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

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.

• Authors: Lia Gore, Mace L Rothenberg, Cindy L O'Bryant, Mary Kay Schultz, Alan B Sandler, Denise Coffin, Candice McCoy, Astrid Schott, Catherine Scholz, S Gail Eckhardt
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 14 Pg. 4517-25 (Jul 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18579665 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Pyridines
• entinostat

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Histone Deacetylase Inhibitors
• Humans
• Lymphoma (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics)