Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas
Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas
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DOI：
10.1007/s11060-014-1710-0
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Kalamarides, Michel
中科院分区：
文献类型：
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作者：
Goutagny, Stephane;Raymond, Eric;Kalamarides, Michel
神经纤维瘤病2型（NF 2）是一种遗传性疾病，以双侧前庭神经鞘瘤（VS）为最常见的表现。Merlin，NF 2肿瘤抑制因子，被鉴定为雷帕霉素复合物1的哺乳动物靶标的负调节剂。小鼠的临床前数据显示，mTORC 1抑制延迟了NF 2神经鞘瘤的生长。我们进行了一项前瞻性单机构开放标签II期研究，以评估依维莫司在10例进行性VS的NF 2患者中的作用。每3个月监测一次药物活性。依维莫司口服给药12个月，如果肿瘤体积从基线减少> 20%，则继续治疗另外12个月。其他患者在完成12个月的依维莫司治疗后停止治疗，但在1年随访期间VS体积> 20%时允许恢复治疗。9例患者可评价。使用CTCAE 3.0标准评价安全性。依维莫司给药12个月后，未观察到体积减少20%。4例患者疾病进展，5例患者疾病稳定，中位年增长率从治疗前的67%/年降至治疗期间的0.5%/年。在这些患者中，肿瘤生长在治疗停止后3-6个月内恢复。然后重新引入依维莫司，24个月时VS中位数下降6.8%。肿瘤进展时间从治疗前的4.2个月增加到> 12个月。治疗期间听力稳定。依维莫司的安全性是可控的。虽然未达到主要终点，但需要进一步研究来证实依维莫司的稳定潜力。
Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was > 20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was > 20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume a parts per thousand yen20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus.