Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: A National Cancer Institute of Canada Clinical Trials Group investigational new drug study

Abstract

DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.

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

“…The number of courses and cumulative dose received are summarized in Table 2. The adverse event profile reported across the dose levels in this trial was similar to that reported in other clinical trials with MG98 (20,23,24). Compiled grade 3 and 4 adverse events, including those commonly observed in patients with MDS and AML and therefore non -dose limiting, are detailed in Table 3.…”

“…Similar to other studies with MG98, the most common toxicities were fatigue and fever, and asthenia that led to patient withdrawal from the study (20,23,24), which prevented us from further escalating MG98 that may have produced greater target down-regulation. This toxicity profile is similar to that observed with other phosphothiorate compounds, where improvements in tolerability were described once different administration schedules were adopted (20 -24).…”

DNA Demethylating Antineoplastic Strategies: A Comparative Point of View

“…100,101 The best-tolerated protocol was chosen for phase II studies but, unfortunately, did not show any antitumoral activity in patients with metastatic renal carcinoma. 102 In a recent phase I trial, MG98 has been also tested for the treatment of patients with high-risk MDS and AML. Even in this case, this approach failed to result in appreciable effects, and the dose escalation was stopped due to severe toxicity.…”

Reprogramming epigenetic silencing: artificial transcription factors synergize with chromatin remodeling drugs to reactivate the tumor suppressor mammary serine protease inhibitor

“…To date, the most widely used chromatin remodeling drug is the DNA methyltransferase inhibitor 5-aza-2 ¶-deoxycytidine (5-aza-2 ¶-dC), recently approved for therapeutic treatment (15). Several methyltransferase inhibitors [such as 5-aza-dC and MG98 (16,17)] and HDAC inhibitors [such as suberoylanilide hydroxamic acid (SAHA; ref. 18), valproic acid (19), and pivaloyloxymethyl butyrate (20,21)] are presently in phase I and II clinical trials.…”