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

Francis 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

*Corresponding author for this work

Research output: Contribution to journalArticle

85 Scopus citations

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 96h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120mg/m2 per day, and the maximum tolerated dose (MTD) was 160mg/m2 per day. Three of eight patients receiving 160mg/m2 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 96h infusion was administered at a fixed dose of 140mg/m2 per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160mg/m2 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 1μM. 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.

Original languageEnglish (US)
Pages (from-to)1077-1083
Number of pages7
JournalLeukemia Research
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2003

Keywords

  • Phase I
  • Refractory myeloid leukemia
  • Ribonucleotide reductase
  • Triapine®

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Giles, F. J., Fracasso, P. M., Kantarjian, H. M., Cortes, J. E., Brown, R. A., Verstovsek, S., Alvarado, Y., Thomas, D. A., Faderl, S., Garcia-Manero, G., Wright, L. P., Samson, T., Cahill, A., Lambert, P., Plunkett, W., Sznol, M., DiPersio, J. F., & Gandhi, V. (2003). Phase I and pharmacodynamic study of Triapine®, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. Leukemia Research, 27(12), 1077-1083. https://doi.org/10.1016/S0145-2126(03)00118-8