Midatech Pharma PLC, an R&D biotechnology company focused on improving the bio‐delivery and biodistribution of medicines, announced encouraging headline results from a Phase I study at the
University of California, San Francisco (“UCSF”) in patients with Diffuse Intrinsic Pontine Glioma (“DIPG”) (the “UCSF study” NCT03566199).
The primary endpoint of the study was to determine the dosage regimen to be used in a proposed Phase II study of the safety and efficacy of MTX110 in patients with DIPG. Preliminary high‐level data from the UCSF study supports a dose of between 60μM and 90μM of MTX110, depending upon patient tolerance over the course of 12 infusions in Phase II.
In total, seven patients were recruited into the UCSF study. Patients were newly diagnosed with DIPG and received focal external beam radiation therapy four to 14 weeks before commencement of MTX110 treatment. Eligibility required a pontine location of the tumour with diffuse involvement of at least two thirds of the pons and no evidence of metastatic disease. Patients were not excluded by total tumour volume. MTX110 was administered directly into the tumour via a micro‐catheter using convection enhanced delivery (“CED”) with gadolinium‐enhanced intra‐operative MRI to guide and track drug distribution to the tumour. Patients could receive up to 12 cycles of treatment every four to eight weeks. The dose was escalated between and within patients as tolerated initially by increasing the infusion volume at a concentration of 30μM MTX110 and then with higher drug concentrations of 60μM and 90μM as the sixth and seventh dose increments, respectively.
The proposed Phase II trial is expected to evaluate overall survival at 12 months as the primary endpoint in 19 evaluable patients. The planned design is single arm and statistically powered for comparisons with defined historical survival data. MTX110 is expected to be delivered using an alternative CED catheter system that enables regular drug infusions directly into the tumour without a need for repeated surgery.
MTX110 is a water‐soluble form of panobinostat free base, achieved through complexation with hydroxypropyl‐β‐cyclodextrin (HPBCD), that enables convection‐enhanced delivery (CED) at potentially chemotherapeutic doses directly to the site of the tumour. Panobinostat is a hydroxamic acid and acts as a non‐selective histone deacetylase inhibitor (pan‐HDAC inhibitor). The currently available oral formulation of panobinostat lactate (Farydak®) is not suitable for treatment of brain cancers owing to poor blood‐brain barrier penetration and inadequate brain drug concentrations. Based on favourable translational science data, MTX110 is being evaluated clinically as a treatment for DIPG (NCT03566199, NCT04264143) and recurrent medulloblastoma (NCT04315064), and preclinically for treatment of glioblastoma (SNO 2020 Abstract TMOD‐27). MTX110 is delivered directly into and around the patient’s tumour via a catheter system (e.g. CED or fourth ventricle infusions) to bypass the blood‐brain barrier. This technique exposes the tumour to very high drug concentrations while simultaneously minimising systemic drug levels and the potential for toxicity and other side effects. Panobinostat has demonstrated high potency against DIPG tumour cells in in vitro and in vivo models, and in a key study it was the most promising of 83 anticancer agents tested in 14 patient‐derived DIPG cell lines (Grasso et al, 2015. Nature Medicine 21(6), 555‐559).