PNOC015: Repeated convection-enhanced delivery of MTX110 (aqueous panobinostat) in children with newly diagnosed diffuse intrinsic pontine glioma

Abstract

Objective To determine the safety, tolerability and distribution of MTX110 (aqueous panobinostat) delivered by convection enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT). Methods Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across seven dose levels (DL) (30-90 µM; volumes ranging from 3 mL to two consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4-8 weeks. Quality of life (QOL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy. Results Between May 2018-March 2020 seven patients, who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5-21). Three patients experienced dose-limited toxicities. Four grade 3 treatment related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% CI: 14.8-not reached). Progression free survival was 4-14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6–81.0%. Increased CED infusions was negatively associated with self-reported QOL assessments. Conclusion Repeat CED of MTX110 with real time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.

Diffuse Midline Gliomas: Challenges and New Strategies in a Changing Clinical Landscape

“…This study further highlighted the importance of delivery monitoring, achieved here with PET imaging of the radiolabeled therapeutic agents. This work using a theranostic and similar experience using surrogate tracers reveal a variable degree of overlap of drug distribution with tumor volume, which can present a challenge for successful therapeutic deliveries [ 4 , 60 ].…”

“…A recently published phase I clinical trial, however, failed to show any significant clinical benefit in young patients with DIPG or other DMGs because of the development of significant systemic dose-limiting toxicities (e.g., myelosuppression and thrombocytopenia) that made dose escalation not possible [ 81 ]. CED rose as a possible solution to this issue: repeated CED of MTX110 (a soluble HDAC inhibitor) was shown to be tolerable and achieved a median overall survival of 26.1 months in seven children with previously radiated DIPG [ 60 ].…”

Current landscape of treating different cancers using nanomedicines: Trends and perspectives

“…Encapsulating drugs in nanobase carriers improves their solubility and allows for more effective delivery using convection‐enhanced delivery (CED). Clinical trial Phase I and II studies investigated the side effects of panobinostat nanoparticle formulation termed MTX110 in treating patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (Mueller et al, 2023). The MTX110 is composed of panobinostat, an active ingredient combined with several excipients such as hydroxypropyl‐β‐cyclodextrin, sodium citrate dihydrate, and citric acid to improve their solubility.…”

“…The improved solubility of panobinostat enables the effective administration of MTX110 via intratumoral CED. The clinical trial study enrolled seven patients diagnosed with DIPG, and the safety and tolerability aspects of MTX110 were assessed for up to 24 months (Mueller et al, 2023). The results suggest that this nano‐formulation was safe and tolerable for enrolled patients.…”

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults

“…Most toxicities patients experienced were of neurological etiology. Compared with historical controls, the OS with a median of 26.1 months was encouraging but due to the limited number of participants must be interpreted with caution ( 63 ). New HDAC inhibitors are under clinical investigation to overcome the drawbacks from panobinostat, among them, quisinostat and romidepsin.…”