Wee1 kinase inhibitor adavosertib with radiation in newly diagnosed diffuse intrinsic pontine glioma: A Children's Oncology Group phase I consortium study

Sabine Mueller, Tabitha Cooney, Xiaodong Yang, Sharmistha Pal, Ralph Ermoian, Amar Gajjar, Xiaowei Liu, Komal Prem, Charles G. Minard, Joel M. Reid, Marvin Nelson, Daphne Haas-Kogan, Elizabeth Fox, Brenda J. Weigel

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Methods: Using a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) 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. Results: 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/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control. Conclusion: 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.

Original languageEnglish (US)
Article numbervdac073
JournalNeuro-Oncology Advances
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2022

Keywords

  • adavosertib
  • DIPG
  • radiation-sensitization
  • toxicity
  • Wee1

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery

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