A Phase I, Open-Label Study of the Safety, Tolerability and Pharmacokinetics of GW572016 in Combination With Trastuzumab [Herceptin†]

Study start date: March 1, 2004

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