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Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)

From the Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX; Children's Oncology Group Operations Center, Arcadia, CA; Rainbow Babies and Children's Hospital, Cleveland, OH; Hospital Ste-Justine, Montréal, Canada; and Children's Hospital of Philadelphia, Philadelphia, PA.

Address reprint requests to Susan M. Blaney, MD, Texas Children's Cancer Center, 6621 Fannin, CC 1410.00, Houston, TX 77030; e-mail: sblaney{at}txccc.org

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.

Supported by National Cancer Institute grant No. U01 CA97552 and National Center for Research Resources grant No. M01 RR00188-37.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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