title: A Phase I and pharmacokinetic study of VNP40101M, a novel sulfonylhydrazine alkylating agent, in patients with refractory leukemia.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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 approximately 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/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) 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.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. fgiles@mdanderson.org
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Miloslav
authors.initials: M
authors.lastname: Beran
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Ann
authors.initials: A
authors.lastname: Cahill
authors.forename: Caroline
authors.initials: C
authors.lastname: Clairmont
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000477:Alkylating Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009325:Nausea / Q000139:chemically induced; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000477:Alkylating Agents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine