Description of Individual Radiosensitivity With Molecular Biomarkers in a Pediatric Oncology Population (ARPEGE BioM)

Integrative Molecular Analysis of Individual Radiosensitivity Among a Population of Pediatric Patients Treated With Radiation in Eastern France.

This study aims to explore prospectively the distribution of individual radiosensitivity in the pediatric population and to determine the predictive power of individual radiosensitivity biomarkers from an immunofluorescence technique on primary dermal fibroblasts

Study Overview

• Status: Terminated
• Conditions: Cancer-related Problem/Condition
• Intervention / Treatment: Other: skin biopsy

Detailed Description

900 children and adolescents benefit from radiation each year in France. The mean age at diagnosis is 5 years; life expectancy for the 80% of them who could cure is long, and the incidence of radiation-related acute and mainly late complications - not evaluated to date - could exceed that of adults. Dysfunction of irradiated organs and growth disorders are specific to the pediatric subpopulation. Individual radiosensitivity of children and adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. These complications are largely attributable to inter individual constitutional variations of cellular response to DNA damage.

Subject to radiation-induced DNA damages such as double-strand breaks (DSB), cells reacts by triggering a whole series of phosphorylation events coordinated within multi protein complexes whose interplay is still misknown (DNA damage response i.e. DDR). Indirect Immunofluorescence cell scanning has revolutionized radiation biology research by permitting the detection of individual DSB in each cell nucleus in a dose range from 1 mGy to 10 Gy. This technique has notably confirmed that yield of unrepaired DSB is correlated with cell RS. From a broad spectrum of human radiosensitive skin fibroblast cell lines, the Inserm CRU 1052 team proposed a general model of DSB signaling and repair and a molecular assay to stratify patients according to their individual RS.

ARPEGE biomarqueurs is a prospective multicenter study to prospectively evaluate with this assay the RS of children and adolescents treated over a year in all pediatric oncology departments of the Region Grand Est and set thresholds in this population. 150 children are thus potentially includable in different centers. The assay will be performed on primary fibroblasts cultured from a skin biopsy taken at diagnosis. The RS of patients will be measured in blind. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease ...) will be reported. In parallel the RT-acute toxicity will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years.

Screening hypersensitive patients would be a major step forward in the management of cancers, opening a view to personalized medicine.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Besançon, France, 25 000
    • CHU de Besançon
  • Dijon, France, 21 000
    • CHU de Dijon
  • Dijon, France, 21 000
    • Georges-François-Leclerc
  • Lyon, France, 69 000
    • Centre Leon Berard
  • Reims, France, 51 100
    • CHU de Reims
  • Strasbourg, France, 67 065
    • Centre Paul Strauss
  • Strasbourg, France, 67 098
    • Hopital de Hautepierre
  • Toulouse, France, 31059
    • CHRU Toulouse
  • Toulouse, France, 31059
    • IUCT Oncopole
  • Vandoeuvre-lès-Nancy, France, 54 500
    • Institut de Cancérologie de Lorraine
  • Vandoeuvre-lès-Nancy, France, 54500
    • CHRU Nancy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children < 18 years old
• Patient with an indication of radiotherapy
• Patient must be affiliated to a social security system
• Patient under parental autority
• Ability to provide an informed written consent form

Exclusion Criteria:

• Contraindications for skin biopsy
• Contraindications for radiotherapy
• Referred to palliative radiotherapy
• Prior radiotherapy in the same area
• Indication of hypofractionated radiotherapy
• Patient monitoring impossible
• Patients deprived of liberty or under supervision

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: ARPEGE BioM; N/A (not a randomized study)	Other: skin biopsy; skin biopsy performed prior radiation to characterize in blind the individual radiosensitivity of the patient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
skin fibroblast radiosenstivity	residual double-strand breaks 24h after ex vivo radiation assessed with indirect immunofluorescence (gammaH2AX marker).	up to 5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
early cutaneous, mucosal and hematological early radiation toxicity	early radiation toxicity pattern assessed according to CTACAE v4.0 scale	3 months
pATM nucleoshuttling	pATM foci counted 10 minutes and 1 hour after ex vivo radiation assessed with indirect immunofluorescence (pATM marker).	up to 5 months
mean micronuclei number	micronuclei counted 24 hours after ex vivo radiation assessed with indirect immunofluorescence (DAPI marker).	up to 5 months
late radiation toxicity	deterministic tissue effects as well as secondary malignancies occurring in radiation field more than 3 months and up to 15 years after RT, using CTCAE v4.0 scale	15 years

Collaborators and Investigators

• Sponsor: Institut de Cancérologie de Lorraine
• Investigators: Principal Investigator: BERNIER CHASTAGNER VALERIE, MD, Institut de Cancérologie de Lorraine

Publications and helpful links

General Publications

• Bernier-Chastagner V, Hettal L, Gillon V, Fernandes L, Huin-Schohn C, Vazel M, Tosti P, Salleron J, Francois A, Cerimele E, Perreira S, Peiffert D, Chastagner P, Vogin G. Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE). BMC Cancer. 2018 Jul 6;18(1):719. doi: 10.1186/s12885-018-4652-7.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Actual): February 7, 2020
• Study Completion (Actual): February 7, 2020

Study Registration Dates

• First Submitted: July 6, 2016
• First Submitted That Met QC Criteria: July 6, 2016
• First Posted (Estimate): July 11, 2016

Study Record Updates

• Last Update Posted (Actual): February 12, 2021
• Last Update Submitted That Met QC Criteria: February 9, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: radiotherapy; radiosensitivity; pediatric oncology
• Other Study ID Numbers: 2015-A00975-44

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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