An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma

NCT02265770 | Recruiting Phase 2 DMC

• 3 other identifiers: SIOP Ependymoma II (ET-13-002)2013-002766-39VHP358
• Study Type: interventional
• Target: 536
• Locations: 15 countries
• Sites: 40

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 .

Conditions

Childhood Ependymoma

Outcome Measures

Primary Outcomes (3)

• Gross Total Resection rate

  Overall program, depends on the stratum (from 0.5 years to 3 years)

  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

  Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.

  15 months after final patient inclusion

Secondary Outcomes (9)

• 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

• Evaluation of neuropsychological morbidity

  from date of randomization up to 5 years after the end of treatment

• Comparison of neuroendocrine morbidity

  from date of randomization up to 5 years after the end of treatment

Study Arms (6)

Stratum 1 arm A

EXPERIMENTAL

Conformal radiotherapy followed by 16 weeks of VEC + CDDP.

Drug: 16 weeks of VEC + CDDP; Radiation: Conformal radiotherapy

Stratum 1 arm B

ACTIVE COMPARATOR

Conformal radiotherapy.

Radiation: Conformal radiotherapy

Stratum 2 arm A

EXPERIMENTAL

VEC + HD-MTX followed by conformal radiotherapy +/- boost

Drug: VEC + HD-MTX; Radiation: conformal radiotherapy +/- boost

Stratum 2 arm B

ACTIVE COMPARATOR

VEC followed by conformal radiotherapy +/- boost

Drug: VEC; Radiation: conformal radiotherapy +/- boost

Stratum 3 arm A

EXPERIMENTAL

Chemotherapy + Valproate.

Drug: Chemotherapy + Valproate

Stratum 3 arm B

ACTIVE COMPARATOR

Chemotherapy

Drug: Chemotherapy

Interventions

16 weeks of VEC + CDDP DRUG

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.

Also known as: Vincristine, Etoposide, Cyclophosphamide, Cisplatin

Stratum 1 arm A

VEC + HD-MTX DRUG

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.

Also known as: Vincristine, Etoposide, Cyclophosphamide, Methotrexate

Stratum 2 arm A

Chemotherapy + Valproate DRUG

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.

Also known as: Vincristine, Carboplatin, Methotrexate, Cyclophosphamide, Cisplatin, Valproate

Stratum 3 arm A

Conformal radiotherapy RADIATION

Conformal radiotherapy: 59.4Gy (children \<18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.

Stratum 1 arm A; Stratum 1 arm B

VEC DRUG

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

Also known as: Vincristine, Etoposide, Cyclophosphamide

Stratum 2 arm B

Chemotherapy DRUG

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.

Also known as: Vincristine, Carboplatin, Methotrexate, Cyclophosphamide, Cisplatin

Stratum 3 arm B

conformal radiotherapy +/- boost RADIATION

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 A; Stratum 2 arm B

Eligibility Criteria

• Age: Up to 22 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre Leon Berard: lead

Study Sites (40)

Medical University of Graz-Department of Pediatrics and Adolescent Medicine

Graz, 8036, Austria

RECRUITING

CHR de la CITADELLE

Liège, 4000, Belgium

RECRUITING

University Hospital Brno

Brno, 61300, Czechia

RECRUITING

Aarhus University Hospital

Aarhus, 8200, Denmark

RECRUITING

CHRU STRASBOURG - Hôpital de Hautepierre

Strasbourg, Bas-Rhin, 67098, France

RECRUITING

AP-HM - Hôpital d'Enfants de La Timone

Marseille, Bouches-du-Rhône, 13385, France

RECRUITING

CHU Dijon - Hôpital des Enfants

Dijon, Côte d'Or, 21079, France

RECRUITING

CHRU BESANCON - Hôpital Jean Minjoz

Besançon, Doubs, 25030, France

RECRUITING

CHRU BREST - Hôpital Morvan

Brest, Finistère, 29609, France

RECRUITING

CHU de Bordeaux-Hôpital des enfants Pellegrin

Bordeaux, Gironde, 33000, France

RECRUITING

CHU de TOULOUSE - Hôpital des Enfants

Toulouse, Haute-Garonne, 31059, France

RECRUITING

CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve

Montpellier, Herault, 34295, France

RECRUITING

CHU de RENNES - Hôpital Sud

Rennes, Ille-et-Vilaine, 35203, France

RECRUITING

CHRU Tours - Hôpital Clocheville

Tours, Indre-et-Loire, 37044, France

RECRUITING

CHU GRENOBLE - Hôpital Couple-Enfant

La Tronche, Isère, 38700, France

RECRUITING

Chu Angers

Angers, Maine-et-Loire, 49100, France

RECRUITING

CHU REIMS - American Memorial Hospital

Reims, Marne, 51092, France

RECRUITING

CHU NANCY - Brabois Hôpital d'Enfants

Vandœuvre-lès-Nancy, Meurthe-et-Moselle, 54511, France

RECRUITING

Centre OSCAR LAMBRET

Lille, Nord, 59000, France

RECRUITING

CHRU Saint-Etienne

Saint-Étienne-de-Montluc, Pays de la Loire Region, 42055, France

RECRUITING

CHU Clermont- Ferrand - Hôpital Estaing

Clermont-Ferrand, Puy-de-Dôme, 63003, France

RECRUITING

Centre LEON BERARD

Lyon, Rhône, 69473, France

RECRUITING

CHU Rouen - Hôpital Charles Nicolle

Rouen, Seine Maritime, 76031, France

RECRUITING

CHU AMIENS-PICARDIE - Hôpital Nord

Amiens, Somme, 80054, France

RECRUITING

CHU POITIERS - Hôpital de la Milétrie

Poitiers, Vienne, 86021, France

RECRUITING

CHU Limoges

Limoges, France

RECRUITING

CHU Nice - Hôpital de l'Archet 2

Nice, 06202, France

RECRUITING

CHU La Réunion

Saint-Denis, 97400, France

RECRUITING

Fondation Institut Curie

Paris, Île-de-France Region, 75005, France

RECRUITING

Institut Gustave Roussy

Villejuif, Île-de-France Region, 94805, France

RECRUITING

University Medical Center Hamburg-Eppendorf

Hamburg, 20246, Germany

RECRUITING

Our Lady's Children's Hospital

Dublin, Ireland

RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

RECRUITING

Princess Maxima Center for pediatric oncology

Utrecht, Netherlands

RECRUITING

Department of Paediatric, Haukeland University Hospital

Bergen, 5021, Norway

RECRUITING

University Medical Center Ljubljana

Ljubljana, 1000, Slovenia

NOT YET RECRUITING

Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda

Seville, 41071, Spain

RECRUITING

Skåne University Hospital

Lund, 22185, Sweden

NOT YET RECRUITING

University Children's Hospital

Zurich, 8032, Switzerland

RECRUITING

Queen's Medical Centre

Nottingham, United Kingdom

RECRUITING

Related Publications (1)

• 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.

  PMID: 35720069 DERIVED

MeSH Terms

Conditions

Familial ependymoma

Interventions

Vincristine; Etoposide; Cyclophosphamide; Cisplatin; Methotrexate; Drug Therapy; Valproic Acid; Carboplatin; Radiotherapy, Conformal

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Aminopterin; Pterins; Pteridines; Therapeutics; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Fatty Acids, Volatile; Fatty Acids; Lipids; Coordination Complexes; Radiotherapy, Computer-Assisted; Radiotherapy

Study Officials

• Pierre LEBLOND, MD

  IHOP

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pierre LEBLOND, MD

CONTACT

+33 4 69 16 66 14; pierre.leblond@lyon.unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2014
• First Posted: October 16, 2014
• Study Start: June 2, 2015
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): August 1, 2031
• Last Updated: April 26, 2024

Record last verified: 2024-04

Locations

CH (1); SL (1); CZ (1); NO (1); SE (1); FR (26); BE (1); IT (1); ES (1); NL (1); AU (1); DK (1); DE (1); GB (1); IE (1)