A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS)

• Published in: Journal of clinical oncology Vol. 31; no. 15_suppl; p. 7116
• Main Authors: Luger, Selina M., O'Connell, Casey Lee, Klimek, Virginia, Cooper, Maureen A., Besa, Emmanuel C., Rossetti, James M., Reid, Gregory K., Humphrey, Rachel, Martell, Robert E., Garcia-Manero, Guillermo
• Format: Journal Article
• Language: English
• Published: 20.05.2013
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.31.15_suppl.7116

Abstract only 7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m 2 SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.