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Phase I Pharmacokinetic and Pharmacodynamic Study of a New Anthrapyrazole, CI-937 (DUP937)¹

Department of Medicine, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada M4X 1K9 [C. E., M. M.]; Toronto Bayview Regional Cancer Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5 [I. G. K.] Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 48105 [B. W., L. R. W.]; and National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario, Canada K7L 3M6 [E. E., B. Z.]

We performed a phase I trial of CI-937 (DUP937), an anthrapyrazole, with the following objectives: (a) to determine the maximally tolerated dose in humans; (b) to define the toxicity spectrum of this agent; (c) to describe the pharmacokinetics of the drug; (d) to test a pharmacokinetics based hypothesis of dose escalation; and (e) to relate drug pharmacokinetics to pharmacodynamics. CI-937 was administered as a single bolus injection every 3–4 weeks at doses ranging from 3.6 to 25.2 mg/m². Thirty-two patients and 57 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 30 patients on the first course using a sensitive and selective radioimmunoassay. The maximally tolerated dose in patients with no prior therapy was 25.2 mg/m² and dose-limiting toxicity was neutropenia. Thrombocytopenia, nausea, vomiting, stomatitis, and alopecia were mild. A partial response was recorded in a patient with mesothelioma. The area under the curve increased linearly with dose, and total body clearance of CI-937 was independent of dose. The mean total body clearance was 107 ± 55.8 ml/min/m², mean steady state volume of distribution was 492 ± 469 liters/m², and terminal half-life was 3.78 ± 2.86 days. The extended factors of 2 methods of pharmacologically guided dose escalation were intended for use but ultimately were equivalent to that of the modified Fibonacci dose escalation method. Dose and the area under the curve were significant predictors of a percentage change in WBC and neutrophil count in a univariate analysis. Only dose and baseline neutrophil count predicted a percentage change in WBCs in a multifactor analysis. Dose and prior chemotherapy predicted percentage change in neutrophil count in a multifactor analysis. We conclude that the dose-limiting toxicity of CI-937 is neutropenia and that the recommended phase II starting dose is 22 mg/m².

¹ This work was supported in part by Warner-Lambert and the National Cancer Institute (Canada).

² To whom requests for reprints should be addressed, at Princess Margaret Hospital, 500 Sherbourne Ave., Toronto, Ontario, Canada M4X 1K9.

Received 5/ 9/91. Accepted 9/19/91.