A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas

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Clinical Cancer Research, 10.1158/1078-0432.CCR-07-1461

A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor,

MS-275, in Patients with Refractory Solid Tumors and Lymphomas

Lia Gore 1*, Mace L. Rothenberg , L. O' , Kay Schultz , Alan B.

Sandler , Coffin , McCoy , Astrid Schott , Scholz , S.

Gail Eckhardt

1 1University of Colorado Cancer Center, Aurora, Colorado; 2Vanderbilt-Ingram

Cancer Center, Nashville, Tennessee; 3Bayer Healthcare, Seattle, Washington; and

4Bayer Schering Pharma AG, Berlin, Germany

* To whom correspondence should be addressed. E-mail: lia.gore@... .

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.