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Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia.

Abstract
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.
AuthorsFrancis J Giles, Paula M Fracasso, Hagop M Kantarjian, Jorge E Cortes, Randy A Brown, Srdan Verstovsek, Yesid Alvarado, Deborah A Thomas, Stefan Faderl, Guillermo Garcia-Manero, Lisa P Wright, Tom Samson, Ann Cahill, Paula Lambert, William Plunkett, Mario Sznol, John F DiPersio, Varsha Gandhi
JournalLeukemia research (Leuk Res) Vol. 27 Issue 12 Pg. 1077-83 (Dec 2003) ISSN: 0145-2126 [Print] England
PMID12921943 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA, Neoplasm
  • Deoxyadenine Nucleotides
  • Deoxyguanine Nucleotides
  • Enzyme Inhibitors
  • Pyridines
  • Thiosemicarbazones
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • 2'-deoxyadenosine triphosphate
  • deoxyguanosine triphosphate
  • DNA
  • Ribonucleotide Reductases
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • DNA (biosynthesis)
  • DNA, Neoplasm (metabolism)
  • Deoxyadenine Nucleotides (metabolism)
  • Deoxyguanine Nucleotides (metabolism)
  • Enzyme Inhibitors (administration & dosage, pharmacology)
  • Female
  • Humans
  • Infusions, Intravenous
  • Leukemia, Lymphoid (blood, drug therapy)
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (blood, drug therapy)
  • Leukocyte Count
  • Male
  • Middle Aged
  • Pyridines (pharmacology, supply & distribution)
  • Ribonucleotide Reductases (antagonists & inhibitors)
  • Safety
  • Thiosemicarbazones (pharmacology, supply & distribution)

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