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Clin Cancer Res. 2008 Jul 15;14(14):4517-25. doi: 10.1158/1078-0432.CCR-07-1461. Epub 2008 Jun 25.

A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.

Author information

1
University of Colorado Cancer Center, Aurora, Colorado, USA. lia.gore@uchsc.edu

Abstract

PURPOSE:

To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules.

EXPERIMENTAL DESIGN:

Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined.

RESULTS:

Twenty-seven patients received > or =149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation.

CONCLUSIONS:

MS-275 is well tolerated at doses up to 6 mg/m(2) every other week or 4 mg/m(2) weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m(2) given weekly for 3 weeks every 28 days or 2 to 6 mg/m(2) given once every other week.

PMID:
18579665
PMCID:
PMC2813676
DOI:
10.1158/1078-0432.CCR-07-1461
[Indexed for MEDLINE]
Free PMC Article

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