Phase 1 and Pharmacologic Study of MS-275, a Histone Deacetylase Inhibitor, in Adults with Refractory and Relapsed Acute Leukemias

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2006 Dec 21

PMID 17179232

Citations 128

Authors

Ivana Gojo

Anchalee Jiemjit

Jane B Trepel

Alex Sparreboom

William D Figg

Sandra Rollins

Michael L Tidwell

Jacqueline Greer

Eun Joo Chung

Min-Jung Lee

Steven D Gore

Edward A Sausville

James Zwiebel

Judith E Karp

Affiliations

Soon will be listed here.

Abstract

MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly x 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease.

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