GW572016 and Trastuzumab in Treating Patients With Metastatic Breast Cancer That Overexpresses HER2/Neu

OBJECTIVES:

Primary

- Determine the optimally tolerated regimen of GW572016 when administered with
trastuzumab (Herceptin^®) in patients with metastatic breast cancer that overexpresses
HER2/neu.

- Determine the safety and tolerability of this regimen in these patients.

Secondary

- Determine the pharmacokinetic parameters of this regimen in these patients.

- Determine the clinical response in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter, dose-escalation study of GW572016.

Patients receive oral GW572016 once daily on days 1-28 and trastuzumab (Herceptin^®) IV over
90 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of GW572016 until the optimally tolerated
regimen (OTR) is determined. The OTR is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity. Once the OTR is determined, 10-18 additional
patients are entered and treated at the OTR.

Patients are followed at 28 days.

PROJECTED ACCRUAL: A total of 3-35 patients will be accrued for this study.

Inclusion Criteria:

- Histologically or cytologically confirmed breast cancer

- Metastatic disease

- Measurable or evaluable disease

- HER2/neu overexpression (2+ or 3+) confirmed by immunohistochemistry and/or HER2 gene
amplification by fluorescence in situ hybridization

- Brain metastases treated by surgery and/or radiotherapy allowed provided the
following criteria are met:

- Neurologic status stable 2 weeks after discontinuing dexamethasone

- No concurrent anticonvulsants that induce metabolism (e.g., phenytoin,
carbamazepine, or phenobarbital)

- 18 and over

- Male or female

- Karnofsky 70-100%

- Life expectancy, At least 12 weeks

- Hematopoietic

- Absolute granulocyte count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- AST and ALT ≤ 3 times upper limit of normal (ULN) (5 times ULN if patient has
liver metastases)

- Bilirubin < 1.5 mg/dL

- Creatinine clearance > 30 mL/min

- Cardiovascular

- LVEF > 50%

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 4 weeks after study
participation

- Adequate venous access

- Able to swallow and retain oral medication

- Prior adjuvant/neoadjuvant chemotherapy allowed

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin.

- More than 4 weeks since prior radiotherapy

- More than 4 weeks since prior major surgery

- Recovered from all prior therapy

- More than 28 days since prior participation in another investigational study

- More than 28 days since prior investigational drugs

Exclusion Criteria:

- extensive tumor, pleural effusions, or parenchymal masses) resulting in dyspnea at
rest

- uncontrolled brain metastases or leptomeningeal disease

- prior myocardial infarction

- pre-existing cardiac dysfunction (e.g., congestive heart failure)

- clinically significant cardiac disease

- angina pectoris

- symptomatic intrinsic pulmonary disease (e.g., asthma or chronic obstructive
pulmonary disease) resulting in dyspnea at rest

- pregnant or nursing

- active infection

- known hypersensitivity to Chinese Hamster Ovary cell proteins or any component of
this product

- known immediate or delayed hypersensitivity reaction or idiosyncrasy to products of
similar chemical composition as study drug

- known contraindications to trastuzumab (Herceptin^®)

- malabsorption syndrome

- disease significantly affecting gastrointestinal function

- psychiatric disorder that would preclude study compliance

- other serious illness or condition

- concurrent biologic therapy

- prior cumulative dose of doxorubicin > 400 mg/m^2 (including liposomal doxorubicin)

- concurrent hormonal therapy*

- concurrent glucocorticoids

- concurrent radiotherapy

- prior major resection of the stomach or small bowel that could affect absorption of
GW572016

- concurrent cytotoxic therapy

- other concurrent anticancer therapy

- other concurrent investigational drugs during and for 28 days after study treatment

- concurrent administration of any of the following medications or substances:

- Antibiotics

- Clarithromycin

- Erythromycin

- Troleandomycin

- Ciprofloxacin

- Rifampin

- Norfloxacin

- Rifabutin

- HIV antivirals

- Delaviridine

- Indinavir

- Nelfinavir

- Ritonavir

- Saquinavir

- Efavirenz

- Nevirapine

- Amprenavir

- Lopinavir

- Anticonvulsants

- Phenytoin

- Carbamazepine

- Phenobarbital

- Antidepressants

- Fluoxetine

- Nefazodone

- Fluvoxamine

- Antifungals

- Itraconazole

- Ketoconazole

- Fluconazole

- Voriconazole

- Antacids (within 1 hour before and after study drug administration)

- Cimetidine

- Amiodarone

- Diltiazem

- Pioglitazone

- Hypericum perforatum (St. John's wort)

- Grapefruit or grapefruit juice

- Rifabutin

- Diethyldithiocarbamate

- Gestodene

- Mifepristone

- Modafinil