A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

B Vormoor; G J Veal; M J Griffin; A V Boddy; J Irving; L Minto; M Case; U Banerji; K E Swales; J R Tall; A S Moore; M Toguchi; G Acton; K Dyer; C Schwab; C J Harrison; J D Grainger; D Lancaster; P Kearns; D Hargrave; J Vormoor

doi:10.1002/pbc.26351

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

Pediatr Blood Cancer. 2017 Jun;64(6). doi: 10.1002/pbc.26351. Epub 2016 Dec 1.

Authors

B Vormoor^{1

2}, G J Veal¹, M J Griffin¹, A V Boddy¹, J Irving¹, L Minto¹, M Case¹, U Banerji^{3

4}, K E Swales³, J R Tall³, A S Moore^{3

4}, M Toguchi⁵, G Acton⁶, K Dyer⁶, C Schwab¹, C J Harrison¹, J D Grainger^{7

8}, D Lancaster⁴, P Kearns⁹, D Hargrave¹⁰, J Vormoor^{1

2}

Affiliations

¹ Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
² Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
³ Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.
⁴ The Royal Marsden Hospital, Sutton, UK.
⁵ Astex Pharmaceuticals, Cambridge Science Park, Cambridge, UK.
⁶ Cancer Research UK Centre for Drug Development, London, UK.
⁷ Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁸ Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK.
⁹ Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.
¹⁰ Great Ormond Street Hospital for Children, London, UK.

PMID: 27905678
DOI: 10.1002/pbc.26351

Abstract

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Keywords: AT9283; aurora kinase; leukemia; pediatric; phase I/II trial.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Adolescent
Aurora Kinases / antagonists & inhibitors*
Benzimidazoles / administration & dosage*
Benzimidazoles / adverse effects
Benzimidazoles / pharmacokinetics*
Child
Child, Preschool
Female
Humans
Infant
Leukemia / drug therapy*
Leukemia / enzymology
Male
Maximum Tolerated Dose
Neoplasm Proteins / antagonists & inhibitors*
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / pharmacokinetics*
Urea / administration & dosage
Urea / adverse effects
Urea / analogs & derivatives*
Urea / pharmacokinetics

Substances

1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
Benzimidazoles
Neoplasm Proteins
Protein Kinase Inhibitors
Urea
Aurora Kinases

Grants and funding

9835/CRUK_/Cancer Research UK/United Kingdom