State University of New York, Health Science Center, Syracuse, New York, USA.
Pediatr Blood Cancer. 2010 Dec 15;55(7):1323-8. doi: 10.1002/pbc.22609. Epub 2010 Aug 13.
To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors.
Ispinesib was administered as 1-hr intravenous infusion weekly × 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12 mg/m(2) /dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose.
Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12 mg/m(2) dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m(2) dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44) hr and the plasma drug clearance was 5 (1-14) L/hr/m(2) .
The maximum tolerated and recommended phase II dose for ispinesib administered weekly × 3 every 28 days for children with solid tumors is 9 mg/m(2) /dose. Plans for a phase II trial in select pediatric solid tumors are in development.
确定在复发或难治性实体瘤的儿科患者中，驱动蛋白纺锤体蛋白抑制剂伊匹尼西布的最大耐受剂量、剂量限制性毒性和药代动力学。
伊匹尼西布每周静脉输注 1 小时，每周 3 次，每 28 天 1 次。5、7、9 和 12mg/m(2)/剂量的患者分为 3-6 个队列。首次给药后采集用于药代动力学分析的连续血浆样本。
该研究共纳入了 24 名（13 名女性）中位年龄（范围）为 10 岁（1-19 岁）的患者。在 12mg/m(2)剂量水平，2/6 例患者发生剂量限制性中性粒细胞减少症，1/6 例患者发生高胆红素血症，而在 9mg/m(2)剂量水平，1/6 例患者发生剂量限制性中性粒细胞减少症。无客观缓解，但 3 名患者（诊断为间变性星形细胞瘤、肺泡软组织肉瘤和室管膜瘤）有 4-7 个疗程的稳定疾病。药物处置存在很大的个体间差异。中位（范围）终末消除半衰期为 16（8-44）小时，血浆药物清除率为 5（1-14）L/hr/m(2)。
对于接受每周静脉输注 1 小时，每周 3 次，每 28 天 1 次的固体肿瘤儿童，伊匹尼西布的最大耐受和推荐的 II 期剂量为 9mg/m(2)/剂量。正在制定在选定的儿科实体瘤中进行 II 期试验的计划。
