Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias.

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.

• 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
• Journal: Blood (Blood) Vol. 109 Issue 7 Pg. 2781-90 (Apr 01 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17179232 (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
• Histones
• Neoplasm Proteins
• Pyridines
• entinostat

Topics

• Acetylation
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Benzamides (administration & dosage, pharmacokinetics, therapeutic use)
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Female
• Histone Deacetylase Inhibitors
• Histones (metabolism)
• Humans
• Leukemia (drug therapy, metabolism)
• Male
• Middle Aged
• Neoplasm Proteins (metabolism)
• Pyridines (administration & dosage, pharmacokinetics, therapeutic use)