Icf - delivery

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of paediatric tumours responsible for most childhood brain tumour deaths. Current standard of care (SOC) is fractionated focal radiotherapy given with palliative intent, providing transient improvement of symptoms. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Despite an increase in the understanding of the biology, and numerous studies of systemic chemotherapy, there has been no improvement in survival. This failure is, in part, due to the blood-brain barrier (BBB) and blood-tumour barrier (BTB), preventing therapeutic concentrations of drug from penetrating the tumour. New therapeutics are urgently needed. Convection-enhanced drug delivery (CED) overcomes the BBB and BTB by infusing drugs under controlled pressure directly into the tumour via implanted micro-catheters. Our proposal combines a preclinical active drug, panobinostat, specifically formulated for CED (MTX110), using the novel implantable Renishaw Drug Chronic Delivery System (RDDS) in paediatric DMG confined to the pons (previous DIPG) following standard fractionated radiotherapy. We have previously demonstrated safety and feasibility of repeated administrations of carboplatin and sodium valproate directly into the DMG via the RDDS in patients treated on a compassionate use basis. MTX110 is a soluble form of the pan-HDAC inhibitor, panobinostat, designed for intratumoural administration by CED to bypass the BBB and BTB allowing for increased tumour drug concentrations. Panobinostat has been shown to be highly effective at reducing tumour growth in preclinical DMG patient-derived xenograft (PDX) models. The safety, tolerability, and recommended Phase 2 dose of MTX110 after repeated intratumoural CED infusions have been evaluated in patients with DIPG in two investigator-initiated trials (PNOC015). Previous CED trials have used a single catheter/single use system which resulted in the inability to deliver repeated treatment cycles and inadequate tumour coverage. We hypothesize that repeated CED of MTX110 following standard of care radiotherapy is safe and will provide a survival benefit in children with newly diagnosed pontine DMG using a novel implantable RDDS. Up to 12 evaluable paediatric patients with DMG will be enrolled. Following implantation of the 4 catheter RDDS, patients will receive 48-hour MTX110 infusions every 2-3 weeks until tumour progression. The maximum tolerated infusion rate per catheter and optimal MTX110 concentration have been predetermined in previous studies. On day 1 and 2 of each cycle, infusions will be delivered sequentially via each catheter for a maximum of 6 hours within a 24-hour period in order to reach the planned volume of distribution (Vd) and provide optimal tumour coverage. Infusions can be reduced/stopped or adjusted by catheter for future cycles, if severe adverse events occur (AEs). The primary endpoints of this study are the frequency and nature of AEs related to MTX110 CED and the RDDS device as well as feasibility of implantation and delivery. Secondary objectives include measuring the brain distribution of infusate using co-infused gadolinium-enhanced magnetic resonance imaging (MRI), tumour progression, survival, and quality of life. The study builds upon published data for MTX110 CED and the RDDS chronic delivery device in paediatric DMG. This safety and feasibility study of the combination of these two innovative interventions in this proof-of-concept trial would support future trials not only in paediatric DMG but in other child and adult brain tumours and non-cancer neurological conditions.