title: Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children's Oncology Group phase I consortium report.
abstract: OBJECTIVE
  The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.
  
  
  METHODS
  Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).
  
  
  RESULTS
  Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.
  
  
  CONCLUSIONS
  In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA. maryam.fouladi@cchmc.org
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Paula
authors.initials: P
authors.lastname: Schaiquevich
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Roseanne
authors.initials: R
authors.lastname: Speights
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007008:Hypokalemia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D014212:Tretinoin / Q000008:administration & dosage*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D014212:Tretinoin; D000077337:Vorinostat