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

• Published in: Clinical cancer research Vol. 13; no. 5; pp. 1516 - 1522
• Main Authors: HORTON, Terzah M, PATI, Debananda, BLANEY, Susan M, PLON, Sharon E, THOMPSON, Patrick A, BOMGAARS, Lisa R, ADAMSON, Peter C, INGLE, Ashish M, WRIGHT, John, BROCKMAN, Adam H, PATON, Martin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-03-2007
• Subjects: Adolescent; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Boronic Acids - pharmacokinetics; Boronic Acids - therapeutic use; Bortezomib; Child; Child, Preschool; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Hematologic and hematopoietic diseases; Humans; I-kappa B Kinase - drug effects; Immunoblotting; Infant; Leukemia - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Maximum Tolerated Dose; Medical sciences; NF-kappa B - drug effects; NF-κB; pediatric; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; phase 1 trial; Proteasome Endopeptidase Complex - drug effects; PS-341; Pyrazines - pharmacokinetics; Pyrazines - therapeutic use; Velcade; Human; Antineoplastic agent; Pediatrics; Treatment resistance; Bortezomib; Leukemia; Infant; Malignant hemopathy; Malignant tumor; Cancerology; Analog; Proteasome inhibitor; Dipeptides; Phase I trial; Child
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2173

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 κB (NF-κB) 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-κB 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-κB activity, bortezomib had little activity as a single agent in this population.