Odia Yazmin, Koschmann Carl, Vitanza Nicholas A, de Blank Peter, Aguilera Dolly, Allen Jeffrey, Daghistani Doured, Hall Matthew, Khatib Ziad, Kline Cassie, MacDonald Tobey, Mueller Sabine, Faison Shamia L, Allen Joshua E, Naderer Odin J, Ramage Samuel C, Tarapore Rohinton S, McGovern Susan Lynne, Khatua Soumen, Zaky Wafik, Gardner Sharon L
Department of Neuro-Oncology, Miami Cancer Institute at Baptist Health South Florida, Miami, Florida, USA.
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
Neuro Oncol. 2024 May 3;26(Supplement_2):S155-S164. doi: 10.1093/neuonc/noae001.
This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma.
This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2). The actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator.
Twelve patients received D1D2 ONC201 (DL1, n = 3; DL1, n = 3; DL2, n = 6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250 mg, n = 3; D1-625 mg, n = 3; D1D2-250 mg, n = 2; D1D2-625 mg, n = 2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly.
ONC201 given D1D2 was well tolerated at all DLs and associated with greater AUC0-48.
本研究评估了连续两天每周给药两次的口服ONC201在新诊断的弥漫性脑桥胶质瘤（DIPG）和/或复发/难治性H3 K27M胶质瘤儿科患者中的安全性和药代动力学（PK）。
这项1期剂量递增和扩展研究纳入了接受过≥1线治疗的H3 K27M突变型胶质瘤和/或DIPG儿科患者（NCT03416530）。ONC201在第1天和第2天以3个剂量水平（DLs；-1、1和2）给药。各剂量水平内的实际给药剂量取决于体重。在所有剂量水平评估安全性；在剂量水平2进行药代动力学分析。接受每周一次ONC201（第1天）的患者作为药代动力学对照。
12例患者接受了第1天和第2天的ONC201治疗（剂量水平1，n = 3；剂量水平1，n = 3；剂量水平2，n = 6）；未发生剂量限制性毒性或≥3级治疗相关不良事件。剂量水平2的药代动力学分析（第1天-250 mg，n = 3；第1天-625 mg，n = 3；第1天和第2天-250 mg，n = 2；第1天和第2天-625 mg，n = 2）显示，Cmax、AUC0-24和AUC0-48存在变异性，不同体重组的暴露量相当。第1天和第2天给药未出现蓄积；大多数ONC201在第二次给药前已清除。Cmax在各组之间存在差异，但似乎未随第1天和第2天给药而增加。第1天和第2天给药的AUC0-48高于每周一次给药。
第1天和第2天给予ONC201在所有剂量水平均耐受性良好，且与更高的AUC0-48相关。
