Phase I and Pharmacodynamic Study of Triapine, a Novel Ribonucleotide Reductase Inhibitor, in Patients With Advanced Leukemia

Leuk Res. 2003 Dec;27(12):1077-83. doi: 10.1016/s0145-2126(03)00118-8.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA / biosynthesis
  • DNA, Neoplasm / metabolism
  • Deoxyadenine Nucleotides / metabolism
  • Deoxyguanine Nucleotides / metabolism
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Infusions, Intravenous
  • Leukemia, Lymphoid / blood
  • Leukemia, Lymphoid / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukocyte Count
  • Male
  • Middle Aged
  • Pyridines / pharmacology
  • Pyridines / supply & distribution*
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Safety
  • Thiosemicarbazones / pharmacology
  • Thiosemicarbazones / supply & distribution*

Substances

  • DNA, Neoplasm
  • Deoxyadenine Nucleotides
  • Deoxyguanine Nucleotides
  • Enzyme Inhibitors
  • Pyridines
  • Thiosemicarbazones
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • deoxyguanosine triphosphate
  • DNA
  • Ribonucleotide Reductases
  • 2'-deoxyadenosine triphosphate