title: Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia.
abstract: MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts <or= 5%). Pharmacokinetic analyses indicated absorption of MGCD0103 within 1 hour and an elimination half-life in plasma of 9 (+/- 2) hours. Exposure to MGCD0103 was proportional to dose up to 60 mg/m(2). Analysis of peripheral white cells demonstrated induction of histone acetylation and dose-dependent inhibition of HDAC enzyme activity. In summary, MGCD0103 was safe and had antileukemia activity that was mechanism based in patients with advanced leukemia.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ggarciam@mdanderson.org
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Sarit
authors.initials: S
authors.lastname: Assouline
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Willie M
authors.initials: WM
authors.lastname: Newsome
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.forename: Caroline
authors.initials: C
authors.lastname: Rousseau
authors.forename: Ann
authors.initials: A
authors.lastname: Kalita
authors.forename: Claire
authors.initials: C
authors.lastname: Bonfils
authors.forename: Marja
authors.initials: M
authors.lastname: Dubay
authors.forename: Tracy-Ann
authors.initials: TA
authors.lastname: Patterson
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Gregory
authors.initials: G
authors.lastname: Reid
authors.forename: Eric
authors.initials: E
authors.lastname: Laille
authors.forename: Robert E
authors.initials: RE
authors.lastname: Martell
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011743:Pyrimidines; C523184:mocetinostat; D006655:Histone Deacetylases