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Phase I Clinical Trial of Fazarabine as a Twenty-four-Hour Continuous Infusion¹

University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792 [H. B., K. D. T., R. Z. A., M. B. T., D. A., J. B., G. W.], and William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin 53705 [G. W.]

A phase I trial of fazarabine (ara-AC, 1-ß-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 24 adults with solid tumor malignancies. The majority of patients had received prior marrow-suppressive therapy. Level 7 (54.5 mg/m²/h for 24 h) was the maximum tolerated dose since during 6 evaluable first courses, 2 episodes of grade 4 granulocytopenia and 3 episodes of grade 3 occurred. Moderate thrombocytopenia also occurred at level 7 with 3 episodes of grade 1 and 1 episode of grade 4 thrombocytopenia during 6 first course treatments. Minimal myelosuppression, principally leukopenia, was seen prior to level 7. The nadir WBC through 47 courses had a linear relationship with plasma steady-state concentrations of ara-AC. The only other toxicity noted was moderate nausea/vomiting, which did not appear to be dose related. Plasma steady-state concentrations of ara-AC were reached in all patients within 4–6 h and ranged from 1.1 µM (11 mg/m²/h for 24 h) to 7.5 µM (54.5 mg/m²/h for 24 h). The mean total body clearance of ara-AC for 47 courses, levels 1–7, was 592 ± 147 (SD) ml/min/m² which is similar to prior pharmacokinetic data from the 24-h and 72-h infusion trials of the Pediatric and Medicine Branches, respectively. There were no objective disease responses during the trial. The recommended adult phase II dose for a 24-h infusion of ara-AC is 45–50 mg/m²/h.

¹ Supported by NIH Contract NO1-CM57735.

² H. B. is a recipient of an American Cancer Society Clinical Oncology Fellowship Award (89-189).

³ Recipient of an American Cancer Society Career Development Award. To whom requests for reprints should be addressed.

Received 9/17/90. Accepted 12/ 5/90.

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