Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia

Guillermo Garcia-Manero, Sarit Assouline, Jorge Cortes, Zeev Estrov, Hagop Kantarjian, Hui Yang, Willie M. Newsome, Wilson H. Miller, 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

Research output: Contribution to journalArticlepeer-review

222 Scopus citations


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/m2). 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 ≤ 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.

Original languageEnglish (US)
Pages (from-to)981-989
Number of pages9
Issue number4
StatePublished - Aug 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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