Midatech Pharma PLC announced that following completion of one month of treatment with MTX-110 in the first patient, its Phase I study of MTX-110 in recurrent glioblastoma (rGB) (NCT 05324501) will continue with a planned dose escalation following a positive recommendation from the study's Data Safety Monitoring Board (DSMB). The Phase I study, the MAGIC-G1 study, is an open-label, dose escalation study designed to assess the feasibility and safety of intermittent infusions of MTX-110 administered by convection enhanced delivery (CED) via implanted refillable pump and catheter. The study aims to recruit two cohorts, each with a minimum of four patients; the first cohort will receive MTX-110 only and the second cohort will receive MTX-110 in combination with lomustine.

The first patient in the study was dosed at 60uM of MTX-110 via direct-to-tumour delivery and has received four 48-hour infusions over a period of four weeks. No treatment-associated adverse events were noted in the patient during this period. Following successful completion of the first month of treatment, the DSMB reviewed the available data on 11 January 2023 and recommended dose escalation in the study to 90uM.

This dose is expected to be the optimal one of MTX-110 and is the one currently being used in the ongoing Phase I study of patients with diffuse intrinsic pontine glioma (DIPG) at the Columbia University, USA. Patient 1 continues treatment as per the study protocol and patient 2 is expected to start treatment by the end of January 2023 and will receive the 90uM dose. GB is the most common and devastating primary malignant brain tumour in adults encompassing 14.3% of all primary brain and central nervous system neoplasms. With an incidence of approximately 3.2 per 100,000 population in the USA, approximately 12,300 people in the USA will be diagnosed with GB per annum.

Standard of care for treatment of GB is typically maximal surgical resection followed by radiotherapy plus concomitant and maintenance temozolomide chemotherapy with or without the Optune® device. Notwithstanding, the multidisciplinary approach, almost all patients experience tumour progression with nearly universal mortality. The median survival from initial diagnosis is less than 21 months.

Currently, no standard of care is established for rGB. MTX110 is a water-soluble form of panobinostat free base, achieved through complexation with hydroxypropyl-ß-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 favorable 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 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).