Phase I study of GTI-2040, an antisense to ribonucleotide reductase, in combination with high-dose cytarabine in patients with acute myeloid leukemia.

Abstract

PURPOSE:

Inhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine (AraC) cytotoxicity. We performed a phase I dose escalation trial of AraC combined with GTI-2040, a 20-mer antisense oligonucleotide shown in preclinical studies to decrease levels of the R2 subunit of ribonucleotide reductase, to determine the maximum tolerated dose in adults with relapsed/refractory acute myeloid leukemia.

EXPERIMENTAL DESIGN:

Twenty-three adults (ages 18-59 years) were enrolled in this dose escalation phase I trial, receiving high-dose AraC twice daily combined with infusional GTI-2040. An ELISA-based assay measured plasma and intracellular concentrations of GTI-2040. R2 protein changes were evaluated by immunoblotting in pretreatment and post-treatment bone marrow samples.

RESULTS:

The maximum tolerated dose was 5 mg/kg/d GTI-2040 (days 1-6) and 3 g/m2/dose AraC every 12 hours for 8 doses. Neurotoxicity was dose limiting. Eight patients (35%) achieved complete remission. Mean bone marrow intracellular concentration of GTI-2040 were higher at 120 hours than at 24 hours from the start of GTI-2040 (P = 0.002), suggesting intracellular drug accumulation over time. Reductions in bone marrow levels of R2 protein (>50%) were observed at 24 and 120 hours. Higher baseline R2 protein expression (P = 0.03) and reductions after 24 hours of GTI-2040 (P = 0.04) were associated with complete remission.

CONCLUSIONS:

GTI-2040 and high-dose AraC were coadministered safely with successful reduction of the intended R2 target and encouraging clinical results. The clinical efficacy of this combination will be tested in an upcoming phase II study.

• Authors: Rebecca B Klisovic, William Blum, Xiaohui Wei, Shujun Liu, Zhongfa Liu, Zhiliang Xie, Tamara Vukosavljevic, Cheryl Kefauver, Lenguyen Huynh, Jiuxia Pang, James A Zwiebel, Steven Devine, John C Byrd, Michael R Grever, Kenneth Chan, Guido Marcucci
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 12 Pg. 3889-95 (Jun 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18559610 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Oligodeoxyribonucleotides
• Oligonucleotides, Antisense
• Cytarabine
• GTI2040
• Ribonucleotide Reductases

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Cytarabine (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Oligodeoxyribonucleotides (administration & dosage, adverse effects, pharmacokinetics)
• Oligonucleotides, Antisense (administration & dosage, adverse effects)
• Ribonucleotide Reductases (antagonists & inhibitors)
• Treatment Outcome