Mueller Sabine, Cooney Tabitha, Yang Xiaodong, Pal Sharmistha, Ermoian Ralph, Gajjar Amar, Liu Xiaowei, Prem Komal, Minard Charles G, Reid Joel M, Nelson Marvin, Haas-Kogan Daphne, Fox Elizabeth, Weigel Brenda J
Department of Neurology, University of California, San Francisco, San Francisco, California.
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.
Neurooncol Adv. 2022 May 20;4(1):vdac073. doi: 10.1093/noajnl/vdac073. eCollection 2022 Jan-Dec.
Children with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress.
Using a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m alternating weeks, 50 mg/m alternating with weeks of every other day, 50 mg/m, then 95, 130, 160, 200 mg/m) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage.
A total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3-21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean T, T and Cl on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control.
Adavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.
弥漫性脑桥内在型胶质瘤（DIPG）患儿的预后很差。阿伐替尼（AZD1775）是一种口服、可穿透血脑屏障的Wee1激酶抑制剂。辐射诱导的复制应激可增强其对DIPG的临床前疗效。
采用滚动六期设计，评估了7个阿伐替尼剂量水平（DLs）（50mg/m² 隔周给药、50mg/m² 与隔日给药周交替、50mg/m²，然后是95、130、160、200mg/m²）。阿伐替尼仅在颅脑放射治疗（CRT）当天给药。CRT的持续时间（30次分割给予54Gy；6周）构成剂量限制毒性（DLT）期。终点包括耐受性、药代动力学、总生存期（OS）以及作为DNA损伤标志物的外周血γH2AX水平。
共纳入46例新诊断的DIPG合格患者[中位（范围）年龄6（3 - 21）岁；52%为女性]。阿伐替尼的推荐2期剂量（RP2D）为CRT期间200mg/m²/天。剂量限制毒性包括谷丙转氨酶升高（n = 1，DL4）和中性粒细胞减少（n = 1，DL7）。第1天的平均Tmax、T1/2和Cl分别为2小时、4.4小时和45.2L/小时/平方米。与第1天的AUC相比，第5天观察到阿伐替尼有适度蓄积（蓄积比 = 1.6）。OS为11.1个月（95%CI：9.4，12.5），与历史对照无差异。
阿伐替尼联合CRT在新诊断的DIPG患儿中耐受性良好，然而，与历史对照相比，并未改善OS。这些结果可为未来高危癌症患儿的试验设计提供参考。
