MSCE, The Children's Hospital of Philadelphia, Pediatric Oncology/Stem Cell Transplant, Philadelphia, PA 19104-4318, USA.
J Clin Oncol. 2011 Mar 1;29(7):839-44. doi: 10.1200/JCO.2010.30.7231. Epub 2011 Jan 24.
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.
达沙替尼是一种口服的酪氨酸激酶抑制剂，对 SRC 家族激酶、BCR-ABL、c-KIT、EPHA2 和 PDGF-β 受体具有低纳摩尔的活性。达沙替尼在儿科临床前测试计划的几种肿瘤模型中被发现具有选择性活性。
对患有难治性实体瘤或伊马替尼耐药、费城染色体阳性白血病的儿科患者进行了达沙替尼的 I 期研究。每天两次口服，每次 50、65、85 和 110mg/m²/剂量，28 天为一疗程，无中断重复给药。在初始剂量时进行药代动力学研究。
共纳入 39 例患者（实体瘤 28 例，慢性髓性白血病 [CML] 9 例，急性淋巴细胞白血病 2 例）。在 50、65 和 85mg/m² 剂量水平下，未观察到剂量限制毒性（DLT）。在 110mg/m² 时，6 例患者中有 2 例发生 DLT，包括 2 级腹泻和头痛。在白血病患儿中，观察到 50mg/m² 级 4 低钾血症、85mg/m² 级 3 腹泻和 50mg/m² 级 2 肌酐升高。在后续疗程中，观察到胸腔积液、血管瘤病和胃肠道出血等 DLT。在可评估的 CML 患者中，观察到 3 例完全细胞遗传学反应、3 例部分细胞遗传学反应和 2 例部分/最小细胞遗传学反应。
总的来说，达沙替尼的药物处置和耐受性与在成年患者中观察到的相似。
