Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies.
Triapine, a potent inhibitor of ribonucleotide reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1-5 and 15-19 or 1-5 and 8-12 of a 4-week cycle. When administered twice a day on days 1-5 and 8-12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2-5.5 microM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.
Gojo
Ivana
I
University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA. igojo@umm.edu
Tidwell
Michael L
ML
Greer
Jacqueline
J
Takebe
Naoko
N
Seiter
Karen
K
Pochron
Mary F
MF
Johnson
Bonny
B
Sznol
Mario
M
Karp
Judith E
JE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D012264:Ribonucleotide Reductases