Daw Najat C, Furman Wayne L, Stewart Clinton F, Iacono Lisa C, Krailo Mark, Bernstein Mark L, Dancey Janet E, Speights Rose Anne, Blaney Susan M, Croop James M, Reaman Gregory H, Adamson Peter C
Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA.
J Clin Oncol. 2005 Sep 1;23(25):6172-80. doi: 10.1200/JCO.2005.11.429.
Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors.
Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28).
Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults.
Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
表皮生长因子受体在儿童恶性实体瘤中表达。我们开展了一项吉非替尼（一种表皮生长因子受体酪氨酸激酶抑制剂）用于难治性实体瘤患儿的Ⅰ期试验。
将吉非替尼（150、300、400或500mg/m²）口服给予每组三至六名患者，每日一次持续给药，直至疾病进展或出现显著毒性。在疗程1（第1天至28天）期间进行药代动力学研究。
25名入组患者中，19名（中位年龄15岁）可进行全面毒性评估并接受了54个疗程的治疗。剂量限制性毒性为2名接受500mg/m²治疗的患者出现皮疹，1名接受400mg/m²治疗的患者出现ALT和AST升高。最大耐受剂量为400mg/m²/天。最常见的非剂量限制性毒性为1级或2级皮肤干燥、贫血、腹泻、恶心和呕吐。1例尤因肉瘤患者出现部分缓解。2例肾母细胞瘤患者和2例脑干胶质瘤患者（1例为外生性）疾病稳定8周至≥60周。在400mg/m²剂量下，吉非替尼血浆峰值浓度中位数为2.2μg/mL（范围为1.2至3.6μg/mL），在给药后中位数2.3小时（范围为2.0至8.3小时）出现。表观清除率中位数和半衰期中位数分别为14.8L/h/m²（范围为3.8至24.8L/h/m²）和11.7小时（范围为5.6至22.8小时）。吉非替尼的全身暴露量与成人抗肿瘤活性相关的暴露量相当。
口服吉非替尼在儿童中耐受性良好。将继续探索该药物与细胞毒性化疗联合应用的研究。
