Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.
Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.
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DOI：
10.1056/nejmoa1605943
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发表时间：
2016-12-29
期刊：
影响因子：
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通讯作者：
Widemann BC
中科院分区：
文献类型：
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作者：
Dombi E;Baldwin A;Marcus LJ;Fisher MJ;Weiss B;Kim A;Whitcomb P;Martin S;Aschbacher-Smith LE;Rizvi TA;Wu J;Ershler R;Wolters P;Therrien J;Glod J;Belasco JB;Schorry E;Brofferio A;Starosta AJ;Gillespie A;Doyle AL;Ratner N;Widemann BC
1型神经纤维瘤病相关丛状神经纤维瘤的治疗缺乏有效的药物治疗，其特征在于RAS-促分裂原活化蛋白激酶（MAPK）信号传导升高。我们在患有1型神经纤维瘤病和无法手术的丛状神经纤维瘤的儿童中进行了一项司美替尼（AZD 6244或ARRY-142886）的I期试验，以确定最大耐受剂量并评估血浆药代动力学。司美替尼是一种MAPK激酶（MEK）1和2的口服选择性抑制剂。司美替尼每天给药两次，剂量为20 - 30 mg/m2体表面积，连续给药方案（28天为一个周期）。我们还使用1型神经纤维瘤病相关神经纤维瘤的小鼠模型测试了司美替尼。对治疗的反应（即，丛状神经纤维瘤体积从基线的增加或减少）通过使用体积磁共振成像分析来监测，以测量丛状神经纤维瘤的尺寸变化。共有24名中位肿瘤体积为1205 ml（范围：29 - 8744）的儿童（中位年龄：10.9岁;范围：3.0 - 18.5岁）接受了司美替尼治疗。患者能够长期接受司美替尼治疗;中位周期数为30（范围：6 - 56）。最大耐受剂量为25 mg/m2（约为推荐成人剂量的60%）。与司美替尼相关的最常见毒性反应包括痤疮样皮疹、胃肠道反应和无症状肌酸激酶升高。本试验中儿童中司美替尼的药代动力学评价结果与成人中发表的结果相似。司美替尼治疗导致24名儿童中的17名（71%）确认部分缓解（肿瘤体积较基线减少≥20%），18只小鼠中的12只（67%）神经纤维瘤体积较基线减少。迄今为止，尚未观察到疾病进展（肿瘤体积较基线增加≥20%）。观察到肿瘤相关疼痛、毁容和功能损害减少的轶事证据。我们的早期数据表明，患有神经纤维瘤病1型和不可手术的丛状神经纤维瘤的儿童受益于长期剂量调整的司美替尼治疗，而没有过度的毒性作用。（由美国国立卫生研究院和其他机构资助; ClinicalTrials.gov编号，NCT 01362803。
Effective medical therapies are lacking for the treatment of neurofibromatosis type 1– related plexiform neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling. We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1–related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.)