Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks.
OBJECTIVE
MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks.


METHODS
Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45.


RESULTS
Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed.


CONCLUSIONS
This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.
Davis
Alison J
AJ
National Cancer Institute, Canada.
Gelmon
Karen A
KA
Siu
Lillian L
LL
Moore
Malcolm J
MJ
Britten
Carolyn D
CD
Mistry
Nisha
N
Klamut
Henry
H
D'Aloisio
Susan
S
MacLean
Martha
M
Wainman
Nancy
N
Ayers
Debbie
D
Firby
Patricia
P
Besterman
Jeffrey M
JM
Reid
Gregory K
GK
Eisenhauer
Elizabeth A
EA
D000328:Adult; D000368:Aged; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis; D006801:Humans; D007262:Infusions, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011506:Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000097:blood; D013873:Thionucleotides; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D014746:Vimentin / Q000097:blood / Q000235:genetics; D000097642:GADD45 Proteins
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D005319:Fetal Hemoglobin; D047908:Intracellular Signaling Peptides and Proteins; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D013873:Thionucleotides; D014746:Vimentin; D000097642:GADD45 Proteins; C483603:MG 98 phosphorothioate antisense oligodeoxynucleotide; C000619380:DNMT1 protein, human