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