Mocetinostat (MGCD0103) is an orally available, spectrum-selective, non-hydroxamate histone deacetylase (HDAC) inhibitor targeting HDACs 1, 2, 3 and 11. Single-agent activity has been observed in Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. Preclinical studies demonstrating potential synergy between hypomethylating agents and HDAC inhibitors in relieving transcriptional repression support the evaluation of mocetinostat in combination with 5-azacitidine (AZA) in MDS and AML.


The objectives of this open-label, Phase I/II trial of patients with MDS or AML were to determine the MTD of mocetinostat when combined with AZA (75 mg/m2 SC; days 1-7 every 28 days) and to estimate the overall response rate of this combination. In addition, we conducted an ad hoc, independent response assessment for all patients in this study (ASCO 2013) and performed a retrospective, subset analysis on those patients entering this study with 5-20% bone marrow blasts at screening to represent a population with RAEB-1 and RAEB-2.


A total of 66 subjects with AML and intermediate and high-risk MDS were enrolled in this phase I/II trial. In the Phase I component, 24 patients were treated at 5 dose levels of mocetinostat that ranged from 35 to 135 mg administered 3x/wk starting on Day 5 of treatment with AZA, and in the Phase II component, 42 patients were treated at 90 mg or 110 mg of mocetinostat 3x/wk with AZA. We were interested in analyzing the responses of MDS patients enrolled in this study to gauge the potential for improved activity compared to AZA monotherapy. Therefore, the subset of interest for the current analysis included 22 with baseline bone marrow blast counts of 5-20%, including 8 with 5-9% and 14 with 10-20% bone marrow blasts. The median age was 73 (range 41-82) with 13M and 9F. Thirteen pts received no prior treatment with chemotherapy or other agents for MDS, and 9 were previously treated. Cytogenetic analyses were available for 7 patients: diploid, 2; monosomy 7, 3 (all with other anomalies); complex, 1; and trisomy 8, 1. Chromosome 5 abnormalities occurred in the presence of other abnormalities (2 with monosomy 7). Eighteen patients initiated dosing at 90 mg, 3 at 110 mg, and 1 at 135 mg. The most common ≥ Grade 3 drug-related adverse events were diarrhea (23%), fatigue (18%), thrombocytopenia (18%), and anemia (14%). The CR+CRi rate was 13/22 (59%), with 1 additional patient demonstrating hematologic improvement. The CR+CRi rate appeared similar regardless of line of therapy and the percentage of blasts at baseline (5-9% vs. 10-20%). Most patients (68%) demonstrated decreases in bone marrow blast counts on at least one post-treatment assessment. Of 17 patients who were either RBC or platelet transfusion dependent at baseline, 6 patients (35%) became transfusion-free of both red cells and platelets.


The combination of mocetinostat and AZA is active in patients with MDS, including some patients who were previously treated and is associated with a 59% rate of CR+CRi in a subset of patients with 5-20% bone marrow blasts at screening, and with 35% of transfusion-dependent patients becoming transfusion independent. A randomized study is planned to further evaluate the clinical activity of mocetinostat plus AZA in MDS.


Chao:Mirati Therapeutics: Employment. Humphrey:Mirati Therapeutics Inc.: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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