A Research Study of CP-724,714 in Patients With HER2 Overexpressing Metastatic Breast Cancer

Inclusion Criteria:

• Signed written and voluntary informed consent
• Histologically or cytologically confirmed breast cancer
• Stage IV (metastatic) breast cancer
• Biopsy (fresh or archival) of primary breast cancer or metastatic site demonstrating HER2 gene amplification as determined in study-specified central laboratory by fluorescence in situ hybridization (FISH)
• Prior treatment and progressive disease with at least 1 but not more than 2 cytotoxic chemotherapy regimen(s) for metastatic disease
• Those for whom the use of an investigational HER2 inhibitor is appropriate because they do not have access to approved HER2 inhibitors (e.g., Herceptin®) or for whom treatment with currently available HER2 inhibitors is inappropriate
• Limited visceral disease burden (i.e., <30% involvement of any organ) and limited disease-related symptoms (i.e., well controlled with supportive care measures)
• Presence of at least one measurable target lesion [i.e., malignant tumor mass that can be accurately measured in at least 1 dimension of >=2 cm with conventional radiographic techniques or magnetic resonance imaging, or >=1 cm with spiral CT scan as per RECIST], excluding previously irradiated lesions, bone metastasis or pleural effusion as sole manifestations of disease. If the measurable disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by cytology/histology
• Eastern Cooperative Oncology Group (ECOG) performance status 0 1
• Patient available for treatment, monitoring, and follow-up. Willing and able to comply with scheduled visits, therapy plan, laboratory tests and blood sampling for pharmacokinetic (PK) analyses
• Recovery to baseline or NCI CTCAE Version 3.0 Grade 1 toxicity from all acute effects related to prior treatment, except alopecia
• Adequate Bone Marrow Function, including: a. Absolute neutrophil count (ANC) >=1500 cells/mm3; b. Platelets >=100,000 cells/mm3
• Adequate Renal Function, including: a. Estimated creatinine clearance >=60 mL/min; b. SrCr <1.5 x ULN
• Adequate Liver Function, including: a. Bilirubin <=ULN (upper limit of normal); b. AST (SGOT) <=2.5 x ULN; c. ALT (SGPT) <=2.5 x ULN
• Adequate Cardiac Function, including: a. 12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention; b. QTc interval <=450 msec and without history of Torsades des Pointes or other symptomatic QTc abnormality; c. Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal and 45% as measured by echocardiogram or multi gated radionuclide angiography (MUGA) within 4 weeks prior to start of study treatment
• >= 18 years old
• Female

Exclusion Criteria:

• Women of child-bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after study
• Women who are pregnant or breastfeeding
• Women with a positive pregnancy test on enrollment or within 72 hours prior to study drug administration
• Prior treatment with trastuzumab (Herceptin®) or other HER2-targeting agents [e.g., lapatinib (GW572016), pertuzumab (Omnitarg™; rhuMab 2C4), CI 1033, EKB 569, CP 724,714]
• Cumulative dose >450 mg/m2 of doxorubicin or doxorubicin equivalents
• Prior high-dose chemotherapy requiring hematopoetic stem cell transplantation within 12 months of study treatment start
• Radiotherapy, investigational chemotherapy, biologic therapy within 4 weeks of study treatment start
• Previous (within the last 5 years) or current malignancies arising from sites other than breast, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri
• Known or clinically suspected brain metastasis or leptomeningeal disease (no screening CT scan required) requiring therapy. Patients with asymptomatic previously treated CNS metastases that no longer require therapy or corticosteroids/anticonvulsants for at least 4 weeks prior to start of study treatment are eligible
• Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form, prior complete/partial gastrectomy or intestinal resection, or a requirement for H2 antagonists or proton pump inhibitors
• Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol
• Uncontrolled or significant cardiovascular disease, including: a. Myocardial infarction within 12 months; b. Uncontrolled angina within 6 months; c. Congestive heart failure within 6 months or left ventricular ejection fraction below local institutional lower limit of normal or below 45%; d. Diagnosed or suspected congenital long QT syndrome; e. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsade de pointes); f. Prolonged QTc interval on pre-entry electrocardiogram (>450 msec); g. Any history of second or third degree heart block (may be eligible if currently have a pacemaker); h. Heart rate <50/minute on pre-entry electrocardiogram; i. Uncontrolled hypertension
• History of drug-induced hyperbilirubinemia
• Concurrent treatment with approved or investigational chemotherapy, hormonal therapy, immunotherapy, or radiotherapy (hormone replacement therapy is permitted)
• Concurrent treatment with H2 antagonists and/or proton pump inhibitors. However, H2 antagonists can be used for the treatment of an unexpected hypersensitivity reaction during the study period. Antacids are allowed but only up to 2 hours before and 2 hours after study drug administration
• Concurrent treatment or treatment within 4 weeks of first dose with potent and/or irreversible CYP3A4 inhibitors including: ketoconazole, itraconazole, troleandomycin, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, mibefradil, amiodarone and grapefruit juice
• Concurrent treatment or treatment within 4 weeks of first dose with potent inducers of CYP3A4 including: rifampin, rifabutin, rifamycins, phenytoin, barbiturates, carbamazepine, glucocorticoids, modafinil, phenobarbital, troglitazone, pioglitazone, efavirenz, nevirapine, dexamethasone, and St. John's wort
• Prisoners or patients who are compulsorily detained or involuntarily incarcerated (e.g., for treatment of infectious disease, psychiatric illness, etc.)