Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia.
In a phase I study, 24 patients with refractory leukemia received Triapine, a novel ribonucleotide reductase (RR) inhibitor, as a continuous intravenous infusion over 96 h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120 mg/m(2) per day, and the maximum tolerated dose (MTD) was 160 mg/m(2) per day. Three of eight patients receiving 160 mg/m(2) per day in the first course, and one patient escalated to this dose in a second course, developed hepatic dose-limiting toxicity (DLT). For the days 1 and 8 regimen, the first 96 h infusion was administered at a fixed dose of 140 mg/m(2) per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160 mg/m(2) per day without observing DLT. No objective responses occurred. Over 70% of patients had a >50% reduction in white blood cell counts. The steady-state levels of Triapine were between 0.6 and 1 microM. As expected from the in vitro studies, at these plasma concentrations there was a decline in dATP and dGTP pools and a decrease in DNA synthetic capacity of the circulating leukemia cells. Based on these clinical, pharmacokinetic, and pharmacodynamic data, Triapine warrants further study in patients with hematologic malignancies.
Giles
Francis J
FJ
Department of Leukemia, M.D. Anderson Cancer Center, University of Texas, Box 428, Houston, TX 77030, USA. frankgiles@aol.com
Fracasso
Paula M
PM
Kantarjian
Hagop M
HM
Cortes
Jorge E
JE
Brown
Randy A
RA
Verstovsek
Srdan
S
Alvarado
Yesid
Y
Thomas
Deborah A
DA
Faderl
Stefan
S
Garcia-Manero
Guillermo
G
Wright
Lisa P
LP
Samson
Tom
T
Cahill
Ann
A
Lambert
Paula
P
Plunkett
William
W
Sznol
Mario
M
DiPersio
John F
JF
Gandhi
Varsha
V
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007945:Leukemia, Lymphoid / Q000097:blood / Q000188:drug therapy*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology / Q000600:supply & distribution*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D012449:Safety; D013882:Thiosemicarbazones / Q000494:pharmacology / Q000600:supply & distribution*
D004273:DNA, Neoplasm; D003838:Deoxyadenine Nucleotides; D003848:Deoxyguanine Nucleotides; D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C029603:deoxyguanosine triphosphate; D004247:DNA; D012264:Ribonucleotide Reductases; C026600:2'-deoxyadenosine triphosphate