A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
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DOI：
10.1007/s11060-020-03641-2
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发表时间：
2020-10-09
影响因子：
3.9
通讯作者：
Fouladi, Maryam
中科院分区：
文献类型：
--
作者：
DeWire, Mariko;Fuller, Christine;Fouladi, Maryam
目的：探讨细胞周期蛋白依赖性激酶-视网膜母细胞瘤（CDK-RB）通路在弥漫性桥脑胶质瘤（DIPG）中的表达。我们评估了CDK 4/6抑制剂ribociclib在新诊断的DIPG患者放疗后给药的安全性、可行性和早期疗效。方法放疗后，符合条件的患者接受28天周期的ribociclib治疗（350 mg/m2; 21天给药/7天停药）。可行性终点包括至少6个疗程的耐受性，以及1次剂量降低后重新开始治疗的延迟不超过2周。通过1年和中位总生存期（OS）来衡量早期疗效。前瞻性地完成了患者/家长代理报告结局测量信息系统（PROMIS）评估。结果研究包括10例可评估的患者，9例DIPG和1例弥漫性中线胶质瘤（DMG）-年龄均为3.7至19.8岁。中位疗程数为8（范围3-14）。3例患者因4级中性粒细胞减少症需要减量，1例患者在疗程4后因血液学毒性停止治疗。最常见的3/4级毒性是骨髓抑制。2个疗程后，4例患者的MRI评估显示坏死体积增加，3例患者伴有新的神经系统症状。DIPG的1年和中位OS分别为89%和16.1个月（范围10-30）; DMG患者在诊断后6个月死亡。5例患者捐献了脑组织和肿瘤; 3例为RB+。结论Ribociclib在DIPG和DMG放疗后给药是可行的。肿瘤坏死增加可能代表治疗效果。这些数据保证了进一步的肿瘤坏死的前瞻性体积分析。可行性和稳定性研究结果支持进一步研究ribociclib联合治疗。
Purpose Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. Methods Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m(2); 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. Results The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . Conclusions Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies.