Hargrave, Darren R;
Pearson, Andrew DJ;
Moreno, Lucas;
Morland, Bruce;
Elliott, Martin;
Makin, Guy;
Campbell-Hewson, Quentin;
Wyld, Peter J.;
Halford, Sarah E. R.;
Lock, Victoria;
Lyons, John F.;
Boddy, Alan V.;
Yule, Murray
A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours
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Media type:
E-Article
Title:
A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours
Contributor:
Hargrave, Darren R;
Pearson, Andrew DJ;
Moreno, Lucas;
Morland, Bruce;
Elliott, Martin;
Makin, Guy;
Campbell-Hewson, Quentin;
Wyld, Peter J.;
Halford, Sarah E. R.;
Lock, Victoria;
Lyons, John F.;
Boddy, Alan V.;
Yule, Murray
Published:
American Society of Clinical Oncology (ASCO), 2012
Published in:
Journal of Clinical Oncology, 30 (2012) 15_suppl, Seite 9542-9542
Description:
9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK & ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged >2 to <19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas & 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 & considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day & Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre & post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]