Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial
Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial
复制标题
DOI：
10.1016/s0140-6736(12)61134-9
复制
发表时间：
2013-01-12
期刊：
影响因子：
168.9
通讯作者：
Jozwiak, Sergiusz
中科院分区：
文献类型：
--
作者：
Franz, David Neal;Belousova, Elena;Jozwiak, Sergiusz
背景：结节性硬化症是一种遗传性疾病，可导致哺乳动物雷帕霉素靶蛋白（mTOR）的组成性激活和几种器官中良性肿瘤的生长。在大脑中，室管膜下巨细胞星形细胞瘤的生长可引起危及生命的症状，如脑积水，需要手术治疗。在一项开放标签的1/2期研究中，mTOR抑制剂依维莫司显著减少了室管膜下巨细胞星形细胞瘤的体积。我们评估了依维莫司在伴有结节性硬化症的室管膜下巨细胞星形细胞瘤患者中的疗效和安全性。在这项双盲、安慰剂对照的3期试验中，澳大利亚、比利时、加拿大、德国、英国、意大利、荷兰、波兰、俄罗斯联邦和美国的24个中心的患者（年龄0-65岁）被随机分配，使用交互式互联网反应系统，以2:1的比例口服依维莫司4.5 mg/m(2) /天（滴定至血谷浓度为5-15 ng/mL）或安慰剂。符合条件的患者明确诊断为结节性硬化症，至少有一个直径为1cm或更大的病变，室管膜下巨细胞星形细胞瘤的连续生长，1 cm或更大的新病变，或新的或恶化的脑积水。主要终点是确认缓解的患者比例，即相对于基线，室管膜下巨细胞星形细胞瘤靶体积减少50%或更多。分析的目的是治疗。本研究已在ClinicalTrials.gov注册，编号NCT00789828。117例患者被随机分配到依维莫司组（n=78）或安慰剂组（n=39）。依维莫司组27例（35%）患者的室管膜下巨细胞星形细胞瘤体积减少了至少50%，而安慰剂组没有(差异35%，95% CI 15-52；单侧精确Cochran-Mantel-Haenszel检验，p
Background Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms-eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.Methods In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4.5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response-ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.Findings 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p