cp-724,714 in treating patients with metastatic breast cancer

Conditions: Breast Cancer

Summary: 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.

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.

Eligibility criteria:
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

Keywords: recurrent breast cancer stage iv breast cancer male breast cancer