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Blood, 15 August 2008, Vol. 112, No. 4, pp. 981-989.
Prepublished online as a Blood First Edition Paper on May 21, 2008; DOI 10.1182/blood-2007-10-115873.
 Previous Article | Next Article 
Submitted October 3, 2007
Accepted March 22, 2008
Phase I 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 Mae Newsome, Wilson H. Miller Jr, Caroline Rousseau, Ann Kalita, Jianghong Liu, Marja Dubay, Tracy-Ann Patterson, Zuomei Li, Jeffrey M. Besterman, Gregory Reid, Eric Laille, Robert E. Martell, and Mark D. Minden
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Jewish General Hospital, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
MethylGene, Inc., Montreal, Quebec, Canada
Pharmion Corporation, Boulder, CO, United States
Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
* Corresponding author; email: ggarciam{at}mdanderson.org.
MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3 and 11. In a Phase I 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 of 29 patients (83%) had received  1 prior chemotherapy (range 0-5), and 18 of 29 patients (62%) had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m2, with 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 h and an elimination half-life in plasma of 9 ±2 h. Exposure to MGCD0103 was proportional to dose up to 60 mg/m2. 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 anti-leukemia activity which was mechanism-based in patients with advanced leukemia.
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