Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia.
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.
Garcia-Manero
Guillermo
G
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ggarciam@mdanderson.org
Assouline
Sarit
S
Cortes
Jorge
J
Estrov
Zeev
Z
Kantarjian
Hagop
H
Yang
Hui
H
Newsome
Willie M
WM
Miller
Wilson H
WH
Rousseau
Caroline
C
Kalita
Ann
A
Bonfils
Claire
C
Dubay
Marja
M
Patterson
Tracy-Ann
TA
Li
Zuomei
Z
Besterman
Jeffrey M
JM
Reid
Gregory
G
Laille
Eric
E
Martell
Robert E
RE
Minden
Mark
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011743:Pyrimidines; C523184:mocetinostat; D006655:Histone Deacetylases