多激酶抑制剂索拉非尼联合克拉屈滨和阿糖胞苷治疗儿科复发/难治性白血病的 I 期药代动力学和药效学研究。
Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia.
机构信息
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
出版信息
J Clin Oncol. 2011 Aug 20;29(24):3293-300. doi: 10.1200/JCO.2011.34.7427. Epub 2011 Jul 18.
PURPOSE
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
PATIENTS AND METHODS
Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
RESULTS
At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
CONCLUSION
Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
目的
评估多激酶抑制剂索拉非尼与克拉屈滨和阿糖胞苷联合用于治疗复发/难治性儿童白血病的毒性、药代动力学和药效学。
患者和方法
12 名急性白血病患者（11 例急性髓系白血病[AML]）接受索拉非尼治疗，第 1 天至第 7 天，然后同时接受阿糖胞苷（1 g/m2）和克拉屈滨（第 1 层：40 mg/m2，n=10；第 2 层[最近移植或真菌感染]：20 mg/m2，n=2），第 8 天至第 12 天。如果耐受，索拉非尼可持续使用至第 28 天。计划使用两种索拉非尼剂量水平（200 mg/m2 和 150 mg/m2，每日两次）。在第 7 天和第 8 天进行了索拉非尼药代动力学和药效学研究。
结果
在索拉非尼 200 mg/m2 时，第 1 层的 4 名患者中有 2 名和第 2 层的 2 名患者中有 1 名发生 3 级手足皮肤反应和/或皮疹，为剂量限制毒性（DLT）。在索拉非尼 150 mg/m2 的第 1 层的 6 名患者中未观察到 DLT。索拉非尼抑制白血病细胞中 AKT、S6 核糖体蛋白和 4E-BP1 的磷酸化。索拉非尼转化为其代谢物索拉非尼 N-氧化物的转化率很高（平均 33%；范围 17%至 69%）。在体外，N-氧化物强烈抑制 FLT3 内部串联重复（ITD；结合常数 70 nmol/L）和五种 AML 细胞系的活力。第 8 天，12 名患者中有 10 名（中位数 66%；范围 9%至 95%）的白血病细胞比例下降。在联合化疗后，6 名患者（3 名 FLT3-ITD 和 3 名 FLT3 野生型 AML）达到完全缓解，2 名（均为 FLT3-ITD AML）达到不完全血液计数恢复的完全缓解，1 名（FLT3 野生型 AML）达到部分缓解。
结论
索拉非尼与克拉屈滨和阿糖胞苷联合使用耐受性良好，并在复发/难治性儿童 AML 中显示出活性。
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