Chronic convection-enhanced delivery of MTX110 into the brainstem for pediatric diffuse midline glioma, phase I trial

Abstract Background Diffuse Midline Gliomas (DMGs) are deadly and diffusely infiltrating gliomas. Histone deacetylase inhibitors have been found preclinically to be extremely active agents against DMGs but are limited by low blood-brain barrier penetration and systemic toxicity. Using an implantable subcutaneous pump in the abdomen connected to a catheter placed in the pons, we conducted a phase I, dose-escalation study to investigate the safety and feasibility of repeated infusions of MTX110, a water-soluble formulation of panobinostat, via convection-enhanced delivery (CED). Methods Eligible trial participants included pediatric patients 3-21 years old with newly diagnosed pontine DMG following radiation therapy. Patients underwent tumor biopsy followed by catheter and pump implantation, then received two 48-hour infusion pulses 7 days apart. Three dose levels of MTX110 infusions (30, 60, 90 mM) were studied. The infusion pump was prefilled with MTX110 and co-infused gadolinium, administered using the wireless N’Vision clinical programmer (0.2 mL/hr). Results Nine patients were treated in the study (30 mM, n = 3; 60 mM, n = 4; 90 mM, n = 2). All patients had an H3K27M mutated tumor. The treatment was well tolerated, and satisfactory tumor coverage was achieved in most patients. MRI vector analysis demonstrates reversible morphological changes in the brainstem during CED. One patient suffered a reversible, severe AE related to the infusion and tumor anatomy, and three patients had Grade 2 transient neurological deficits related to infusion (n = 3). Median PFS was 10 months from diagnosis (8-20 m) and median OS was 16.5 months (12-35m). Conclusions Chronic CED of MTX110 into the pons in DMG patients achieves satisfactory tumor coverage and is well tolerated. Further trials should evaluate chronic CED treatment with extended durations alongside non-invasive assessments.