title: 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.
authors.affiliation: London Health Sciences Centre, 790 Commissioners Road East, London, Ontario, Canada, N6A 4L6. eric.winquist@lhsc.on.ca
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
authors.forename: Jennifer
authors.initials: J
authors.lastname: Knox
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Ayoub
authors.forename: Lori
authors.initials: L
authors.lastname: Wood
authors.forename: Nancy
authors.initials: N
authors.lastname: Wainman
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Reid
authors.forename: Laura
authors.initials: L
authors.lastname: Pearce
authors.forename: Ajit
authors.initials: A
authors.lastname: Shah
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D002170:Canada; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000097:blood; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013873:Thionucleotides / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C411744:DMAP1 protein, human; C483603:MG 98 phosphorothioate antisense oligodeoxynucleotide; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012097:Repressor Proteins; D013873:Thionucleotides