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A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia

Authors' Affiliations: ¹ Division of Hematology and Oncology, Department of Medicine, and ² Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ³ Section of Hematology/Oncology, Department of Medicine, University of Chicago and University of Chicago Cancer Research Center, Chicago, Illinois; ⁴ MGI Pharma, Inc., Bloomington, Minnesota; and ⁵ Methylgene, Inc., Montreal, Quebec, Canada

Requests for reprints: Guido Marcucci, Division of Hematology and Oncology, Department of Medicine, The Ohio State University, A437A Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-5738; Fax: 614-293-7525; E-mail: guido.marcucci{at}osumc.edu.

Purpose: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML.

Experimental Design: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which 50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days).

Results: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients.

Conclusions: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.