کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8447020 1547183 2011 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours
چکیده انگلیسی
This phase I study (ClinicalTrials.gov ID: NCT00424632) evaluated the safe dose, pharmacokinetics, and pharmacodynamics of the aurora kinase A and B inhibitor, PF-03814735. Patients with advanced solid tumours received oral, once-daily (QD) PF-03814735 on Schedule A: days 1-5 (5-100 mg); or Schedule B: days 1-10 (40-60 mg) of 21-day cycles. Fifty-seven patients were treated: 32 and 25 on Schedules A and B, respectively. Dose-limiting toxicities were: febrile neutropenia (Schedule A); and increased levels of aspartate amino transferase, left ventricular dysfunction, and prolonged low-grade neutropenia (Schedule B). Maximum tolerated doses were 80 mg QD (Schedule A) and 50 mg QD (Schedule B). Common treatment-related adverse events were mainly mild to moderate and included diarrhoea, fatigue, nausea, and vomiting. Nineteen patients achieved stable disease, which was prolonged in four cases. PF-03814735 was rapidly absorbed and demonstrated linear pharmacokinetics up to 100 mg QD; mean terminal half-life ranged from 14.4 to 23.6 h. Aurora B activity, assessed by histone H3 phosphorylation in mitotic cells, decreased in tumour tissue from 10/12 patients evaluated (range: −70% to −3%). 18F-fluorodeoxyglucose positron emission tomography demonstrated metabolic responses in only 1/21 patients. PF-03814735 was generally well tolerated with manageable toxicities, and a recommended phase II dose could be established for both schedules. Aurora B activity was inhibited in tumour tissue, but clinical or metabolic antitumour activity was limited.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Cancer - Volume 47, Issue 15, October 2011, Pages 2256-2264
نویسندگان
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