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

Research output: Contribution to journalArticle

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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/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
Volume28
Issue number22
DOIs
StatePublished - Aug 1 2010

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Pharmacokinetics
Pediatrics
Isotretinoin
Maximum Tolerated Dose
Neutropenia
Thrombocytopenia
Histones
Blood Cells
Neoplasms
Suspensions
vorinostat
Hypokalemia
Hypertriglyceridemia
Anorexia
Neuroblastoma
Capsules
Leukemia
Western Blotting
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Fouladi, M., Park, J. R., Stewart, C. F., Gilbertson, R. J., Schaiquevich, P., Sun, J., ... Adamson, P. C. (2010). Pediatric phase I trial and pharmacokinetic study of vorinostat: A children's oncology group phase I consortium report. Journal of Clinical Oncology, 28(22), 3623-3629. https://doi.org/10.1200/JCO.2009.25.9119

Pediatric phase I trial and pharmacokinetic study of vorinostat : A children's oncology group phase I consortium report. / Fouladi, Maryam; Park, Julie R.; Stewart, Clinton F.; Gilbertson, Richard J.; Schaiquevich, Paula; Sun, Junfeng; Reid, Joel M; Ames, Matthew M.; Speights, Roseanne; Ingle, Ashish M.; Zwiebel, James; Blaney, Susan M.; Adamson, Peter C.

In: Journal of Clinical Oncology, Vol. 28, No. 22, 01.08.2010, p. 3623-3629.

Research output: Contribution to journalArticle

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 2010, 'Pediatric phase I trial and pharmacokinetic study of vorinostat: A children's oncology group phase I consortium report', Journal of Clinical Oncology, vol. 28, no. 22, pp. 3623-3629. https://doi.org/10.1200/JCO.2009.25.9119
Fouladi, Maryam ; Park, Julie R. ; Stewart, Clinton F. ; Gilbertson, Richard J. ; Schaiquevich, Paula ; Sun, Junfeng ; Reid, Joel M ; Ames, Matthew M. ; Speights, Roseanne ; Ingle, Ashish M. ; Zwiebel, James ; Blaney, Susan M. ; Adamson, Peter C. / Pediatric phase I trial and pharmacokinetic study of vorinostat : A children's oncology group phase I consortium report. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 22. pp. 3623-3629.
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AU - Schaiquevich, Paula

AU - Sun, Junfeng

AU - Reid, Joel M

AU - Ames, Matthew M.

AU - Speights, Roseanne

AU - Ingle, Ashish M.

AU - Zwiebel, James

AU - Blaney, Susan M.

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N2 - 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.

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