TRLS-07. Pnoc016: Intratumoral Pharmacokinetics and Pharmacodynamic (Pk/Pd) Results From a Target Validation Study of a Novel Pan-Hdac and Pi3k Inhibitor, Fimepinostat, in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (Dipg), Recurrent Medulloblastoma (Mb), and Recurrent High-Grade Glioma (Hgg)

Abstract BACKGROUND An intact blood-brain barrier is a limitation to effective therapies for pediatric brain tumors. PNOC016 investigated the tumor penetration of an orally available, promising pan-HDAC and PI3K-inhibitor, fimepinostat, in high-risk pediatric brain tumors, including DIPG, MB, and HGG. Fimepinostat is active as a primary drug and via its metabolite, M2, which exhibits PI3K inhibition. METHODS Patients between 3 and 39 years old with newly diagnosed DIPG (stratum A), recurrent MB (stratum B), or recurrent HGG (stratum C) were eligible. Disease-based strata enrolled independently up to 10. Patients received 3 neoadjuvant doses before standard-of-care resection/biopsy and underwent tissue collection for PK/PD analysis. Patients continued single-agent maintenance therapy for up to 12 months with ongoing collection of circulating tumor DNA (ctDNA) from blood, quality of life (QOL) measures, survival, and response outcomes. RESULTS Thirty-one patients enrolled between August 2019 and August 2022 (n=1 replaced due to disease progression before treatment started). All patients with completed PK analysis had detectable fimepinostat (n=18), metabolite M1 (n=23), or metabolite M2 (n=24) in tumor. Median intratumoral levels of fimepinostat, M1, and M2 (nM) by stratum were as follows: stratum A-2.6, 4.9, 28.3; stratum B-9.5, 6.5, 32.4; stratum C-9.9, 10.7, 15.9. The lowest intratumoral levels were seen in stratum A. Pre-surgical blood PK positively trended with intratumoral PK. Phosphorylation and acetylation PD analyses are underway. The most common grade 3 or above related adverse events were hematologic, with platelet decrease being the most frequent (n=9). Median OS from the diagnosis for stratum A was 13 months. PFS from surgery for stratum B and C was 3 and 3 months. CONCLUSION Fimepinostat crossed the blood-brain barrier in newly diagnosed DIPG and recurrent MB and HGG. PD assessment is underway to correlate PK with biological effects. PD correlation, survival analyses, ctDNA, and QOL will be presented.