Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium

• Published in: Journal of clinical oncology Vol. 29; no. 7; pp. 839 - 844
• Main Authors: Aplenc, Richard, Blaney, Susan M, Strauss, Lewis C, Balis, Frank M, Shusterman, Suzanne, Ingle, Ashish Mark, Agrawal, Shruti, Sun, Junfeng, Wright, John J, Adamson, Peter C
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01.03.2011
• Subjects: Administration, Oral; Adolescent; Biological and medical sciences; Child; Child, Preschool; Dasatinib; Dose-Response Relationship, Drug; Drug Administration Schedule; Faze; Female; Follow-Up Studies; Hematologic Neoplasms - diagnosis; Hematologic Neoplasms - drug therapy; Hospitals, Pediatric; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - diagnosis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Male; Maximum Tolerated Dose; Medical sciences; Neoplasms - drug therapy; Neoplasms - pathology; Original Reports; Patient Selection; Pediatrics; Philadelphia; Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Risk Assessment; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Treatment Outcome; Tumors; Young Adult; Philadelphia; Human; Antineoplastic agent; Dasatinib; Pediatrics; Tyrosine kinase inhibitor; Malignant tumor; Cancerology; Treatment; S Phase; Cell cycle; Phase I trial; Multikinase inhibitor; Pharmacokinetics; Child; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2010.30.7231

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.