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

FOULADI M; PARK JR; STEWART CF; GILBERTSON RJ; SCHAIQUEVICH P; SUN J; REID JM; AMES MM; SPEIGHTS R; INGLE AM; ZWIEBEL J; BLANEY SM; ADAMSON PC

JOURNAL OF CLINICAL ONCOLOGY

AMER SOC CLINICAL ONCOLOGY

Año: 2010 vol. 128 p. 3623 - 3629

0732-183X

PurposeThe purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limitingtoxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and incombination 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 MethodsVorinostat 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).ResultsSixty-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  ,291 ng/mL hr) and oral suspension (range, 1,186 to 4,780 ng/mL 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.ConclusionIn 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.