title: A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. CNIO, Madrid, Spain.
authors.forename: Lucas
authors.initials: L
authors.lastname: Moreno
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Lynley V
authors.initials: LV
authors.lastname: Marshall
authors.affiliation: The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: Birmingham Children's Hospital, Birmingham, United Kingdom.
authors.forename: Bruce
authors.initials: B
authors.lastname: Morland
authors.affiliation: Leeds General Infirmary, Leeds, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Elliott
authors.affiliation: Great North Children's Hospital, Newcastle, United Kingdom.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Campbell-Hewson
authors.affiliation: 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.
authors.forename: Guy
authors.initials: G
authors.lastname: Makin
authors.affiliation: Drug Development Office, Cancer Research United Kingdom, London, United Kingdom.
authors.forename: Sarah E R
authors.initials: SE
authors.lastname: Halford
authors.affiliation: Drug Development Office, Cancer Research United Kingdom, London, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Acton
authors.affiliation: Drug Development Office, Cancer Research United Kingdom, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Ross
authors.affiliation: Drug Development Office, Cancer Research United Kingdom, London, United Kingdom.
authors.forename: Shamim
authors.initials: S
authors.lastname: Kazmi-Stokes
authors.affiliation: Astex Therapeutics Ltd., Cambridge, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lock
authors.affiliation: Astex Therapeutics Ltd., Cambridge, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Astex Therapeutics Ltd., Cambridge, United Kingdom.
authors.forename: John F
authors.initials: JF
authors.lastname: Lyons
authors.affiliation: Northern Institute for Cancer Research, Newcastle, United Kingdom.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.affiliation: Northern Institute for Cancer Research, Newcastle, United Kingdom.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Griffin
authors.affiliation: Astex Therapeutics Ltd., Cambridge, United Kingdom.
authors.forename: Murray
authors.initials: M
authors.lastname: Yule
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. darren.hargrave@gosh.nhs.uk.
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D064127:Aurora Kinases / Q000037:antagonists & inhibitors; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome; 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; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014508:Urea; D064127:Aurora Kinases