Abstract |
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.
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Authors | Guillermo Garcia-Manero, Sarit Assouline, Jorge Cortes, Zeev Estrov, Hagop Kantarjian, Hui Yang, Willie M Newsome, Wilson H Miller Jr, 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 |
Journal | Blood
(Blood)
Vol. 112
Issue 4
Pg. 981-9
(Aug 15 2008)
ISSN: 1528-0020 [Electronic] United States |
PMID | 18495956
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzamides
- Histone Deacetylase Inhibitors
- Histones
- Pyrimidines
- mocetinostat
- Histone Deacetylases
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Topics |
- Administration, Oral
- Adult
- Aged
- Aged, 80 and over
- Benzamides
(administration & dosage, pharmacokinetics, toxicity)
- Cells, Cultured
- Dose-Response Relationship, Drug
- Female
- Histone Deacetylase Inhibitors
- Histone Deacetylases
(metabolism)
- Histones
(metabolism)
- Humans
- Leukemia
(complications, drug therapy)
- Leukemia, Myeloid, Acute
(complications, drug therapy)
- Male
- Maximum Tolerated Dose
- Middle Aged
- Pharmacokinetics
- Pyrimidines
(administration & dosage, pharmacokinetics, toxicity)
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