A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

Francis J. Giles, Deborah Thomas, Guillermo Garcia-Manero, Stefan Faderl, Jorge Cortes, Srdan Verstovsek, Alessandra Ferrajoli, Sima Jeha, Miloslav Beran, Charles Koller, Michael Andreeff, Ann Cahill, Caroline Clairmont, Mario Sznol, Hagop Kantarjian

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Purpose: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). Experimental Design: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m 2 was escalated by ∼33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. Results: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m2 for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m2 was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m 2 and 1 with acute myeloid leukemia treated with 600 mg/m 2, achieved complete remission. Conclusions: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.

Original languageEnglish (US)
Pages (from-to)2908-2917
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number9
DOIs
StatePublished - May 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Giles, F. J., Thomas, D., Garcia-Manero, G., Faderl, S., Cortes, J., Verstovsek, S., Ferrajoli, A., Jeha, S., Beran, M., Koller, C., Andreeff, M., Cahill, A., Clairmont, C., Sznol, M., & Kantarjian, H. (2004). A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia. Clinical Cancer Research, 10(9), 2908-2917. https://doi.org/10.1158/1078-0432.CCR-03-0738