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Annals of Oncology 13:760-769, 2002
© 2002 European Society for Medical Oncology

Original Paper

Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients

E. Cellarier1,2,+, C. Terret3, P. Labarre2, R. Ouabdesselam1, H. Curé1, C. Marchenay1,2, J. C. Maurizis2, J. C. Madelmont2, P. Chollet1,2 and J. P. Armand3

1Centre Jean Perrin and 2INSERM U484 Clermont-Ferrand; 3Institut Gustave Roussy, Villejuif, France

Received 8 March 2001; revised 1 October 2001; accepted 23 October 2001.

Background

Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated.

Patients and methods

Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period.

Results

Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean {alpha} half-life of 4 min and mean terminal half-life of 49 min.

Conclusions

There was a clear linear relationship between the area under the blood drug concentration–time curve (AUC) and the dose of cystemustine (P <0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P <0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

Key words: chloroethylnitrosourea, cystemustine, hematotoxicity, pharmacokinetic–pharmacodynamic relationships, phase I


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