A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study.

Autor:	Moreno L; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. CNIO, Madrid, Spain., Marshall LV; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom., Pearson AD; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom., Morland B; Birmingham Children's Hospital, Birmingham, United Kingdom., Elliott M; Leeds General Infirmary, Leeds, United Kingdom., Campbell-Hewson Q; Great North Children's Hospital, Newcastle, United Kingdom., Makin G; Institute of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, and Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom., Halford SE; Drug Development Office, Cancer Research United Kingdom, London, United Kingdom., Acton G; Drug Development Office, Cancer Research United Kingdom, London, United Kingdom., Ross P; Drug Development Office, Cancer Research United Kingdom, London, United Kingdom., Kazmi-Stokes S; Drug Development Office, Cancer Research United Kingdom, London, United Kingdom., Lock V; Astex Therapeutics Ltd., Cambridge, United Kingdom., Rodriguez A; Astex Therapeutics Ltd., Cambridge, United Kingdom., Lyons JF; Astex Therapeutics Ltd., Cambridge, United Kingdom., Boddy AV; Northern Institute for Cancer Research, Newcastle, United Kingdom., Griffin MJ; Northern Institute for Cancer Research, Newcastle, United Kingdom., Yule M; Astex Therapeutics Ltd., Cambridge, United Kingdom., Hargrave D; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. darren.hargrave@gosh.nhs.uk.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Jan 15; Vol. 21 (2), pp. 267-73. Date of Electronic Publication: 2014 Nov 04.
DOI:	10.1158/1078-0432.CCR-14-1592
Abstrakt:	Purpose: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity. Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m(2)/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. Results: Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m(2)/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system-primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m(2)/d. Conclusion: AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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