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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2781-2790.
Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-05-021873.
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CLINICAL TRIALS AND OBSERVATIONS
Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
Ivana Gojo1,
Anchalee Jiemjit2,
Jane B. Trepel3,
Alex Sparreboom3,
William D. Figg3,
Sandra Rollins1,
Michael L. Tidwell1,
Jacqueline Greer2,
Eun Joo Chung3,
Min-Jung Lee3,
Steven D. Gore2,
Edward A. Sausville1,
James Zwiebel3, and
Judith E. Karp2
1 University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD;
2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD;
3 National Cancer Institute, Bethesda, MD
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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