HGG comprises diffuse midline gliomas (DMG), including diffuse infiltrating brainstem glioma
(DIPG), characterised by histone gene mutations, as well as non-DM HGGs mainly in non-midline
supratentorial areas, with distinct molecular abnormalities. First-line treatment comprises
surgery when doable (non-DM HGGs), and radiotherapy in all cases. Chemotherapy or other drugs
in clinical trials may be added during and/or after radiotherapy depending on the HGG
subtype. The recurrence rate is nevertheless high in all paediatric and adolescent HGGs. If
the time interval between the end of first-line radiotherapy and relapse is long enough,
re-irradiation often provides good palliation of symptoms, delays disease progression,
improves quality of life and has minimal and manageable toxicity. Nevertheless, strategies to
increase efficacy without increasing toxicity in the treatment of recurrent paediatric HGG
are much needed.
AsiDNA™ is a DNA repair inhibitor that increases the vulnerability of tumour cells to
irradiation without increasing toxicity in healthy tissues. Its novel mechanism of action,
based on perturbation of the DNA damage recognition steps in DNA repair, makes its activity
specific to tumour cells. Intravenous administration of AsiDNA is currently being
investigated in adults with advanced solid tumours. The MTD was not reached during the
escalating dose study on the safety, pharmacokinetics and pharmacodynamics of AsiDNA
administered as a 1-hour infusion, however an optimal dose range (400-600 mg) was identified
for further development, based on the favourable safety and PK profiles. Preclinical studies
on AsiDNA added to radiotherapy have shown increased survival and no increase in short- or
long-term toxicity due to the high doses of irradiation.
The study will provide paediatric patients who have recurrent HGG with early access to
innovation, even during the early drug development stage in adults.