IngentaConnect A phase I study of antisense oligonucleotide GTI-2040 given by co...

Authors: Desai, A. A.¹; Schilsky, R. L.¹; Young, A.²; Janisch, L.¹; Stadler, W. M.¹; Vogelzang, N. J.¹; Cadden, S.²; Wright, J. A.²; Ratain, M. J.¹

Source: Annals of Oncology, Volume 16, Number 6, June 2005 , pp. 958-965(8)

Publisher: Oxford University Press

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

Document Type: Research article

DOI: 10.1093/annonc/mdi178

Affiliations: 1: Section of Hematology and Oncology, University of Chicago, Chicago, USA; 2: Lorus Therapeutics, Toronto, Canada

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