Abstract
BACKGROUND
Subjects diagnosed with diffuse midline glioma (DMG) face extremely poor prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, multi-institutional, international trial that aims to investigate combination therapies for patients with DMG. Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2).
METHODS
Children and young adults aged 2-39 years were enrolled 4-14 weeks post-radiation and received maintenance therapy with weekly ONC201 (weight-based adult equivalent of 625 mg) and daily paxalisib (27mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and circulating tumor DNA (ctDNA) were collected at multiple timepoints.
RESULTS
Sixty-eight patients with biopsy-proven DMG enrolled between November 2021 and June 2023 (median age 9 years [range 3-37], n=41 female [60%]). Site-determined tumor location includes 47 pontine (69%), 16 thalamic (24%), 3 spinal cord (4%) and 2 cerebellar (2%) DMGs. Median overall survival (OS) from time of diagnosis is 16.5 months (lower 95% CI 11.6 months) with a median follow-up time of 9.9 months (95% CI: 8.5, 11.4). The H3K27M mutation was found in 91% (n=50) and 9% were classified as H3K27-altered (n=5). TP53 was mutant in 50% (22/44 available). Most common grade 3 and above treatment-related adverse events were neutrophil count decreased (n=4); mucositis (n=3); and, colitis, DRESS, lymphocyte count decreased, hyperglycemia, hypokalemia (n=2). PK and ctDNA analyses are being finalized.
CONCLUSIONS
The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.