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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.
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CLINICAL TRIALS AND OBSERVATIONS
Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia
Guillermo Garcia-Manero1,
Sarit Assouline2,
Jorge Cortes1,
Zeev Estrov1,
Hagop Kantarjian1,
Hui Yang1,
Willie M. Newsome1,
Wilson H. Miller, Jr2,
Caroline Rousseau2,
Ann Kalita3,
Claire Bonfils3,
Marja Dubay3,
Tracy-Ann Patterson3,
Zuomei Li3,
Jeffrey M. Besterman3,
Gregory Reid3,
Eric Laille4,
Robert E. Martell3, and
Mark Minden5
1 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston;
2 Jewish General Hospital, Montréal, QC;
3 MethylGene, Montréal, QC;
4 Pharmion, Boulder, CO; and
5 Princess Margaret Hospital, Toronto, ON
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/m2, 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/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 antileukemia activity that was mechanism based in patients with advanced leukemia.
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