title: A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. tmhorton@txccc.org
authors.forename: Terzah M
authors.initials: TM
authors.lastname: Horton
authors.forename: Debananda
authors.initials: D
authors.lastname: Pati
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Bomgaars
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Adam H
authors.initials: AH
authors.lastname: Brockman
authors.forename: Martin
authors.initials: M
authors.lastname: Paton
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001897:Boronic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects; D015151:Immunoblotting; D007223:Infant; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D016328:NF-kappa B / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex