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

Abstract

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.

• Authors: Terzah M Horton, Debananda Pati, Sharon E Plon, Patrick A Thompson, Lisa R Bomgaars, Peter C Adamson, Ashish M Ingle, John Wright, Adam H Brockman, Martin Paton, Susan M Blaney
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 5 Pg. 1516-22 (Mar 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17332297 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adolescent
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Boronic Acids (pharmacokinetics, 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, therapeutic use)