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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.
AuthorsGuillermo Garcia-Manero, Sarit Assouline, Jorge Cortes, Zeev Estrov, Hagop Kantarjian, Hui Yang, Willie M Newsome, Wilson H Miller Jr, Caroline Rousseau, Ann Kalita, Claire Bonfils, Marja Dubay, Tracy-Ann Patterson, Zuomei Li, Jeffrey M Besterman, Gregory Reid, Eric Laille, Robert E Martell, Mark Minden
JournalBlood (Blood) Vol. 112 Issue 4 Pg. 981-9 (Aug 15 2008) ISSN: 1528-0020 [Electronic] United States
PMID18495956 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Histones
  • Pyrimidines
  • mocetinostat
  • Histone Deacetylases
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Benzamides (administration & dosage, pharmacokinetics, toxicity)
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases (metabolism)
  • Histones (metabolism)
  • Humans
  • Leukemia (complications, drug therapy)
  • Leukemia, Myeloid, Acute (complications, drug therapy)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Pharmacokinetics
  • Pyrimidines (administration & dosage, pharmacokinetics, toxicity)

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