Clinical trial NCT05394558: AsiDNA Children, Adolescents and Young Adults
Official title: A Phase Ib/II Study on AsiDNA in Association With Re-irradiation in Children, Adolescents and Young Adults With High-grade Glioma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Recurrent High-grade Glioma
Lead sponsor: Institut Curie
Sponsor class: OTHER
First posted: 2022-05-27
Enrollment: 8
Sex: ALL
Minimum age (years): 12
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: DLT(Dose-Limiting Toxicities)
timeFrame: 8 weeks after treatment initiation
measure: Activity
timeFrame: 3 months after treatment initiation
Secondary outcomes:
measure: Late Onset toxicity
timeFrame: 8 weeks and until 12 months after treatment initiation
measure: MR pattern of disease response and of potential treatment-related toxicity,
timeFrame: 3 months after treatment initiation
measure: Best objective Response Rate
timeFrame: 3 months after treatment initiation
measure: Overall survival
timeFrame: 12 months after treatment initiation
measure: Palliation of symptoms 1
timeFrame: 3 months after treatment initiation
measure: Palliation of symptoms 2
timeFrame: 3 months after treatment initiation
measure: Palliation of symptoms 2
timeFrame: 3 months after treatment initiation
measure: Pharmacokinetic parameters of AsiDNA.
timeFrame: 1 week after treatment initiation
measure: Pharmacokinetic parameters of AsiDNA.
timeFrame: 1 week after treatment initiation
measure: Pharmacokinetic parameters of AsiDNA.
timeFrame: 1 week after treatment initiation
measure: Pharmacokinetic parameters of AsiDNA.
timeFrame: 1 week after treatment initiation
measure: Pharmacokinetic parameters of AsiDNA.
timeFrame: 1 week after treatment initiation
Other outcomes:
Locations:
city: Angers
country: France
facility: Chu Angers
city: Bordeaux
country: France
facility: Chru Bordeaux
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Chu La Timone Hopital Enfants
city: Nancy
country: France
facility: Chu Nancy
city: Paris
country: France
facility: Institut Curie
city: Strasbourg
country: France
facility: Chu Strasbourg
city: Toulouse
country: France
facility: Chu Toulouse
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
References: