Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML).

Abstract Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-azacitidine with or without MGCD0103 in AML and MDS.

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