Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium
PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND...
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Published in | Journal of clinical oncology Vol. 29; no. 7; pp. 839 - 844 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Society of Clinical Oncology
01.03.2011
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Subjects | |
Online Access | Get full text |
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Summary: | PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m²/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose.
A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m² dose levels. At 110 mg/m², two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m²), grade 3 diarrhea (85 mg/m²), and grade 2 creatinine elevation (50 mg/m²) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients. |
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ISSN: | 0732-183X 1527-7755 |
DOI: | 10.1200/JCO.2010.30.7231 |