Pediatric phase I trial and pharmacokinetic study of vorinostat: A children's oncology group phase I consortium report

Maryam Fouladi, Julie R. Park, Clinton F. Stewart, Richard J. Gilbertson, Paula Schaiquevich, Junfeng Sun, Joel M. Reid, Matthew M. Ames, Roseanne Speights, Ashish M. Ingle, James Zwiebel, Susan M. Blaney, Peter C. Adamson

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125 Scopus citations


Purpose: 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. Patients and Methods: Vorinostat was administered orally daily starting at 180 mg/m2/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/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/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/m2/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. Conclusion: In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Original languageEnglish (US)
Pages (from-to)3623-3629
Number of pages7
JournalJournal of Clinical Oncology
Issue number22
StatePublished - Aug 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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