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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 2 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; and 3 Vion Pharmaceuticals, Inc., New Haven, Connecticut
Requests for reprints: Francis J. Giles, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Box 428, Houston, TX 77030. Phone: 713-792-7305; Fax: 713-794-4297; E-mail: frankgiles{at}aol.com.
Purpose: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-ß-D-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease.
Design: Ara-C was given i.v. at a fixed dose of 1.5 gm/m2/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages 
65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m2, with escalation in 100 mg/m2 increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AGT) was measured at baseline.
Results: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of 400 mg/m2 in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P 
0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m2 of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule.
Conclusion: The recommended cloretazine dose schedule for future studies is 600 mg/m2 combined with 1.5 gm/m2/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.
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