Tinkle Christopher L, Broniscer Alberto, Chiang Jason, Campagne Olivia, Huang Jie, Orr Brent A, Li Xiaoyu, Patay Zoltan, Zhang Jinghui, Baker Suzanne J, Merchant Thomas E, Jain Vinay, Onar-Thomas Arzu, Stewart Clinton F, Wetmore Cynthia, Gajjar Amar
Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Neurooncol Adv. 2021 Dec 1;3(1):vdab179. doi: 10.1093/noajnl/vdab179. eCollection 2021 Jan-Dec.
Platelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).
We used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays.
Fifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC and did not differ significantly for crushed versus whole-tablet administration. Overall, alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by status, and overall survival of stratum A was similar to that of historical controls.
Children tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.
血小板衍生生长因子受体（PDGFR）信号传导直接参与小儿高级别胶质瘤的发生。本研究评估了强效、选择性PDGFR介导的磷酸化抑制剂克伦洛尼对小儿高级别胶质瘤（HGG）患者的安全性和耐受性。
我们采用滚动6设计来研究克伦洛尼每日一次给药的最大耐受剂量（MTD），该药物在新诊断的弥漫性脑桥内胶质瘤（DIPG）（A组）或复发/进展性HGG（B组）患儿的局部放射治疗期间及之后使用。在第一个周期的首次给药和稳态（第28天）时研究药代动力学。通过Sanger测序或外显子组测序以及间期荧光原位杂交或单核苷酸多态性阵列评估基因改变。
两个组共纳入了50例可评估患者，两组的MTD均确定为170mg/m²。剂量限制性毒性在两组中主要为肝酶升高和血细胞计数抑制。碾碎给药与整片给药相比，克伦洛尼的AUC和Cmax无显著差异。总体而言，A组和B组分别有25%和30%的患者观察到基因改变。克伦洛尼治疗持续时间和生存结果在基因状态方面均无显著差异，A组的总生存期与历史对照相似。
儿童对克伦洛尼的耐受性良好，剂量略高于已确定的成人MTD，毒性谱一般与成人相似。需要在生物标志物富集的患者中进行评估肿瘤内PDGFR途径抑制的研究，以进一步评估克伦洛尼在该人群中的临床应用价值。
