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Annals of Oncology Advance Access published online on April 11, 2005
Annals of Oncology, doi:10.1093/annonc/mdi178
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© 2005 European Society for Medical Oncology
Received July 16, 2004
Revised January 4, 2005
Accepted January 10, 2005

Original article

A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors

A. A. Desai 1, R. L. Schilsky 2*, A. Young 3, L. Janisch 4, W. M. Stadler 5, N. J. Vogelzang 5, S. Cadden 3, J. A. Wright 3, and M. J. Ratain 6

1 Section of Hematology and Oncology, University of Chicago, Chicago, USA; 2Committee on Clinical Pharmacology and Pharmacogenomics, Chicago, USA;
2 Section of Hematology and Oncology, University of Chicago, Chicago, USA; 3University of Chicago Cancer Research Center, Chicago, USA and
3 Lorus Therapeutics, Toronto, Canada
4 Section of Hematology and Oncology, University of Chicago, Chicago, USA;
5 Section of Hematology and Oncology, University of Chicago, Chicago, USA; 3University of Chicago Cancer Research Center, Chicago, USA and
6 Section of Hematology and Oncology, University of Chicago, Chicago, USA; 2Committee on Clinical Pharmacology and Pharmacogenomics, Chicago, USA; 3University of Chicago Cancer Research Center, Chicago, USA and

* To whom correspondence should be addressed.
R. L. Schilsky, E-mail: rschilsk{at}medicine.bsd.uchicago.edu


  Abstract

Background: This study of GTI-2040, a 20-mer phosphorothioate oligonucleotide complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase (RNR), was conducted to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the agent in patients with advanced solid tumors or lymphoma. Plasma pharmacokinetics of GTI-2040 and suppression of RNR expression in peripheral blood mononuclear cells were also studied.

Patients and methods: GTI-2040 was administered as a continuous intravenous infusion for 21 days every 4 weeks. Dose escalation was performed using an accelerated, dose-doubling schedule until any drug related toxicity≥grade 2 was observed; subsequent dose escalation followed a more conservative dose escalation scheme with three patients/cohort.

Results: A total of 49 cycles of therapy were administered to 36 patients at GTI-2040 doses ranging from 18.5 mg/m2/day to 222 mg/m2/day. GTI-2040 was generally well tolerated. At the highest dose level examined, two patients experienced dose limiting reversible hepatic toxicity. Constitutional toxicities consisting of fatigue and anorexia were the most common toxicities.

Conclusions: The recommended dose of GTI-2040 given on this infusion schedule is 185 mg/m2/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.

Keywords: antisense therapies; GTI-2040; pharmacokinetics; phase I trial; phosphorothioate oligonucleotides; ribonucleotide reductase inhibition.
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