A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.
A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.
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DOI：
10.1002/pbc.28787
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发表时间：
2021-03
影响因子：
3.2
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中科院分区：
文献类型：
--
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评价依维莫司单药治疗影像学进展性低级别胶质瘤（LGG）儿童患者的疗效、药代动力学（PK）和药效学（PD）。依维莫司以5 mg/m2片剂或液体形式每日一次给药，计划持续48周或直至出现不可接受的毒性或疾病进展。排除1型神经纤维瘤病患者。在知情同意的患者中评估PK和PD终点。入组了23例合格患者（中位年龄：9.2岁）。所有患者均接受过既往化疗（既往方案的中位数：2）和/或放疗（2例患者）。到第48周，2例患者部分缓解，10例疾病稳定，11例临床或放射学进展; 2例在1年前终止研究（毒性：1例，医生确定：1例）。中位随访时间为1.8年（范围：0.2-6.7年），2、3和5年PFS分别为39± 11%、26± 11%和26± 11%; 2例患者死于疾病。2、3、5年OS均为93± 6%。1级和2级毒性占主导地位;发生了两起明确相关的3级毒性（粘膜炎和中性粒细胞减少症）。1例患者的4级肝酶升高可能相关。给药前血药浓度在5-15 ng/mL的目标范围内有45.5%低于和18.2%高于，PD分析显示磷酸化S6，4 E-BP 1的显著抑制和c-Myc表达的调节。每日口服依维莫司为多次复发、影像学进展的儿童LGG提供了一种耐受性良好的替代治疗。基于这些结果，正在进一步研究依维莫司在该患者人群中的应用。
To evaluate efficacy, pharmacokinetics(PK) and pharmacodynamics (PD) of single-agent everolimusin pediatric patients with radiographically progressive low-grade glioma (LGG). Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and PDendpoints were assessed in consenting patients. Twenty-three eligible patients (median age: 9.2 years) were enrolled. All patients received prior chemotherapy(median number of prior regimens: 2)and/orradiotherapy (two patients). By week 48, two patients had a partial response, 10stable disease, and 11 clinical or radiographic progression; two discontinued study prior to one year (toxicity: 1, physician determination:1). With a median follow-up of 1.8 years (range: 0.2–6.7 years), the 2, 3, and 5-year PFS were 39±11%, 26±11%, and 26±11%, respectively; two patients died of disease. The 2, 3 and 5-year OS were all 93±6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Pre-dose blood levelsshowed substantial variability between patientswith 45.5% below and 18.2% above the target range of 5–15 ng/mL.PD analysis demonstrated significant inhibition in phospho-S6, 4E-BP1 and modulation of c-Myc expression. Daily oral everolimusprovides a well-tolerated, alternative treatment for multiply recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
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影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
通讯作者：
Franz, David Neal
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