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A Phase I Trial of AT9283 (a Selective Inhibitor of Aurora Kinases) in Children and Adolescents with Solid Tumors: A Cancer Research UK Study

Lookup NU author(s): Professor Andrew Pearson, Dr Quentin Campbell Hewson, Professor Alan Boddy, Melanie Griffin

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Abstract

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/ m2/ 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/ m2/ 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/ m2/ 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. (C) 2014 AACR.


Publication metadata

Author(s): Moreno L, Marshall LV, Pearson ADJ, Morland B, Elliott M, Campbell-Hewson Q, Makin G, Halford SER, Acton G, Ross P, Kazmi-Stokes S, Lock V, Rodriguez A, Lyons JF, Boddy AV, Griffin MJ, Yule M, Hargrave D

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2015

Volume: 21

Issue: 2

Pages: 267-273

Print publication date: 15/01/2015

Online publication date: 04/11/2014

Acceptance date: 11/09/2014

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-14-1592

DOI: 10.1158/1078-0432.CCR-14-1592


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