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Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors

Lookup NU author(s): Professor Ruth Plummer, Melanie Griffin, Dr Sally Coulthard, Julieann Sludden, Professor Alan Calvert, Professor Alan Boddy

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Abstract

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro. Experimental Design: In this phase 1, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33% of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized. Results: Thirty-three patients were treated at doses of 100 to 250 mg/m(2)/d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m(2)/d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied. Conclusions: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase 11 development.


Publication metadata

Author(s): Plummer ER, Vidal L, Griffin MJ, Lesley M, de Bono J, Coulthard SA, Sludden J, Siu LL, Chen EX, Oza AM, Reid GK, McLeod AR, Besterman JM, Lee C, Judson I, Calvert AH, Boddy AV

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2009

Volume: 15

Issue: 9

Pages: 3177-3183

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association of Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-08-2859

DOI: 10.1158/1078-0432.CCR-08-2859


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