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Unusual central nervous system toxicity in a phase I study of N1N11 diethylnorspermine in patients with advanced
P J Creaven1, R Perez, L Pendyala
1Department of Investigational Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, New York, USA.
Abstract:
The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11 diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1 h i.v. infusion every 12 h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t1/2 of 0.12 h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of > or = 83 mg/m2/day.
Insights
N1N11 diethylnorspermine (DENSPM), a polyamine analog, showed dose-limiting central nervous system toxicity in a Phase I trial for advanced solid tumors. Caution is advised for DENSPM doses of 83 mg/m2/day and higher.
Area of Science:
- Pharmacology
- Oncology
- Toxicology
Background:
- N1N11 diethylnorspermine (DENSPM) is a novel polyamine analog with experimental anti-cancer properties.
- DENSPM inhibits polyamine biosynthesis and promotes degradation via spermine/spermidine N-acetyl transferase.
Purpose of the Study:
- To determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics of DENSPM in patients with advanced solid tumors.
- To evaluate the safety and tolerability of DENSPM administered via intravenous infusion.
Main Methods:
- A Phase I clinical trial using a modified Fibonacci dose escalation design.
- DENSPM administered as a 1-hour IV infusion every 12 hours for 5 days (10 doses).
- Patients with advanced solid tumors were enrolled, starting at 25 mg/m2/day.
Main Results:
- Minor toxicities (Grade I) like flushing, nausea, and headache were observed at doses up to 50 mg/m2/day.
- An acute central nervous system (CNS) toxicity syndrome, including weakness, ataxia, and speech difficulties, occurred at doses of 83 and 125 mg/m2/day.
- Preliminary pharmacokinetics showed dose-linear plasma concentrations and rapid decay (t1/2 = 0.12 h).
Conclusions:
- DENSPM exhibits significant dose-limiting CNS toxicity at doses >= 83 mg/m2/day when administered on this schedule.
- Great caution is warranted when using DENSPM at higher doses due to the observed CNS toxicity syndrome.
- Further investigation into DENSPM's safety profile and potential therapeutic applications requires careful dose management.