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J Clin Oncol. 2010 Aug 1;28(22):3623-9. doi: 10.1200/JCO.2009.25.9119. Epub 2010 Jul 6.

Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children's Oncology Group phase I consortium report.

Author information

  • 1St Jude Children's Research Hospital, Memphis, TN, USA. maryam.fouladi@cchmc.org

Abstract

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/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.

CONCLUSION:

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.

PMID:
20606092
[PubMed - indexed for MEDLINE]
PMCID:
PMC2917318
Free PMC Article

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