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Phase I and Clinical Pharmacology Trial of Crisnatol (BWA770U Mesylate) Using a Monthly Single-Dose Schedule¹

Divisions of Oncology and Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio, Texas 78284-7884 [G. S. H., J. B. C., J. G. K., J. S. L., J. N. T., G. R. W., D. A. T., J. K., D. D. V. H.], and Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709 [R. L. T., V. S. L., W. W., J. K. W.]

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m² were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m² and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and -slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t₁₂ of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m² and 18.3 liters/h/m², respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m².

¹ Supported by NIH Grant RR-01346, a grant from Burroughs Wellcome Co., an American Cancer Society Clinical Oncology Career Development Award (G. R. W.), and the clinical and support services of Audie L. Murphy Memorial Veterans' Administration Hospital, San Antonio, TX.

² To whom requests for reprints should be addressed, at the Division of Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7884.

Received 1/21/88. Revised 5/11/88. Accepted 5/19/88.

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