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

D. J. Stewart, Ross C Donehower, E. A. Eisenhauer, N. Wainman, A. K. Shah, C. Bonfils, A. R. MacLeod, J. M. Besterman, G. K. Reid

Research output: Contribution to journalArticle

Abstract

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/m2 . Dose limiting toxicity was seen in two of three patients at 480 mg/m2 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 Cmax 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/m2. Conclusions: The recommended dose of MG98 was 360 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)766-774
Number of pages9
JournalAnnals of Oncology
Volume14
Issue number5
DOIs
StatePublished - May 1 2003

Fingerprint

Methyltransferases
Pharmacokinetics
DNA
Messenger RNA
Fatigue
Blood Cells
Chills
Partial Thromboplastin Time
Poisons
Anorexia
Transaminases
Tumor Suppressor Genes
Renal Cell Carcinoma
Nausea
Area Under Curve
Vomiting
Diarrhea
Appointments and Schedules
Fever
Enzymes

Keywords

  • Anti-sense oligodeoxynucleotide
  • DNA methyltransferase I
  • MG98
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. / Stewart, D. J.; Donehower, Ross C; Eisenhauer, E. A.; Wainman, N.; Shah, A. K.; Bonfils, C.; MacLeod, A. R.; Besterman, J. M.; Reid, G. K.

In: Annals of Oncology, Vol. 14, No. 5, 01.05.2003, p. 766-774.

Research output: Contribution to journalArticle

Stewart, DJ, Donehower, RC, Eisenhauer, EA, Wainman, N, Shah, AK, Bonfils, C, MacLeod, AR, Besterman, JM & Reid, GK 2003, 'A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly', Annals of Oncology, vol. 14, no. 5, pp. 766-774. https://doi.org/10.1093/annonc/mdg216
Stewart, D. J. ; Donehower, Ross C ; Eisenhauer, E. A. ; Wainman, N. ; Shah, A. K. ; Bonfils, C. ; MacLeod, A. R. ; Besterman, J. M. ; Reid, G. K. / A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. In: Annals of Oncology. 2003 ; Vol. 14, No. 5. pp. 766-774.
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AU - Donehower, Ross C

AU - Eisenhauer, E. A.

AU - Wainman, N.

AU - Shah, A. K.

AU - Bonfils, C.

AU - MacLeod, A. R.

AU - Besterman, J. M.

AU - Reid, G. K.

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N2 - 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/m2 . Dose limiting toxicity was seen in two of three patients at 480 mg/m2 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 Cmax 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/m2. Conclusions: The recommended dose of MG98 was 360 mg/m2 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.

AB - 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/m2 . Dose limiting toxicity was seen in two of three patients at 480 mg/m2 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 Cmax 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/m2. Conclusions: The recommended dose of MG98 was 360 mg/m2 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.

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