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Updated: Aug 1, 2026
Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System
Published on: October 29, 2019
A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with
A A Desai1, R L Schilsky, A Young
1Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637, USA.
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 > or = 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/m(2)/day to 222 mg/m(2)/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/m(2)/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.
Insights
GTI-2040, an RNR-targeting oligonucleotide, showed a manageable toxicity profile in patients with advanced cancers. The recommended dose is 185 mg/m(2)/day, with reversible hepatic toxicity as the dose-limiting factor.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- GTI-2040 is an oligonucleotide targeting the R2 subunit of ribonucleotide reductase (RNR) mRNA.
- This study aimed to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of GTI-2040.
- Pharmacokinetic and RNR suppression data were also collected.
Purpose of the Study:
- Determine the DLT and MTD of GTI-2040 in patients with advanced solid tumors or lymphoma.
- Evaluate the plasma pharmacokinetics of GTI-2040.
- Assess the suppression of RNR expression in peripheral blood mononuclear cells.
Main Methods:
- GTI-2040 was administered via continuous intravenous infusion over 21 days every 4 weeks.
- An accelerated, dose-doubling schedule was used for initial dose escalation.
- Subsequent escalation employed a more conservative approach with three patients per cohort.
Main Results:
- 36 patients received 49 cycles of GTI-2040 at doses from 18.5 to 222 mg/m(2)/day.
- The agent was generally well tolerated, with reversible hepatic toxicity observed at the highest dose.
- Fatigue and anorexia were the most frequent constitutional toxicities.
Conclusions:
- The recommended dose of GTI-2040 is 185 mg/m(2)/day for this infusion schedule.
- GTI-2040 demonstrates a manageable toxicity profile as a single agent.
- The drug is generally well tolerated in patients with advanced solid tumors or lymphoma.
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