EPCT-12. PNOC015: PHASE 1 STUDY OF MTX110 (AQUEOUS PANOBINOSTAT) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PREVIOUSLY TREATED WITH RADIATION THERAPY

Abstract

OBJECTIVETo determine safety and distribution of MTX110 delivered by CED in newly diagnosed DIPG patients.METHODSDIPG patients (3–21 years) were enrolled after radiation. CED of MTX110 combined with gadoteridol was completed based on dose levels (DL) (30–90 µM with volumes ranging from 3 cc (single dose) to 2 consecutive doses of 6 cc; total number of DL=7). Catheter position was chosen to maximize tumor coverage. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks if tolerated. Quality of life (QOL) assessments using PedsQL Generic Core and Brain Tumor modules were obtained at baseline (n=5), 3-months (n=3), and end of therapy (n=2). Single-cell RNA sequencing and analysis of histone modifications was performed to assess pharmacodynamic effects on DIPG cells.RESULTSBetween May 2018-Dec 2019, 6 patients were enrolled (median age 8 years, range 5–21). Dose limiting toxicities included: grade 3 gait disturbance (DL7; cycle 1); grade 3 muscle weakness/vagus nerve disorder (DL5; cycle 4) and grade 2 intolerable dysphagia (DL7; cycle 4). Twelve CED procedures were completed at DL7 and repeated cycles ranged from 2 to 7. Infusion to distribution volume ratio was approximately 1:3.5. There were no significant changes in self-reported QOL. Parent ratings of patients’ worry (p = 0.04) and overall QOL (p = 0.03) significantly decreased at 3-months.CONCLUSIONRepeat CED of MTX110 at the highest dose is tolerable. Tissue concentrations are likely to be substantially higher compared to oral dosing. Pharmacodynamic effects will be presented.