A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly

Background: Hypermethylation and inactivation of tumor suppressor genes by the enzyme DNA methyltransferase may lead to neoplastic transformation. MG98, a phosphorothioate antisense oligodeoxynucleotide that is a specific inhibitor of mRNA for human DNA methyltransferase 1 (DNMT1), was evaluated in a phase I study. Patients and methods: MG98 was given as a 2 h i.v. infusion twice weekly three weeks out of every four to patients with solid tumors. Pharmacokinetic evaluation was performed on days 1 and 15 of cycle 1 and mRNA expression of DNMT1 was measured in peripheral blood mononuclear cells (PBMCs). Results: Nineteen patients were entered onto the study. A total of 74 cycles (range 1-18 cycles) were administered at dose levels from 40 to 480 mg/m(2). Dose limiting toxicity was seen in two of three patients at 480 mg/m(2) and consisted of a constellation of fever, chills, fatigue and, in one case, confusion beginning within 6 h after the first infusion. Other toxic effects included fatigue, anorexia, nausea, vomiting and diarrhea, reversible elevations in transaminases and partial thromboplastin time. Pharmacokinetic evaluation showed C-max and AUC to be dose proportional with low inter- and intra-patient variability. No consistent changes in DNMT1 mRNA expression were noted in PBMCs. One partial response was documented in a patient with renal cell carcinoma treated at 80 mg/m(2). Conclusions: The recommended dose of MG98 was 360 mg/m(2) given by 2 h infusion twice a week for three weeks out of every four. Phase II trials using this dose and schedule are underway.