Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children's Oncology Group study (ADVL0015)

J Clin Oncol. 2004 Dec 1;22(23):4804-9. doi: 10.1200/JCO.2004.12.185.


Purpose: To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.

Patients and methods: An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.

Results: Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2 dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% +/- 7.6% at the 1.2 mg/m2/dose and 76.5% +/- 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses.

Conclusion: Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Controlled Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biological Availability
  • Boronic Acids / administration & dosage*
  • Boronic Acids / adverse effects
  • Boronic Acids / pharmacokinetics*
  • Bortezomib
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Injections, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Multivariate Analysis
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology
  • Neoplasms / drug therapy*
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Probability
  • Proportional Hazards Models
  • Proteasome Inhibitors*
  • Pulse Therapy, Drug
  • Pyrazines / administration & dosage*
  • Pyrazines / adverse effects
  • Pyrazines / pharmacokinetics*
  • Risk Assessment
  • Salvage Therapy*
  • Survival Rate
  • Treatment Outcome


  • Boronic Acids
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib