AsiDNA Children, Adolescents and Young Adults

NCT05394558 | Terminated Phase 1 DMC

• 1 other identifier: IC 2020-21
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 10

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.

Conditions

Recurrent High-grade Glioma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• Late Onset toxicity

  8 weeks and until 12 months after treatment initiation

• MR pattern of disease response and of potential treatment-related toxicity,

  3 months after treatment initiation

• Best objective Response Rate

  3 months after treatment initiation

• Overall survival

  12 months after treatment initiation

• Palliation of symptoms 1

  3 months after treatment initiation

Study Arms (2)

Radiotherapy + AsiDNA

EXPERIMENTAL

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

Radiotherapy

ACTIVE COMPARATOR

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

Interventions

AsiDNA DRUG

Administration of AsiDNA followed by radiotherapy

Radiotherapy; Radiotherapy + AsiDNA

Eligibility Criteria

• Age: 12 Months - 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Written informed consent from patient (depending on age) and/or parents or legal guardian;
• Patient must be ≥ 12 months and \< 25 years of age at the time of enrolment on the study;
• Available tumour material, at least paraffin embedded and/or also frozen material;
• Maximum cumulative radiation dose to optic chiasm and optic nerve \< 56 Gy and \< 54 Gy to upper cervical spine (at level C1);
• Life expectancy \> 2 months at Screening;
• Patient must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) score of ≥ 50 % , not taking into account neurological deficit;
• No significant abnormality on laboratory tests at Screening, including:
• Haemoglobin \> 9 g/dL;
• Neutrophils \> 1.0 x 109/L;
• Platelets \> 100 x 109/L;
• Total bilirubin \< 1.5 x ULN;
• AST and ALT\< 2.5 x ULN;
• Serum creatinine \< 1.5 x ULN for age;
• Normal coagulation tests.
• 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;

Sponsors & Collaborators

• Institut Curie: lead

Study Sites (10)

Chu Angers

Angers, 49033, France

Location

Chru Bordeaux

Bordeaux, 33076, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

Centre Leon Berard

Lyon, 69373, France

Location

Chu La Timone Hopital Enfants

Marseille, 13385, France

Location

Chu Nancy

Nancy, 54500, France

Location

Institut Curie

Paris, 75005, France

Location

Chu Strasbourg

Strasbourg, 67098, France

Location

Chu Toulouse

Toulouse, 31059, France

Location

Gustave Roussy

Villejuif, 94800, France

Location

MeSH Terms

Conditions

Glioma

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2021
• First Posted: May 27, 2022
• Study Start: May 27, 2022
• Primary Completion: September 20, 2023
• Study Completion: September 20, 2023
• Last Updated: December 26, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months
• 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).

Locations

FR (10)