Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium.

Abstract

UNLABELLED:

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.

RESULTS:

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.

• Authors: Richard Aplenc, Susan M Blaney, Lewis C Strauss, Frank M Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J Wright, Peter C Adamson
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 7 Pg. 839-44 (Mar 01 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21263099 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Pyrimidines
• Thiazoles
• Dasatinib

Topics

• Administration, Oral
• Adolescent
• Child
• Child, Preschool
• Dasatinib
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Hematologic Neoplasms (diagnosis, drug therapy)
• Hospitals, Pediatric
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (diagnosis, drug therapy)
• Male
• Maximum Tolerated Dose
• Neoplasms (drug therapy, pathology)
• Patient Selection
• Pediatrics
• Philadelphia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Risk Assessment
• Thiazoles (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Young Adult