TY - JOUR
T1 - Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia
AU - Garcia-Manero, Guillermo
AU - Assouline, Sarit
AU - Cortes, Jorge
AU - Estrov, Zeev
AU - Kantarjian, Hagop
AU - Yang, Hui
AU - Newsome, Willie M.
AU - Miller, Wilson H.
AU - Rousseau, Caroline
AU - Kalita, Ann
AU - Bonfils, Claire
AU - Dubay, Marja
AU - Patterson, Tracy Ann
AU - Li, Zuomei
AU - Besterman, Jeffrey M.
AU - Reid, Gregory
AU - Laille, Eric
AU - Martell, Robert E.
AU - Minden, Mark
PY - 2008/8/15
Y1 - 2008/8/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2007-10-115873
DO - 10.1182/blood-2007-10-115873
M3 - Article
C2 - 18495956
AN - SCOPUS:51649110503
SN - 0006-4971
VL - 112
SP - 981
EP - 989
JO - Blood
JF - Blood
IS - 4
ER -