title: 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.affiliation: University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA. igojo@umm.edu
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.forename: Anchalee
authors.initials: A
authors.lastname: Jiemjit
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Sandra
authors.initials: S
authors.lastname: Rollins
authors.forename: Michael L
authors.initials: ML
authors.lastname: Tidwell
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Greer
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Chung
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009363:Neoplasm Proteins; D011725:Pyridines; C118739:entinostat