title: Phase I study of everolimus in pediatric patients with refractory solid tumors.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.
  
  
  METHODS
  Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients.
  
  
  RESULTS
  There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed.
  
  
  CONCLUSIONS
  Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. maryam.fouladi@stjude.org
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Fred
authors.initials: F
authors.lastname: Laningham
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Melinda A
authors.initials: MA
authors.lastname: O'Shaughnessy
authors.forename: Kristen
authors.initials: K
authors.lastname: Molina
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Spunt
authors.forename: Inga
authors.initials: I
authors.lastname: Luckett
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016879:Salvage Therapy; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus