PTK787 + Trastuzumab for HER2 Overexpressing Metastatic Breast Cancer

OUTLINE: This is a multi-center study.

PTK787 daily plus trastuzumab 4 mg/kg IV week 1, followed by 2 mg/kg weekly with disease
evaluation every other cycle.

Patients may continue treatment until disease progression or toxicity intervenes.

Performance Status: ECOG 0 or 1

Life Expectancy: Not specified

Hematopoietic:

- ANC > 1500 mm3

- Platelets > 100,000 mm3

- Hemoglobin > 9 g/dL

- PTT and INR < 1.5 x ULN

Hepatic:

- ALT and AST < 3 x ULN (< 5 x ULN in patients with known liver metastases)

- Alkaline phosphatase < 2.5 x ULN

- Serum bilirubin < 1.5 x ULN

Renal:

- Serum creatinine < 1.5 x ULN

- Proteinuria < 1+ by dipstick OR total urinary protein < 500 mg/24 hours with measured
creatinine clearance (CrCl) ≥ 50 mL/min

Cardiovascular:

- No clinically significant cardiac disease (e.g. congestive heart failure, symptomatic
coronary artery disease and cardiac arrhythmias not well controlled with medication) or
myocardial infarction within the last 6 months.

- LVEF > LLN by MUGA or ECHO (obtained within 28 days prior to being registered for
protocol therapy)

Pulmonary:

- Not specified

Inclusion Criteria:

- Histologic or cytologic diagnosis of breast cancer with evidence of measurable (1)
unresectable, locally recurrent, or (2) metastatic disease. Locally recurrent disease
must not be amenable to resection OR radiation with curative intent.

- Patient's disease may not involve more than 3 metastatic sites. In addition, patient
may not be symptomatic from pulmonary metastasis or have liver metastasis involving >
50% of parenchyma.

- HER2 gene amplification by FISH. HER protein overexpression by immunohistochemistry
will not be sufficient for entry.

- Negative pregnancy test

Exclusion Criteria:

- No prior cytotoxic chemotherapy or trastuzumab for locally recurrent or metastatic
disease.

- No prior treatment with any VEGF inhibiting agents

- No history or presence of central nervous system (CNS) disease.

- No other forms of cancer therapy including radiation, chemotherapy and hormonal
therapy within 21 days prior to being registered for protocol therapy.

- No major surgery within 28 days prior to being registered for protocol therapy.

- No uncontrolled hypertension (SBP > 170, DBP > 90), history of labile hypertension or
history of poor compliance with antihypertensive therapy.

- No requirement for therapeutic anticoagulation, regular aspirin (> 325 mg/day) or
NSAID use.

- No current breast feeding.

- No impairment of gastrointestinal (GI) function that may significantly alter the
absorption of PTK787.

- No evidence of other serious concomitant systemic disorders incompatible with the
study (at the discretion of the investigator).