Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia

Francis Giles, Srdan Verstovsek, Deborah Thomas, Stanton Gerson, Jorge Cortes, Stefan Faderl, Alessandra Ferrajoli, Farhad Ravandi, Steven Kornblau, Guillermo Garcia-Manero, Elias Jabbour, Susan O'Brien, Verena Karsten, Ann Cahill, Karen Yee, Maher Albitar, Mario Sznol, Hagop Kantarjian

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Purpose: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase t study of cloretazine combined with cytarabine (1-β-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/m 2 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/m 2 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.

Original languageEnglish (US)
Pages (from-to)7817-7824
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number21
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Giles, F., Verstovsek, S., Thomas, D., Gerson, S., Cortes, J., Faderl, S., Ferrajoli, A., Ravandi, F., Kornblau, S., Garcia-Manero, G., Jabbour, E., O'Brien, S., Karsten, V., Cahill, A., Yee, K., Albitar, M., Sznol, M., & Kantarjian, H. (2005). Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia. Clinical Cancer Research, 11(21), 7817-7824. https://doi.org/10.1158/1078-0432.CCR-05-1070