title: Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of Aurora kinase A: a Children's Oncology Group Phase I Consortium study.
abstract: OBJECTIVE
  MLN8237, a selective small-molecule inhibitor of Aurora kinase A, has activity in a broad range of preclinical pediatric cancer models. We conducted a phase I trial in children with refractory/recurrent solid tumors to define the maximum-tolerated dose, toxicities, and pharmacokinetic properties of MLN8237.
  
  
  METHODS
  MLN8237 was administered orally either once daily or divided twice daily for seven days, every 21 days. Using a rolling-six design, four dose levels (45, 60, 80, and 100 mg/m(2)/day) were evaluated on the once-daily schedule, and two dose levels (60 and 80 mg/m(2)/d) on the twice-daily schedule. Pharmacokinetic studies were conducted with the initial dose and trough drug concentrations also measured at the steady state.
  
  
  RESULTS
  Thirty-seven patients were enrolled. On the once-daily dosing schedule, myelosuppression was dose limiting in three of four patients at 100 mg/m(2), and one of six patients had dose-limiting mood alteration at 80 mg/m(2). At 45 mg/m(2), one of six patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m(2) on the twice-daily schedule, and one of five patients at 60 mg/m(2) on the twice-daily schedule experienced a dose-limiting alkaline phosphatase. Five of 11 patients experienced hand-foot-skin syndrome with twice-daily dosing versus one of 21 after once-daily dosing. There was one partial response and six with prolonged stable disease among 33 evaluable subjects.
  
  
  CONCLUSIONS
  The twice-daily dose regimen is well tolerated in adults; however, children experienced a greater frequency of myelosuppression and hand-foot-skin syndrome on this schedule. Children tolerated a higher dose and the recommended pediatric phase II dose is 80 mg/m(2)/d once daily for seven days.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. mosse@chop.edu
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mossé
authors.forename: Emily
authors.initials: E
authors.lastname: Lipsitz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ingle
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Ahern
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001381:Azepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines