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

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

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Alkylating Agents
Leukemia
Pharmacokinetics
Myelodysplastic Syndromes
Maximum Tolerated Dose
Acute Myeloid Leukemia
laromustine
Research Design
Animal Models
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia. / Giles, Francis J.; Thomas, Deborah; Garcia-Manero, Guillermo; Faderl, Stefan; Cortes, Jorge; Verstovsek, Srdan; Ferrajoli, Alessandra; Jeha, Sima; Beran, Miloslav; Koller, Charles; Andreeff, Michael; Cahill, Ann; Clairmont, Caroline; Sznol, Mario; Kantarjian, Hagop.

In: Clinical Cancer Research, Vol. 10, No. 9, 01.05.2004, p. 2908-2917.

Research output: Contribution to journalArticle

Giles, FJ, 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, vol. 10, no. 9, pp. 2908-2917. https://doi.org/10.1158/1078-0432.CCR-03-0738
Giles, Francis J. ; Thomas, Deborah ; Garcia-Manero, Guillermo ; Faderl, Stefan ; Cortes, Jorge ; Verstovsek, Srdan ; Ferrajoli, Alessandra ; Jeha, Sima ; Beran, Miloslav ; Koller, Charles ; Andreeff, Michael ; Cahill, Ann ; Clairmont, Caroline ; Sznol, Mario ; Kantarjian, Hagop. / A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 9. pp. 2908-2917.
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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.",
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T1 - A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

AU - Giles, Francis J.

AU - Thomas, Deborah

AU - Garcia-Manero, Guillermo

AU - Faderl, Stefan

AU - Cortes, Jorge

AU - Verstovsek, Srdan

AU - Ferrajoli, Alessandra

AU - Jeha, Sima

AU - Beran, Miloslav

AU - Koller, Charles

AU - Andreeff, Michael

AU - Cahill, Ann

AU - Clairmont, Caroline

AU - Sznol, Mario

AU - Kantarjian, Hagop

PY - 2004/5/1

Y1 - 2004/5/1

N2 - 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.

AB - 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.

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