CP-724,714 in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

• Determine the safety and tolerability of CP-724,714 in patients with metastatic HER2-overexpressing breast cancer.
• Determine the maximum tolerated dose of this drug in these patients.
• Determine, preliminarily, any antitumor activity of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the relationship of drug-related adverse events to pharmacokinetic exposure parameters in these patients.
• Determine the relationship of changes in serum HER2 extracellular domain and HER2 receptor tyrosine kinase phosphorylation to pharmacokinetic exposure parameters and clinical outcome in patients treated with this drug.

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

Patients receive oral CP-724,714 on days 1 and 3-21 during course 1 and then daily during subsequent courses. Courses repeat every 3 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of CP-724,714 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed for at least 30 days.

PROJECTED ACCRUAL: A total of 3-20 patients will be accrued for this study within 6 months.

Inclusion criteria

• Histologically or cytologically confirmed HER2-overexpressing breast cancer
• Prior or newly documented HER2 amplification by fluorescence in situ hybridization (FISH)
• Progressive metastatic disease
• Must have received at least one prior chemotherapy regimen for metastatic breast cancer
• At least 1 measurable or evaluable lesion
• At least 1 lesion accessible for 2 separate core biopsies for pharmacodynamic evaluation
• 18 and over
• Male or female
• ECOG 0-1
• Life expectancy, More than 3 months
• Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3*
• Platelet count at least 100,000/mm^3* NOTE: *Without hematopoietic growth factors or transfusions
• Hepatic

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
• Renal

• Creatinine no greater than 1.5 times ULN OR
• Creatinine clearance at least 60 mL/min
• Cardiovascular

• 12-lead ECG with normal tracing
• history of cardiovascular disease (i.e., ischemic heart disease, arrhythmia, or congestive heart failure) unless asymptomatic for the past year with no requirement for antiarrhythmics or a clinically significant medical management change
• Gastrointestinal

• Able to take oral medication* Negative pregnancy test
• Fertile patients must use effective contraception
• At least 4 weeks since prior trastuzumab (Herceptin)
• At least 4 weeks since other prior biologic therapy or immunotherapy
• At least 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas)
• At least 6 months since prior doxorubicin or doxorubicin equivalents without any prior or developing signs or symptoms of cardiomyopathy
• No cumulative doses of more than 300 mg/m^2
• At least 2 weeks since prior hormonal therapy for the primary disease
• Concurrent hormone replacement therapy or luteinizing hormone-releasing hormone agonists allowed
• At least 4 weeks since prior radiotherapy
• At least 3 weeks since prior major surgery (2 weeks for minor surgery)
• Recovered from prior therapy
• At least 4 weeks since prior investigational treatment
• Coumarin or heparin derivatives allowed for the prevention of deep vein thrombosis or port patency

Exclusion criteria

• known or clinically suspected brain metastases or leptomeningeal disease
• symptomatic edema or third-space fluid (e.g., ascites or pleural effusions)
• known hepatitis B or C infection
• significant ECG changes that require medical intervention
• QTc interval less than 460 msec
• No history of torsade or other symptomatic QTc abnormality
• LVEF greater than 50% by MUGA
• gastrointestinal abnormality that would require medications (including all antacids)
• persistent symptoms of an esophageal or digestive disorder
• pregnant or nursing
• known HIV infection
• active infection
• concurrent uncontrolled systemic disorders or laboratory abnormalities that would preclude study drug safety evaluation
• mental disorder that would preclude study compliance or ability to give informed consent
• No more than 2 prior trastuzumab-based regimens for advanced disease
• concurrent immunotherapy
• more than 1 prior anthracycline- or anthracenedione-containing regimen (except with approval of the sponsor)
• prior high-dose chemotherapy with hematopoietic stem cell transplantation
• concurrent anticancer chemotherapy
• No concurrent anticancer hormonal therapy, including tamoxifen
• prior radiotherapy to the only disease site that would be assessed for response
• concurrent radiotherapy
• prior partial or complete gastrectomy
• concurrent antiarrhythmics
• concurrent antacids
• concurrent anticoagulant at therapeutic doses
• other concurrent experimental anticancer medications for breast cancer