protocol-based treatment

- Negative Serum pregnancy test

- No receipt of any investigational agents within 30 days prior to commencing study
treatment

Exclusion Criteria:

- Abnormal laboratory results as outlined in the protocol

- Therapeutic anti-coagulation. The use of low dose warfarin, intermittent doses of
TPA, or heparin flushes to prophylax against central venous catheter associated clots
is acceptable.

- Brain metastases or spinal cord compression, unless treated at least 4 weeks before
entry and stable without steroid treatment for one week. Leptomeningeal disease is
not eligible.

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it undesirable for the patient to participate

- Clinically significant cardiac event such as myocardial infarction; NYHA
classification of heart disease greater than or equal to 2; or presence of cardiac
disease that increases the risk of ventricular arrhythmia

- History of arrhythmia which is symptomatic or requires treatment or asymptomatic
sustained ventricular tachycardia

- Previous history of QTc prolongation as a result from other medication that required
discontinuation of that medication

- Congenital long QT syndrome, or 1st degree relative with unexplained sudden death
under 40 years of age

- Presence of left bundle branch block

- QTc with Bazett's correction that is unmeasurable or greater than 480msec on
screening ECG.

- Any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes or induce CYP3A4 function

- Hypertension not controlled by medical therapy

- Currently active diarrhea that may affect the ability of the patient to absorb the
Zactima or tolerate diarrhea

- Previous or current non-breast malignancies within the last 5 years, with the
exception of cervical carcinoma in situ and adequately treated basal cell or squamous
cell carcinoma of the skin

- Major surgery within 4 weeks, or incompletely healed surgical incision before
starting study therapy

- Patients with large or rapidly accumulating pleural or abdominal effusions

- Women who are currently pregnant or breastfeeding