TRLS-14. Pnoc022 Report: A Combination Therapy Trial Using an Adaptive Platform Design for Patients With Diffuse Midline Glioma at Initial Diagnosis, Post-Radiation Therapy, or Progression

Abstract BACKGROUND Children with diffuse midline glioma (DMG) face dismal prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, international trial investigating the efficacy of combination therapies for patients with DMG. We present an early report on Cohorts 1-3, treated with ONC201, an orally available ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor. METHODS Patients aged 2-39 years enrolled pre-radiation (Cohort 1), 4-14 weeks post-radiation (Cohort 2), or at progression (Cohort 3). Patients were randomized to receive ONC201 or paxalisib prior to surgery when biopsy was indicated and/or in combination with radiation when radiation was indicated. Those not planned for biopsy were required to submit archival tissue. All received maintenance therapy with weekly ONC201 (weight based adult equivalent of 625 mg) and daily paxalisib (27 mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and biologic correlates were collected. RESULTS Between November 2021 and September 2023, 132 patients met critera for study therapy (Cohort 1=33; Cohort 2=69; Cohort 3=30; median age 9 years range 2-37, n=73 female 55%; n=86 pontine 65%). Median overall survival (OS) from diagnosis is 13.2 months in Cohort 1 (lower 95% CI 11.1) and 15.8 months in Cohort 2 (lower 95% CI 13.9). Median OS from progression is 8.8 months in Cohort 3 (lower 95% CI 8.6). Most common non-hematologic grade 3 and above treatment-related adverse events (TRAE) were maculopapular rash (n=12); mucositis (n=8); colitis and hyperglycemia (n=7). Most common serious TRAEs were colitis (n=7) and hyperglycemia (n=6). We have collected 169 CSF samples and 600 plasma samples for ctDNA. Cohort 2 PK from CSF and plasma and CSF metabolomics and somatic mutation landscapes are being finalized. CONCLUSIONS We will present somatic mutation profiles, PK analysis, ctDNA, and metabolic signatures from the CSF in association with toxicity, survival, and tumor response via central imaging review.