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A Phase 1 Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients with Refractory Leukemia: a Children's Oncology Group Study

Authors' Affiliations: ¹ Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas; ² Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; ³ Children's Oncology Group Operations Center, Arcadia, California; ⁴ Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, Maryland; ⁵ Department of Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and ⁶ Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories-Boston, Boston, Massachusetts

Requests for reprints: Terzah M. Horton, Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320, Houston, TX 77030. Phone: 832-824-4269; Fax: 832-825-4276; E-mail: tmhorton{at}txccc.org.

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/m² dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor B (NF-B) 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/m² 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/m² revealed a clearance of 11 mL/h/m², a central volume of distribution of 6.7 L/m², and a terminal half-life of 12.6 h. NF-B 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/m²/dose. Although bortezomib treatment inhibited NF-B activity, bortezomib had little activity as a single agent in this population.

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