title: Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.
abstract: OBJECTIVE
  Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease.
  
  
  METHODS
  Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-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 > or =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 < or = 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.
  
  
  CONCLUSIONS
  The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA. frankgiles@aol.com
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
authors.forename: Stanton
authors.initials: S
authors.lastname: Gerson
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Steven
authors.initials: S
authors.lastname: Kornblau
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Verena
authors.initials: V
authors.lastname: Karsten
authors.forename: Ann
authors.initials: A
authors.lastname: Cahill
authors.forename: Karen
authors.initials: K
authors.lastname: Yee
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000477:Alkylating Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D018450:Disease Progression; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D007938:Leukemia / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; D003561:Cytarabine; C483604:laromustine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase