title: 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.
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.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: B
authors.initials: B
authors.lastname: Vormoor
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Veal
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Griffin
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Irving
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: L
authors.initials: L
authors.lastname: Minto
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Case
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.|The Royal Marsden Hospital, Sutton, UK.
authors.forename: U
authors.initials: U
authors.lastname: Banerji
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.
authors.forename: K E
authors.initials: KE
authors.lastname: Swales
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.
authors.forename: J R
authors.initials: JR
authors.lastname: Tall
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.|The Royal Marsden Hospital, Sutton, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Moore
authors.affiliation: Astex Pharmaceuticals, Cambridge Science Park, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Toguchi
authors.affiliation: Cancer Research UK Centre for Drug Development, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Acton
authors.affiliation: Cancer Research UK Centre for Drug Development, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Dyer
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.|Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Grainger
authors.affiliation: The Royal Marsden Hospital, Sutton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lancaster
authors.affiliation: Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: Kearns
authors.affiliation: Great Ormond Street Hospital for Children, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Hargrave
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.|Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Vormoor
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D014508:Urea; D064127:Aurora Kinases
keywords: AT9283; aurora kinase; leukemia; pediatric; phase I/II trial