Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study

Clin Cancer Res. 2008 Feb 15;14(4):1124-30. doi: 10.1158/1078-0432.CCR-07-4242.


Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.

Experimental design: 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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Area Under Curve
  • Brain Neoplasms / drug therapy*
  • Child
  • Child, Preschool
  • Humans
  • Hydrazines / administration & dosage*
  • Hydrazines / adverse effects
  • Hydrazines / pharmacokinetics
  • Infant
  • Maximum Tolerated Dose
  • Neoplasm Recurrence, Local / drug therapy*
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics


  • Antineoplastic Agents
  • Hydrazines
  • Sulfonamides
  • laromustine