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A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas
A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 14(14)
- Publication Year :
- 2008
-
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 ≥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/m2 every other week or 4 mg/m2 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/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week.
- Subjects :
- Adult
Male
Cancer Research
Lymphoma
Maximum Tolerated Dose
medicine.drug_class
Pyridines
Administration, Oral
Antineoplastic Agents
Pharmacology
Peripheral blood mononuclear cell
Article
Histone H3
Pharmacokinetics
Neoplasms
medicine
Humans
Dosing
Enzyme Inhibitors
Aged
business.industry
Histone deacetylase inhibitor
Middle Aged
medicine.disease
Histone Deacetylase Inhibitors
Oncology
Area Under Curve
Toxicity
Benzamides
Female
business
Hypophosphatemia
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 14
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....cf4f685f34004c30ea68be2202c7ccef