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

doi:10.1093/noajnl/vdac073

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

Neurooncol Adv. 2022 May 20;4(1):vdac073. doi: 10.1093/noajnl/vdac073. eCollection 2022 Jan-Dec.

Authors

Sabine Mueller¹, Tabitha Cooney², Xiaodong Yang³, Sharmistha Pal⁴, Ralph Ermoian⁵, Amar Gajjar⁶, Xiaowei Liu⁷, Komal Prem⁸, Charles G Minard⁹, Joel M Reid⁸, Marvin Nelson¹⁰, Daphne Haas-Kogan⁴, Elizabeth Fox⁶, Brenda J Weigel¹¹

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, California.
² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.
³ Department of Neurosurgery, University of California, San Francisco, San Francisco, California.
⁴ Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
⁵ Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington.
⁶ St. Jude Children's Research Hospital, Memphis, Tenesse.
⁷ Children's Oncology Group, Monrovia, California.
⁸ Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota.
⁹ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas.
¹⁰ Children's Hospital Los Angeles, Radiology, Keck USC School of Medicine, Los Angeles, California.
¹¹ Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

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 T_max, T_1/2 and Cl_p 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 AUC_0-8h (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.

Keywords: DIPG; Wee1; adavosertib; radiation-sensitization; toxicity.

Abstract

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