Childhood Ependymoma Clinical Trial
— SIOP-EP-IIOfficial title:
An International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults With Ependymoma
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 .
| Status | Recruiting |
| Enrollment | 536 |
| Est. completion date | August 2031 |
| Est. primary completion date | June 2028 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A to 22 Years |
| Eligibility | After Initial surgery, patients will be enrolled in one of 3 different interventional strata where they will be offered a set of therapeutic interventions based on the outcome of the intervention (no measurable residue vs residual inoperable disease), their age and/or their eligibility /suitability to receive radiotherapy. Patients with centrally and histologically confirmed intracranial ependymoma meeting the following criteria will be enrolled into one of interventional stratum: - Age < 22 years old at diagnosis - Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review - Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial - Males and females of reproductive age and childbearing potential with effective contraception for the duration of their treatment and 6 months after the completion of their treatment - No contraindication to the use if one of the study drugs proposed by the protocol - Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure - No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy - No signs of infection. Common inclusion criteria for Strata 1 and 2: - Age > 12 months and < 22 years at time of study entry - No metastasis on spinal MRI and on CSF cytology assessments - No previous radiotherapy - No previous chemotherapy (except steroids) - No medical contraindication to radiotherapy and chemotherapy - Adequate bone marrow, liver and renal functions Specific inclusion criteria for Stratum 1: • No residual measurable ependymoma based on the central neuroradiological review (R0-1-2) Specific inclusion criteria for Stratum 2: • Residual non reoperable measurable ependymoma based on the central neuroradiological review (R3-4) Inclusion criteria for Stratum 3: - Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician / parent decision and according to national criteria - Adequate bone marrow, liver and renal functions - No previous chemotherapy and radiotherapy - No contraindication to chemotherapy Patients that do not fulfill the inclusion criteria of one of the interventional strata will be enrolled and followed up into an observational study and descriptive analysis will be performed. EXCLUSION CRITERIA for all interventional strata: - Tumour entity other than primary intracranial ependymoma - Primary diagnosis predating the opening of SIOP Ependymoma II - Patients with WHO grade I ependymoma including ependymoma variants: myxopapillary ependymomas and subependymomas,patients with spinal cord location of the primary tumour - Participation within a different trial for treatment of ependymoma - Contraindication to one of the IMP used according to the SmPCs - Concurrent treatment with any anti-tumour agents - Inability to tolerate chemotherapy - Unable to tolerate intravenous hydration - Pre-existing mucositis, peptic ulcer, inflammatory bowel disease ascites, or pleural effusion. Strata 1 and 2: - Ineligible to receive radiotherapy - Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion Stratum 3: - Pre-existing severe hepatic and/or renal damage - Family history of severe epilepsy - Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial - Elevated blood ammonium and lactate level = 1.5 x upper limit of the normal |
| Country | Name | City | State |
|---|---|---|---|
| Austria | Medical University of Graz-Department of Pediatrics and Adolescent Medicine | Graz | |
| Belgium | CHR de la CITADELLE | Liege | |
| Czechia | University Hospital Brno | Brno | |
| Denmark | Aarhus University Hospital | Aarhus | |
| France | CHU AMIENS-PICARDIE - Hôpital Nord | Amiens | Somme |
| France | Chu Angers | Angers | Maine-et-Loire |
| France | CHRU BESANCON - Hôpital Jean Minjoz | Besançon | Doubs |
| France | CHU de Bordeaux-Hôpital des enfants Pellegrin | Bordeaux | Gironde |
| France | CHRU BREST - Hôpital Morvan | Brest | Finistère |
| France | CHU Clermont- Ferrand - Hôpital Estaing | Clermont-Ferrand | Puy-de-Dôme |
| France | CHU Dijon - Hôpital des Enfants | Dijon | Côte d'Or |
| France | CHU GRENOBLE - Hôpital Couple-Enfant | La Tronche | Isère |
| France | Centre OSCAR LAMBRET | Lille | Nord |
| France | CHU Limoges | Limoges | |
| France | Centre LEON BERARD | Lyon | Rhône |
| France | AP-HM - Hôpital d'Enfants de La Timone | Marseille | Bouches-du-Rhône |
| France | CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve | Montpellier | Herault |
| France | CHU Nice - Hôpital de l'Archet 2 | Nice | |
| France | Fondation Institut Curie | Paris | Ile-De-France |
| France | CHU POITIERS - Hôpital de la Milétrie | Poitiers | Vienne |
| France | CHU REIMS - American Memorial Hospital | Reims | Marne |
| France | CHU de RENNES - Hôpital Sud | Rennes | Ille-et-Vilaine |
| France | CHU Rouen - Hôpital Charles Nicolle | Rouen | Seine Maritime |
| France | CHU La Réunion | Saint-Denis | |
| France | CHRU Saint-Etienne | Saint-Etienne | Loire |
| France | CHRU STRASBOURG - Hôpital de Hautepierre | Strasbourg | Bas-Rhin |
| France | CHU de TOULOUSE - Hôpital des Enfants | Toulouse | Haute-Garonne |
| France | CHRU Tours - Hôpital Clocheville | Tours | Indre-et-Loire |
| France | CHU NANCY - Brabois Hôpital d'Enfants | Vandoeuvre-les-Nancy | Meurthe-et-Moselle |
| France | Institut Gustave Roussy | Villejuif | Ile-de-France |
| Germany | University Medical Center Hamburg-Eppendorf | Hamburg | |
| Ireland | Our Lady's Children's Hospital | Dublin | |
| Italy | Fondazione IRCCS Istituto Nazionale dei Tumori | Milan | |
| Netherlands | Princess Maxima Center for pediatric oncology | Utrecht | |
| Norway | Department of Paediatric, Haukeland University Hospital | Bergen | |
| Slovenia | University Medical Center Ljubljana | Ljubljana | |
| Spain | Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda | Sevilla | |
| Sweden | Skåne University Hospital | Lund | |
| Switzerland | University Children's Hospital | Zurich | |
| United Kingdom | Queen's Medical Centre | Nottingham |
| Lead Sponsor | Collaborator |
|---|---|
| Centre Leon Berard |
Austria, Belgium, Czechia, Denmark, France, Germany, Ireland, Italy, Netherlands, Norway, Slovenia, Spain, Sweden, Switzerland, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Gross Total Resection rate | Overall program, depends on the stratum (from 0.5 years to 3 years) | 3 years | |
| Primary | 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 | ||
| Primary | Number of treatment responders | Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines. | 15 months after final patient inclusion | |
| Secondary | Number of participants undergoing a second-look surgery | 9 months | ||
| Secondary | 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 | ||
| Secondary | Quality of Survival | Questionnaire | from date of randomization up to 5 years after the end of treatment | |
| Secondary | Evaluation of neuropsychological morbidity | 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) | from date of randomization up to 5 years after the end of treatment | |
| Secondary | Comparison of neuroendocrine morbidity | 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) | from date of randomization up to 5 years after the end of treatment | |
| Secondary | Number of participants with adverse events as a measure of safety and tolerability | 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) | from date of randomization up to 5 years after the end of treatment | |
| Secondary | 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 | ||
| Secondary | Efficacy in each molecular sub-group | Efficacy in each molecular subtype described in terms of Progression-Free survival and 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 | |
| Secondary | Concordance between central and local radiological assessment of the efficacy of post-operative chemotherapy | Proportion of patients in whom the result of the central radiological review confirms the local review | 15 months after final patient inclusion |