title: Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study.
abstract: OBJECTIVE
  VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.
  
  
  METHODS
  VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O(6)-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
  
  
  RESULTS
  Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m(2)/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy.
  
  
  CONCLUSIONS
  The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m(2)/d in moderately pretreated and 30 mg/m(2)/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA. gurur002@mc.duke.edu
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Melinda
authors.initials: M
authors.lastname: O'Shaughnessy
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kocak
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Peter C
authors.initials: PC
authors.lastname: Phillips
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Verena
authors.initials: V
authors.lastname: Karsten
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007223:Infant; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine