Background

No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.

Methods

We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).

Results

A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.

Conclusions

In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.)

中文翻译：

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塞美替尼治疗患有无法手术的丛状神经纤维瘤的儿童。

 背景

对于 1 型神经纤维瘤病患者无法手术的丛状神经纤维瘤，尚无批准的治疗方法。

 方法

我们进行了 Selumetinib 的开放标签 2 期试验，以确定丛状神经纤维瘤患者的客观缓解率并评估临床获益。患有 1 型神经纤维瘤病和有症状且无法手术的丛状神经纤维瘤的儿童每天两次口服司美替尼，剂量为每平方米体表面积 25 mg，连续给药方案（28 天周期）。至少每四个周期进行一次体积磁共振成像和临床结果评估（疼痛、生活质量、毁容和功能）。儿童对肿瘤疼痛强度进行评分，评分范围为 0（无疼痛）至 10（可想象的最严重疼痛）。

 结果

2015 年 8 月至 2016 年 8 月期间，共有 50 名儿童（中位年龄 10.2 岁；范围 3.5 至 17.4 岁）入组。最常见的神经纤维瘤相关症状是毁容（44 名患者）、运动功能障碍（33 名患者）和疼痛（ 26）。截至2019年3月29日，共有35名患者（70%）确认部分缓解，其中28名患者出现持久缓解（持续≥1年）。治疗 1 年后，儿童报告的肿瘤疼痛强度评分平均下降 2 分，被认为是具有临床意义的改善。此外，儿童和家长报告的日常功能疼痛干扰（分别为 38% 和 50%）以及总体健康相关生活质量（分别为 48% 和 58%）也得到了具有临床意义的改善。如力量（56% 的患者）和运动范围（38% 的患者）的功能结果。 5 名患者因可能与司美替尼相关的毒性作用而停止治疗，6 名患者出现疾病进展。最常见的毒性反应是恶心、呕吐或腹泻；肌酸磷酸激酶水平无症状升高；痤疮样皮疹;和甲沟炎。

 结论

在这项 2 期试验中，大多数患有 1 型神经纤维瘤病和无法手术的丛状神经纤维瘤的儿童都获得了持久的肿瘤缩小，并从司美替尼中获得了临床获益。 （由美国国立卫生研究院和其他机构的校内研究计划资助；ClinicalTrials.gov 编号，NCT01362803。）