An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma
- Conditions
- Childhood Ependymoma
- Interventions
- Radiation: Conformal radiotherapyDrug: VEC + HD-MTXDrug: VECDrug: Chemotherapy + ValproateDrug: 16 weeks of VEC + CDDPDrug: ChemotherapyRadiation: conformal radiotherapy +/- boost
- Registration Number
- NCT02265770
- Lead Sponsor
- Centre Leon Berard
- Brief Summary
The overall aim of this project is to improve the outcome of patients diagnosed with ependymoma by improving and harmonising the staging and the standard of care of this patient population and to improve the investigators understanding of the underlying biology thereby informing future treatment.
The program will evaluate new strategies for diagnosis (centralized reviews of pathology and imaging) and new therapeutic strategies in order to develop treatment recommendations.
Patients will be stratified into different treatment subgroups according to their age, the tumour location and the outcome of the initial surgery. Each subgroup will be studied in a specific randomised study to evaluate the proposed therapeutic strategies.
Stratum 1:
The aim of the stratum 1 is to evaluate the clinical impact of 16-week chemotherapy regimen with VEC-CDDP following surgical resection and conformal radiotherapy in terms of progression free survival in patients who are \> 12 months and \< 22 years at diagnosis, with completely removed intra cranial Ependymoma.
Stratum 2:
This stratum is designed as a phase II trial for patients who are \> 12 months and \< 22 years at diagnosis, with residual disease to investigate the possible activity of HD-MTX by giving to all patients the benefit of VEC chemotherapy whilst randomising half of patients to receive additional HD-MTX.
Patients will receive conformal radiotherapy (cRT). For patients who remain with a residual inoperable disease after induction chemotherapy and cRT, an 8 Gy boost of radiotherapy to the residual tumour will be delivered immediately after the end of the cRT.
Stratum 3 This stratum is designed as a phase II trial to evaluate the benefit of postoperative dose intense chemotherapy administered alone or in combination with valproate in children \<12 months of age or those not eligible to receive radiotherapy .
- Detailed Description
The Ependymoma Program is a comprehensive program to improve the accuracy of the primary diagnosis of ependymoma and explore different therapeutic strategies in children, adolescents and young adults, accordingly. This program is opened to all patients diagnosed with ependymoma below the age of 22 years.
It will include a centralised review of pre and post-operative imaging to assess the completeness of the resection.
It will also include a central review of pathology to confirm the histological diagnosis. The biological markers 1q and 6q gain, Tenascin C status, NELL2 and LAMA2, RELA-fusion and molecular subgroup by methylation array will be prospectively assessed for prospective evaluation of disease subgroups. Further biological evaluations will be coordinated within the linked BIOMECA study.
After surgery and central review of imaging and pathology, patients will be offered the opportunity to undergo second look surgery, if possible. Patients will be enrolled in one of 3 different strata according to the outcome of the initial surgical resection (residual disease vs no residual disease), their age or eligibility / suitability to receive radiotherapy. These 3 different strata correspond to 3 therapeutic strategies according to the patient status.
1. Stratum 1 is designed as a randomised phase III study for patients who have had a complete resection, with no measurable residual disease (as confirmed by centrally reviewed MRI) and are \> 12 months and \< 22 years at diagnosis. Those patients will be randomised to receive conformal radiotherapy followed by either 16 weeks of chemotherapy with VEC-CDDP, or observation.
2. Stratum 2 is designed as a randomised phase II study for patients who have inoperable measurable residual disease and who are \> 12 months and \< 22 years at diagnosis. Those patients will be randomised to two different treatment schedules of chemotherapy either with VEC or VEC+ high dose methotrexate (VEC +HD-MTX). After completion of the frontline chemotherapy, patients will be assessed for response (MRI) and will receive second look surgery when feasible. For those patients who remain unresectable with residual disease despite frontline chemotherapy and for whom second line surgery is not feasible, there will be a study of the safety of a radiotherapy boost of 8 Gy that will be administered to the residual tumour immediately after the completion of the conformal radiotherapy. Patients without evidence of residual disease after the chemotherapy and/or a second look surgery are not eligible for radiotherapy boost. All patients who have not shown progression under chemotherapy will receive, as maintenance therapy, a 16 week course of VEC -CDDP following completion of radiotherapy.
3. Stratum 3 is designed as a randomised phase II chemotherapy study in children \<12 months of age or those not eligible to receive radiotherapy. These patients will be randomised to receive a dose dense chemotherapy alternating myelosuppressive and relatively non-myelosuppressive drugs at 2 weekly intervals, with or without, the addition of the histone deacetylase inhibitor, valproate.
Registry: Patients that do not fulfil the inclusion criteria of one of the interventional strata will be enrolled and followed up via an observational study which will be analysed descriptively.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 536
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stratum 1 arm B Conformal radiotherapy Conformal radiotherapy. Stratum 2 arm A VEC + HD-MTX VEC + HD-MTX followed by conformal radiotherapy +/- boost Stratum 2 arm A conformal radiotherapy +/- boost VEC + HD-MTX followed by conformal radiotherapy +/- boost Stratum 2 arm B VEC VEC followed by conformal radiotherapy +/- boost Stratum 2 arm B conformal radiotherapy +/- boost VEC followed by conformal radiotherapy +/- boost Stratum 3 arm A Chemotherapy + Valproate Chemotherapy + Valproate. Stratum 1 arm A 16 weeks of VEC + CDDP Conformal radiotherapy followed by 16 weeks of VEC + CDDP. Stratum 1 arm A Conformal radiotherapy Conformal radiotherapy followed by 16 weeks of VEC + CDDP. Stratum 3 arm B Chemotherapy Chemotherapy
- Primary Outcome Measures
Name Time Method Gross Total Resection rate 3 years Overall program, depends on the stratum (from 0.5 years to 3 years)
Progression-Free Survival from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 4.5 years Number of treatment responders 15 months after final patient inclusion Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.
- Secondary Outcome Measures
Name Time Method Number of participants undergoing a second-look surgery 9 months Overall Survival from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 3 years after the final patient inclusion Quality of Survival from date of randomization up to 5 years after the end of treatment Questionnaire
Evaluation of neuropsychological morbidity from date of randomization up to 5 years after the end of treatment Scores: evaluation of processing speed (WPPSI-III, WISC-IV, WAIS-IV), verbal skills (WPPSI-III, WISC-IV, WAIS-IV), fluid intelligence (WPPSI-III / Ravens, WISC-IV / Ravens, WAIS-IV / Ravens), working memory (K-ABC / Children's Memory Scale, WISC-IV, WAIS-IV), visuo-spatial abilities (Beery-Buktenica Developmental Test of Visual-Motor Integration/Wide Range Assessment of Visual Motor Abilities - WRAVMA), regarding ability (as to national policy/WIAT-II) and motoric speed (Perdue Pegboard)
Comparison of neuroendocrine morbidity from date of randomization up to 5 years after the end of treatment Weight, height and head circumference, Tanner age, early and delayed pubertal onset, blood sample analysis (evaluation of TSH, fT4, LH and FSH, oestradiol, testosterone, insulin-like growth factor 1)
Number of participants with adverse events as a measure of safety and tolerability from date of randomization up to 5 years after the end of treatment Determination of short and long term safety and toxicity of frontline chemotherapy based on proportion of patients experiencing toxicity grade 3 to 4 (adverse events)
Radiotherapy-free survival rate from date of randomization until the date of first documented progression or date of death from any cause, or radiotherapy intervention, whichever came first, up to 2.5 years after the final patient inclusion Efficacy in each molecular sub-group from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 3 years after the final patient inclusion Efficacy in each molecular subtype described in terms of Progression-Free survival and Overall Survival
Concordance between central and local radiological assessment of the efficacy of post-operative chemotherapy 15 months after final patient inclusion Proportion of patients in whom the result of the central radiological review confirms the local review
Trial Locations
- Locations (40)
AP-HM - Hôpital d'Enfants de La Timone
🇫🇷Marseille, Bouches-du-Rhône, France
CHRU STRASBOURG - Hôpital de Hautepierre
🇫🇷Strasbourg, Bas-Rhin, France
Chu Angers
🇫🇷Angers, Maine-et-Loire, France
CHU de TOULOUSE - Hôpital des Enfants
🇫🇷Toulouse, Haute-Garonne, France
University Hospital Brno
🇨🇿Brno, Czechia
CHU Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, Seine Maritime, France
CHRU Saint-Etienne
🇫🇷Saint-Etienne, Loire, France
Centre LEON BERARD
🇫🇷Lyon, Rhône, France
CHU Limoges
🇫🇷Limoges, France
Medical University of Graz-Department of Pediatrics and Adolescent Medicine
🇦🇹Graz, Austria
CHU Clermont- Ferrand - Hôpital Estaing
🇫🇷Clermont-Ferrand, Puy-de-Dôme, France
CHU AMIENS-PICARDIE - Hôpital Nord
🇫🇷Amiens, Somme, France
CHR de la CITADELLE
🇧🇪Liege, Belgium
Skåne University Hospital
🇸🇪Lund, Sweden
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milan, Italy
Fondation Institut Curie
🇫🇷Paris, Ile-De-France, France
CHU Nice - Hôpital de l'Archet 2
🇫🇷Nice, France
CHU de RENNES - Hôpital Sud
🇫🇷Rennes, Ille-et-Vilaine, France
CHRU BREST - Hôpital Morvan
🇫🇷Brest, Finistère, France
CHU POITIERS - Hôpital de la Milétrie
🇫🇷Poitiers, Vienne, France
Institut Gustave Roussy
🇫🇷Villejuif, Ile-de-France, France
CHU GRENOBLE - Hôpital Couple-Enfant
🇫🇷La Tronche, Isère, France
CHU REIMS - American Memorial Hospital
🇫🇷Reims, Marne, France
Princess Maxima Center for pediatric oncology
🇳🇱Utrecht, Netherlands
Department of Paediatric, Haukeland University Hospital
🇳🇴Bergen, Norway
University Children's Hospital
🇨🇭Zurich, Switzerland
CHU NANCY - Brabois Hôpital d'Enfants
🇫🇷Vandoeuvre-les-Nancy, Meurthe-et-Moselle, France
CHRU Tours - Hôpital Clocheville
🇫🇷Tours, Indre-et-Loire, France
Centre OSCAR LAMBRET
🇫🇷Lille, Nord, France
CHU de Bordeaux-Hôpital des enfants Pellegrin
🇫🇷Bordeaux, Gironde, France
Aarhus University Hospital
🇩🇰Aarhus, Denmark
CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve
🇫🇷Montpellier, Herault, France
CHU Dijon - Hôpital des Enfants
🇫🇷Dijon, Côte d'Or, France
CHRU BESANCON - Hôpital Jean Minjoz
🇫🇷Besançon, Doubs, France
University Medical Center Ljubljana
🇸🇮Ljubljana, Slovenia
University Medical Center Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Our Lady's Children's Hospital
🇮🇪Dublin, Ireland
Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda
🇪🇸Sevilla, Spain
CHU La Réunion
🇫🇷Saint-Denis, France
Queen's Medical Centre
🇬🇧Nottingham, United Kingdom