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

Ivana Gojo, Anchalee Jiemjit, Jane B. Trepel, Alex Sparreboom, William D. Figg, Sandra Rollins, Michael L. Tidwell, Jacqueline Greer, Joo Chung Eun, Min Jung Lee, Steven D. Gore, Edward A. Sausville, James Zwiebel, Judith E. Karp

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2781-2790
Number of pages10
JournalBlood
Volume109
Issue number7
DOIs
StatePublished - Apr 1 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Gojo, I., Jiemjit, A., Trepel, J. B., Sparreboom, A., Figg, W. D., Rollins, S., Tidwell, M. L., Greer, J., Eun, J. C., Lee, M. J., Gore, S. D., Sausville, E. A., Zwiebel, J., & Karp, J. E. (2007). Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood, 109(7), 2781-2790. https://doi.org/10.1182/blood-2006-05-021873