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

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.

• Authors: 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
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 57 Issue 10 Pg. 2307-14 (10 2016) ISSN: 1029-2403 [Electronic] United States
• PMID: 26895565 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Oligodeoxyribonucleotides
• GTI2040
• Ribonucleotide Reductases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Drug Monitoring
• Female
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy)
• Male
• Middle Aged
• Oligodeoxyribonucleotides (pharmacology, therapeutic use)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy)
• Ribonucleotide Reductases (antagonists & inhibitors)
• Treatment Outcome