title: A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.
abstract: BACKGROUND
  This study sought to identify the maximum tolerated dose (MTD) of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics, and preliminary evidence of efficacy.
  
  
  METHODS
  AT9283 was administered as a continuous 72-hour infusion every 21 days. Doses were escalated by a standard 3 + 3 design. After the MTD for the 72-hour infusion was identified, infusion duration was increased incrementally to 96 hours and 120 hours. In total, 48 patients received ≥ 1 cycle of AT9283. Median age was 61 years (range, 22-86 years); 56% were men; 75% were diagnosed with AML; and 89% had received ≥ 3 (up to 16) prior lines of therapy.
  
  
  RESULTS
  324 mg/m(2)/72 h AT9283 was determined to be the MTD. Dose-limiting toxicities (DLTs) were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leukopenia and mucositis. Bone marrow blasts decreased ≥ 38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of Aurora kinase B inhibition. Two patients with accelerated-phase chronic myeloid leukemia showed evidence of benefit, manifested as a cytogenetic response in 1 case; 1 patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional.
  
  
  CONCLUSIONS
  AT9283 tolerability was strongly dose-dependent, with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations.
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
authors.forename: James
authors.initials: J
authors.lastname: Foran
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jan
authors.initials: J
authors.lastname: Burger
authors.affiliation: Astex Pharmaceuticals Inc, Cambridge, United Kingdom.
authors.forename: Murray
authors.initials: M
authors.lastname: Yule
authors.affiliation: Astex Pharmaceuticals Inc, Cambridge, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Langford
authors.affiliation: Astex Pharmaceuticals Inc, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.affiliation: Astex Pharmaceuticals Inc, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Ayrton
authors.affiliation: Astex Pharmaceuticals Inc, Cambridge, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lock
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gautham
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: hkantarj@mdanderson.org.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
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; D047428:Protein Kinase Inhibitors; D014508:Urea
keywords: Blood cancer; Clinical; Dose escalation; Response; Tolerability