Abstract

Background

Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs.

Methods

Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks.

Results

Twenty-three participants (median age, 9.4 y; range, 3.2–21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants.

Conclusion

Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

中文翻译：

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连续口服 mTOR 抑制剂依维莫司治疗复发性、放射学进展性神经纤维瘤病 1 型相关小儿低级别胶质瘤的 II 期研究：神经纤维瘤病临床试验联盟研究

摘要

背景

在 1 型神经纤维瘤病 (NF1) 相关的低级别胶质瘤 (LGG) 中观察到哺乳动物雷帕霉素靶标 (mTOR) 通路的激活，但尚未在该人群中研究抑制该通路的药物，包括 mTOR 抑制剂。我们评估了口服 mTOR 抑制剂依维莫司对放射学进展的 NF1 相关儿科 LGG 的疗效。

方法

患有放射学进展、NF1 相关 LGG 且先前接受过含卡铂化疗的儿童被前瞻性纳入这项 II 期临床试验，以每天接受依维莫司治疗。分析全血中的依维莫司和磷脂酰肌醇 3 激酶 (PI3K)/mTOR 通路抑制标志物。在治疗期间获得了连续 MRI。主要终点是 48 周时的无进展生存期。

结果

23 名参与者（中位年龄为 9.4 岁；范围为 3.2-21.6 岁）被招募。所有参与者最初都对反应进行了评估；1 名患者在发生恶性周围神经鞘瘤后退出研究。22 名参与者中有 15 名 (68%) 表现出反应，定义为缩小（1 例完全反应，2 例部分反应）或肿瘤生长停滞（12 例疾病稳定）。其中，10/15 保持无进展（中位随访时间，33 个月）。所有剩余的 22 名参与者在治疗结束时都还活着。治疗耐受性良好；没有患者因毒性而停止治疗。药代动力学参数和给药前浓度显示出受试者之间的显着差异。

结论

患有复发性/进展性 NF1 相关 LGG 的个体在口服依维莫司治疗期间表现出显着的疾病稳定性/收缩率，具有良好的耐受性。依维莫司非常适合未来考虑作为该患者群体的前期或联合治疗。