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 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.
MSCE, The Children's Hospital of Philadelphia, Pediatric Oncology/Stem Cell Transplant, Philadelphia, PA 19104-4318, USA. raplenc@mail.med.upenn.edu
Richard
R
Aplenc
Susan M
SM
Blaney
Lewis C
LC
Strauss
Frank M
FM
Balis
Suzanne
S
Shusterman
Ashish Mark
AM
Ingle
Shruti
S
Agrawal
Junfeng
J
Sun
John J
JJ
Wright
Peter C
PC
Adamson
D000284:Administration, Oral; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D006776:Hospitals, Pediatric; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018579:Patient Selection; D010372:Pediatrics; D015143:Philadelphia; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib
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