Recurrent High-grade Glioma
Conditions
Brief summary
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.
Interventions
DRUGAsiDNA
Administration of AsiDNA followed by radiotherapy
Sponsors
Institut Curie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
12 Months to 24 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent from patient (depending on age) and/or parents or legal guardian; 2. Patient must be ≥ 12 months and \< 25 years of age at the time of enrolment on the study; 3. Recurrent high-grade glioma (HGG), including diffuse midline glioma (DMG) and non-DMG, based on RAPNO criteria confirmed by central radiological review, with or without histology if biopsy performed prior to inclusion; 4. Available tumour material, at least paraffin embedded and/or also frozen material; 5. For DMG and non-DMG HGG, prior radiation dose prescribed ≤ 60 Gy, completed at least 6 months prior to inclusion, with stable disease; 6. Maximum cumulative radiation dose to optic chiasm and optic nerve \< 56 Gy and \< 54 Gy to upper cervical spine (at level C1); 7. Life expectancy \> 2 months at Screening; 8. Patient must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) score of ≥ 50 % , not taking into account neurological deficit; 9. No significant abnormality on laboratory tests at Screening, including: 1. Haemoglobin \> 9 g/dL; 2. Neutrophils \> 1.0 x 109/L; 3. Platelets \> 100 x 109/L; 4. Total bilirubin \< 1.5 x ULN; 5. AST and ALT\< 2.5 x ULN; 6. Serum creatinine \< 1.5 x ULN for age; 7. Normal coagulation tests. 10. No organ toxicity \> grade 2 according to NCI CTCAE version 5.0 classification, notably cardiovascular, pulmonary or renal diseases, including congenital QT prolongation syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite appropriate treatment, interstitial pulmonary disease, pulmonary hypertension; 11. Negative serum pregnancy test for women of child-bearing potential, and highly effective birth control method for male and female patients of reproductive potential; 12. Patients covered by social security or health insurance in compliance with the national legislation relating to biomedical research.
Exclusion criteria
5\. Prior radiation dose prescribed \> 60 Gy; 6. Massive intra-tumour haemorrhage; 7. Pseudoprogression (including after central review); 8. Metastatic relapse; 9. Other anticancer treatment, on-going or within less than 4 weeks prior to inclusion; 10. Prior or concurrent malignant disease, other than HGG, diagnosed or treated within 5 years prior to inclusion; patients with CMMRD are eligible; 11. Uncontrolled intercurrent disease or active infection; 12. Concomitant disease or other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study; 13. Patients unable to comply with the protocol for any reason; 14. Organ toxicity \> grade 2 according to NCI CTCAE version 5.0 classification, notably cardiovascular, pulmonary or renal diseases, including congenital QT prolongation syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite appropriate treatment, interstitial pulmonary disease, pulmonary hypertension 15. Breastfeeding or pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLT(Dose-Limiting Toxicities) | 8 weeks after treatment initiation | 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. |
| Activity | 3 months after treatment initiation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best objective Response Rate | 3 months after treatment initiation | Best objective response rate, defined as the percentage of patients with complete or partial responses according to RAPNO criteria as assessed by the investigator |
| Overall survival | 12 months after treatment initiation | 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; |
| Late Onset toxicity | 8 weeks and until 12 months after treatment initiation | 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; |
| Palliation of symptoms 2 | 3 months after treatment initiation | Performance Status (KPS) |
| Pharmacokinetic parameters of AsiDNA. | 1 week after treatment initiation | Maximal observed drug concentration (Cmax); |
| Palliation of symptoms 1 | 3 months after treatment initiation | Palliation of symptoms, assessed using the Lansky Play Scale (LPS) or Karnofsky score of ≥ 50 % |
| MR pattern of disease response and of potential treatment-related toxicity, | 3 months after treatment initiation | 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; |
Countries
France
Outcome results
None listed