An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma
NCT ID: NCT02265770
Last Updated: 2024-04-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2/PHASE3
536 participants
INTERVENTIONAL
2015-06-02
2031-08-31
Brief Summary
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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 .
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Stratum 1 arm A
Conformal radiotherapy followed by 16 weeks of VEC + CDDP.
16 weeks of VEC + CDDP
Days 1-36-71-106: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-36-38-71-73-106-108: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-36-71-106: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 22-57-92: Cisplatin: 80 mg/m² over 4 hours + Vincristine:1.5 mg/m² (maximal dose 2 mg) i.v.
Conformal radiotherapy
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Stratum 1 arm B
Conformal radiotherapy.
Conformal radiotherapy
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Stratum 2 arm A
VEC + HD-MTX followed by conformal radiotherapy +/- boost
VEC + HD-MTX
Days 1-22-43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-22-24-43-45: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-22-43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 15-36-57: Administer methotrexate at 8000 mg/m² as a 24 hour IV infusion on days 15-36-57. 10% of the dose should be given over the first hour and 90% over the remaining 23 hours. The infusion must finish at 24 hours even if it has not been completed.
conformal radiotherapy +/- boost
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
In case of persistent residue : Boost of radiation 8 Gy in 2 equivalent fractions
Stratum 2 arm B
VEC followed by conformal radiotherapy +/- boost
VEC
D1: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D1-D3: Etoposide: 100 mg/m² infused over 60 minutes; D1: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D22: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D22-D24: Etoposide: 100 mg/m² infused over 60 minutes; D22: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D43-D45: Etoposide: 100 mg/m² infused over 60 minutes; D43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes
conformal radiotherapy +/- boost
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
In case of persistent residue : Boost of radiation 8 Gy in 2 equivalent fractions
Stratum 3 arm A
Chemotherapy + Valproate.
Chemotherapy + Valproate
Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion.
Valproate: initial dose 30 mg/kg/day for two weeks in 2 divided doses (BID 15 mg/kg). Increasing weekly up to 40 - 50 - 60 mg/kg/day in 2 divided doses.
Stratum 3 arm B
Chemotherapy
Chemotherapy
Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion.
Interventions
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16 weeks of VEC + CDDP
Days 1-36-71-106: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-36-38-71-73-106-108: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-36-71-106: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 22-57-92: Cisplatin: 80 mg/m² over 4 hours + Vincristine:1.5 mg/m² (maximal dose 2 mg) i.v.
VEC + HD-MTX
Days 1-22-43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; Days 1-3-22-24-43-45: Etoposide: 100 mg/m² infused over 60 minutes; Days 1-22-43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; Days 15-36-57: Administer methotrexate at 8000 mg/m² as a 24 hour IV infusion on days 15-36-57. 10% of the dose should be given over the first hour and 90% over the remaining 23 hours. The infusion must finish at 24 hours even if it has not been completed.
Chemotherapy + Valproate
Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion.
Valproate: initial dose 30 mg/kg/day for two weeks in 2 divided doses (BID 15 mg/kg). Increasing weekly up to 40 - 50 - 60 mg/kg/day in 2 divided doses.
Conformal radiotherapy
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
VEC
D1: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D1-D3: Etoposide: 100 mg/m² infused over 60 minutes; D1: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D22: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D22-D24: Etoposide: 100 mg/m² infused over 60 minutes; D22: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes; D43: Vincristine: 1.5 mg/m² (maximal dose 2 mg) i.v.; D43-D45: Etoposide: 100 mg/m² infused over 60 minutes; D43: Cyclophosphamide: 3000 mg/m² in 3 divided infusions (1000 mg/m²/infusion) infused over 60 minutes
Chemotherapy
Days 1-57-113-169-225-281-337: Vincristine and Carboplatin; Days 15-71-127-183-239-295-351: Vincristine and Methotrexate; Days 29-85-141-197-253-309-365: Vincristine and Cyclophosphamide; Days 43-44-99-100-154-155-211-212-267-268-323-324-379-380: Cisplatin 2-day continuous infusion.
conformal radiotherapy +/- boost
Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
In case of persistent residue : Boost of radiation 8 Gy in 2 equivalent fractions
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
• No residual measurable ependymoma based on the central neuroradiological review (R0-1-2)
• Residual non reoperable measurable ependymoma based on the central neuroradiological review (R3-4)
* 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
Exclusion Criteria
* 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
22 Years
ALL
No
Sponsors
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Centre Leon Berard
OTHER
Responsible Party
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Principal Investigators
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Pierre LEBLOND, MD
Role: PRINCIPAL_INVESTIGATOR
IHOP
Locations
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Medical University of Graz-Department of Pediatrics and Adolescent Medicine
Graz, , Austria
CHR de la CITADELLE
Liège, , Belgium
University Hospital Brno
Brno, , Czechia
Aarhus University Hospital
Aarhus, , Denmark
CHRU STRASBOURG - Hôpital de Hautepierre
Strasbourg, Bas-Rhin, France
AP-HM - Hôpital d'Enfants de La Timone
Marseille, Bouches-du-Rhône, France
CHU Dijon - Hôpital des Enfants
Dijon, Côte d'Or, France
CHRU BESANCON - Hôpital Jean Minjoz
Besançon, Doubs, France
CHRU BREST - Hôpital Morvan
Brest, Finistère, France
CHU de Bordeaux-Hôpital des enfants Pellegrin
Bordeaux, Gironde, France
CHU de TOULOUSE - Hôpital des Enfants
Toulouse, Haute-Garonne, France
CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve
Montpellier, Herault, France
CHU de RENNES - Hôpital Sud
Rennes, Ille-et-Vilaine, France
CHRU Tours - Hôpital Clocheville
Tours, Indre-et-Loire, France
CHU GRENOBLE - Hôpital Couple-Enfant
La Tronche, Isère, France
Chu Angers
Angers, Maine-et-Loire, France
CHU REIMS - American Memorial Hospital
Reims, Marne, France
CHU NANCY - Brabois Hôpital d'Enfants
Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France
Centre OSCAR LAMBRET
Lille, Nord, France
CHRU Saint-Etienne
Saint-Étienne-de-Montluc, Pays de la Loire Region, France
CHU Clermont- Ferrand - Hôpital Estaing
Clermont-Ferrand, Puy-de-Dôme, France
Centre LEON BERARD
Lyon, Rhône, France
CHU Rouen - Hôpital Charles Nicolle
Rouen, Seine Maritime, France
CHU AMIENS-PICARDIE - Hôpital Nord
Amiens, Somme, France
CHU POITIERS - Hôpital de la Milétrie
Poitiers, Vienne, France
CHU Limoges
Limoges, , France
CHU Nice - Hôpital de l'Archet 2
Nice, , France
CHU La Réunion
Saint-Denis, , France
Fondation Institut Curie
Paris, Île-de-France Region, France
Institut Gustave Roussy
Villejuif, Île-de-France Region, France
University Medical Center Hamburg-Eppendorf
Hamburg, , Germany
Our Lady's Children's Hospital
Dublin, , Ireland
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, , Italy
Princess Maxima Center for pediatric oncology
Utrecht, , Netherlands
Department of Paediatric, Haukeland University Hospital
Bergen, , Norway
University Medical Center Ljubljana
Ljubljana, , Slovenia
Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda
Seville, , Spain
Skåne University Hospital
Lund, , Sweden
University Children's Hospital
Zurich, , Switzerland
Queen's Medical Centre
Nottingham, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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References
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Leblond P, Massimino M, English M, Ritzmann TA, Gandola L, Calaminus G, Thomas S, Perol D, Gautier J, Grundy RG, Frappaz D. Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol. Front Neurol. 2022 Jun 2;13:887544. doi: 10.3389/fneur.2022.887544. eCollection 2022.
Other Identifiers
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2013-002766-39
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
VHP358
Identifier Type: OTHER
Identifier Source: secondary_id
SIOP Ependymoma II (ET-13-002)
Identifier Type: -
Identifier Source: org_study_id
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