RATIONALE: CP-724,714 may stop the growth of tumor cells by blocking the enzymes necessary
for tumor cell growth.
PURPOSE: Phase I trial to study the effectiveness of CP-724,714 in treating patients who
have metastatic HER2-overexpressing breast cancer.
- 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.
- Histologically or cytologically confirmed HER2-overexpressing breast cancer
- Prior or newly documented HER2 amplification by fluorescence in situ hybridization
- Progressive metastatic disease
- Must have received at least one prior chemotherapy regimen for metastatic breast
- At least 1 measurable or evaluable lesion
- At least 1 lesion accessible for 2 separate core biopsies for pharmacodynamic
- 18 and over
- Male or female
- ECOG 0-1
- Life expectancy, More than 3 months
- Absolute neutrophil count at least 1,500/mm^3*
- Platelet count at least 100,000/mm^3* NOTE: *Without hematopoietic growth
factors or transfusions
- 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)
- Creatinine no greater than 1.5 times ULN OR
- Creatinine clearance at least 60 mL/min
- 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
- 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
- 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
- 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
- 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