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


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.


CONCLUSIONS
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.
Blaney
Susan M
SM
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA. sblaney@txccc.org
Bernstein
Mark
M
Neville
Kathleen
K
Ginsberg
Jill
J
Kitchen
Brenda
B
Horton
Terzah
T
Berg
Stacey L
SL
Krailo
Mark
M
Adamson
Peter C
PC
D001682:Biological Availability; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011336:Probability; D016016:Proportional Hazards Models; D061988:Proteasome Inhibitors; D020551:Pulse Therapy, Drug; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib