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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
8
Administration of AsiDNA followed by radiotherapy
Chu Angers
Angers, France
Chru Bordeaux
Bordeaux, France
Centre Oscar Lambret
Lille, France
Centre Leon Berard
Lyon, France
Chu La Timone Hopital Enfants
Marseille, France
Chu Nancy
Nancy, France
Institut Curie
Paris, France
Chu Strasbourg
Strasbourg, France
Chu Toulouse
Toulouse, France
Gustave Roussy
Villejuif, France
DLT(Dose-Limiting Toxicities)
Dose-limiting toxicities, i.e. grade ≥ 3 toxicities according to NCI-CTCAE version 5.0, considered as at least possibly related to the treatment during the 8 weeks after treatment initiation.
Time frame: 8 weeks after treatment initiation
Activity
3-month progression-free survival (PFS), i.e. the probability for a patient to be alive and free of disease progression based on clinical or radiological criteria, or death from any cause at 3 months after inclusion in the study. Radiological progression will be assessed using RAPNOHGG criteria. Patients lost to follow-up will be counted as failures at the last assessment date.
Time frame: 3 months after treatment initiation
Late Onset toxicity
Late-onset toxicity, defined as any toxicity, i.e. any AE considered as at least possibly related to treatment, that occurs more than 8 weeks after treatment initiation;
Time frame: 8 weeks and until 12 months after treatment initiation
MR pattern of disease response and of potential treatment-related toxicity,
MR pattern of disease response and of potential treatment-related toxicity, assessed by central review based on morphological and functional imaging features present on the various MR examinations;
Time frame: 3 months after treatment initiation
Best objective Response Rate
Best objective response rate, defined as the percentage of patients with complete or partial responses according to RAPNO criteria as assessed by the investigator
Time frame: 3 months after treatment initiation
Overall survival
Overall survival, defined as the time from inclusion in the study to death from any cause. Patients alive or lost to follow-up at the cut-off date will be censored at the last date they were known to be alive;
Time frame: 12 months after treatment initiation
Palliation of symptoms 1
Palliation of symptoms, assessed using the Lansky Play Scale (LPS) or Karnofsky score of ≥ 50 %
Time frame: 3 months after treatment initiation
Palliation of symptoms 2
Performance Status (KPS)
Time frame: 3 months after treatment initiation
Palliation of symptoms 2
Need for corticosteroids and/or bevacizumab
Time frame: 3 months after treatment initiation
Pharmacokinetic parameters of AsiDNA.
Maximal observed drug concentration (Cmax);
Time frame: 1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.
absorption and elimination half-life (t1/2))
Time frame: 1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.
time to reach maximum observed drug concentration (Tmax);
Time frame: 1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.
area under the curve (AUC0-t (experimental time points)
Time frame: 1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.
AUC0-∞ (extrapolated to infinity)
Time frame: 1 week after treatment initiation
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