Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousne...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1987-08, Vol.47 (15), p.4213-4217
Main Authors: PAZDUR, R, REDMAN, B. G, CORBETT, T, PHILLIPS, M, BAKER, L. H
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - therapeutic use
Antineoplastic Agents - toxicity
Biological and medical sciences
Chemotherapy
Cognition Disorders - chemically induced
Consciousness Disorders - chemically induced
Consciousness Disorders - drug therapy
Drug Evaluation
Drug Evaluation, Preclinical
Gastrointestinal Diseases - chemically induced
Humans
Hydantoins - administration & dosage
Hydantoins - therapeutic use
Hydantoins - toxicity
Medical sciences
Mice
Mice, Inbred Strains
Neoplasms - drug therapy
Nitrogen Mustard Compounds - administration & dosage
Nitrogen Mustard Compounds - therapeutic use
Nitrogen Mustard Compounds - toxicity
Pharmacology. Drug treatments
Physostigmine - therapeutic use
Speech Disorders - chemically induced
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Summary:Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.
ISSN:0008-5472
1538-7445