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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

Authors' Affiliations: ¹ University of Colorado Cancer Center, Aurora, Colorado; ² Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; ³ Bayer Healthcare, Seattle, Washington; and ⁴ Bayer Schering Pharma AG, Berlin, Germany

Requests for reprints: Lia Gore, University of Colorado Health Sciences Center at Fitzsimons, Pediatrics, Mail Stop 8302, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-4011; Fax: 303-724-4015; E-mail: lia.gore{at}uchsc.edu.

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.