A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias: a California Cancer Consortium study

Mark H. Kirschbaum, Paul Frankel, Timothy W. Synold, Zhiliang Xie, Yun Yen, Leslie Popplewell, Robert Chen, Omar Aljitawi, Joseph M. Tuscano, Kenneth K. Chan, Edward M. Newman

Research output: Contribution to journalArticle

Abstract

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1–4 and 15–18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.

Original languageEnglish
Pages (from-to)2307-2314
Number of pages8
JournalLeukemia and Lymphoma
Volume57
Issue number10
DOIs
Publication statusPublished - Oct 2 2016
Externally publishedYes

Fingerprint

Antisense Oligonucleotides
Appointments and Schedules
Oxidoreductases
Leukemia
Ribonucleotide Reductases
Troponin I
Neoplasms
Pharmacokinetics
Gene Expression
Messenger RNA
Liver
Enzymes
Pharmaceutical Preparations
GTI2040

Keywords

  • Acute leukemia
  • GTI-2040
  • intermittent infusion
  • pharmacodynamics
  • pharmacokinetics
  • phase I trial
  • ribonucleotide reductase

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias : a California Cancer Consortium study. / Kirschbaum, Mark H.; Frankel, Paul; Synold, Timothy W.; Xie, Zhiliang; Yen, Yun; Popplewell, Leslie; Chen, Robert; Aljitawi, Omar; Tuscano, Joseph M.; Chan, Kenneth K.; Newman, Edward M.

In: Leukemia and Lymphoma, Vol. 57, No. 10, 02.10.2016, p. 2307-2314.

Research output: Contribution to journalArticle

Kirschbaum, MH, Frankel, P, Synold, TW, Xie, Z, Yen, Y, Popplewell, L, Chen, R, Aljitawi, O, Tuscano, JM, Chan, KK & Newman, EM 2016, 'A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias: a California Cancer Consortium study', Leukemia and Lymphoma, vol. 57, no. 10, pp. 2307-2314. https://doi.org/10.3109/10428194.2016.1146947
Kirschbaum, Mark H. ; Frankel, Paul ; Synold, Timothy W. ; Xie, Zhiliang ; Yen, Yun ; Popplewell, Leslie ; Chen, Robert ; Aljitawi, Omar ; Tuscano, Joseph M. ; Chan, Kenneth K. ; Newman, Edward M. / A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias : a California Cancer Consortium study. In: Leukemia and Lymphoma. 2016 ; Vol. 57, No. 10. pp. 2307-2314.
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