AsiDNA Children, Adolescents and Young Adults (AsiDNA)

A Phase Ib/II Study on AsiDNA in Association With Re-irradiation in Children, Adolescents and Young Adults With High-grade Glioma

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 Overview

• Status: Terminated
• Conditions: Recurrent High-grade Glioma
• Intervention / Treatment: Drug: AsiDNA

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Angers, France, 49033
    • CHU Angers
  • Bordeaux, France, 33076
    • Chru Bordeaux
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13385
    • Chu La Timone Hopital Enfants
  • Nancy, France, 54500
    • CHU Nancy
  • Paris, France, 75005
    • Institut Curie
  • Strasbourg, France, 67098
    • CHU Strasbourg
  • Toulouse, France, 31059
    • CHU Toulouse
  • Villejuif, France, 94800
    • Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 24 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiotherapy + AsiDNA; Patients will receive the IMP which is the AsiDNA (etidaligide). AsiDNA will be administered intravenously as a 1-hour infusion. All patients will receive a loading dose for three consecutive days, with Day 1 being the start day of radiotherapy, followed by once weekly administrations during 11 weeks. The infusion of AsiDNA should be administered between 4 and 6 hours before the planned start of radiotherapy. After the administration of AsiDNA, Patients with DIBG will receive a total dose of 18 Gy, delivered in 10 fractions of 1.8 Gy, i.e. 5 fractions per week for 2 weeks, starting on Day 1. Patients with supratentorial non-DMG or DMG will receive a total dose of 36 Gy, delivered in 20 fractions of 1.8 Gy, i.e. 5 fractions per week for 4 weeks, starting on Day 1.	Drug: AsiDNA; Administration of AsiDNA followed by radiotherapy
Active Comparator: Radiotherapy; Patients with DIBG will receive a total dose of 18 Gy, delivered in 10 fractions of 1.8 Gy, i.e. 5 fractions per week for 2 weeks, starting on Day 1. Patients with supratentorial non-DMG or DMG will receive a total dose of 36 Gy, delivered in 20 fractions of 1.8 Gy, i.e. 5 fractions per week for 4 weeks, starting on Day 1.	Drug: AsiDNA; Administration of AsiDNA followed by radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	3 months after treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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;	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;	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	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;	12 months after treatment initiation
Palliation of symptoms 1	Palliation of symptoms, assessed using the Lansky Play Scale (LPS) or Karnofsky score of ≥ 50 %	3 months after treatment initiation
Palliation of symptoms 2	Performance Status (KPS)	3 months after treatment initiation
Palliation of symptoms 2	Need for corticosteroids and/or bevacizumab	3 months after treatment initiation
Pharmacokinetic parameters of AsiDNA.	Maximal observed drug concentration (Cmax);	1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.	absorption and elimination half-life (t1/2))	1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.	time to reach maximum observed drug concentration (Tmax);	1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.	area under the curve (AUC0-t (experimental time points)	1 week after treatment initiation
Pharmacokinetic parameters of AsiDNA.	AUC0-∞ (extrapolated to infinity)	1 week after treatment initiation

Collaborators and Investigators

• Sponsor: Institut Curie

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2022
• Primary Completion (Actual): September 20, 2023
• Study Completion (Actual): September 20, 2023

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: May 23, 2022
• First Posted (Actual): May 27, 2022

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: IC 2020-21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sponsor will share de-identified data sets. Documents generated under the project will be disseminated in accordance with Institut Curie policies.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months
• IPD Sharing Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No