A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study

Clin Cancer Res. 2007 Mar 1;13(5):1516-22. doi: 10.1158/1078-0432.CCR-06-2173.


Purpose: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia.

Experimental design: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle.

Results: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses.

Conclusions: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.

Publication types

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

MeSH terms

  • Adolescent
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use*
  • Boronic Acids / pharmacokinetics*
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • I-kappa B Kinase / drug effects
  • Immunoblotting
  • Infant
  • Leukemia / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • NF-kappa B / drug effects
  • Proteasome Endopeptidase Complex / drug effects
  • Pyrazines / pharmacokinetics*
  • Pyrazines / therapeutic use*


  • Antineoplastic Agents
  • Boronic Acids
  • NF-kappa B
  • Pyrazines
  • Bortezomib
  • I-kappa B Kinase
  • Proteasome Endopeptidase Complex