Clinical trial NCT02265770: An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma
Official title: An International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults With Ependymoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Childhood Ependymoma
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2014-10-16
Enrollment: 536
Sex: ALL
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Gross Total Resection rate
timeFrame: 3 years
measure: Progression-Free Survival
timeFrame: 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
measure: Number of treatment responders
timeFrame: 15 months after final patient inclusion
Secondary outcomes:
measure: Number of participants undergoing a second-look surgery
timeFrame: 9 months
measure: Overall Survival
timeFrame: 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
measure: Quality of Survival
timeFrame: from date of randomization up to 5 years after the end of treatment
measure: Evaluation of neuropsychological morbidity
timeFrame: from date of randomization up to 5 years after the end of treatment
measure: Comparison of neuroendocrine morbidity
timeFrame: from date of randomization up to 5 years after the end of treatment
measure: Number of participants with adverse events as a measure of safety and tolerability
timeFrame: from date of randomization up to 5 years after the end of treatment
measure: Radiotherapy-free survival rate
timeFrame: 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
measure: Efficacy in each molecular sub-group
timeFrame: 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
measure: Concordance between central and local radiological assessment of the efficacy of post-operative chemotherapy
timeFrame: 15 months after final patient inclusion
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz-Department of Pediatrics and Adolescent Medicine
city: Liege
country: Belgium
facility: CHR de la CITADELLE
city: Brno
country: Czechia
facility: University Hospital Brno
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Strasbourg
country: France
facility: CHRU STRASBOURG - Hôpital de Hautepierre
state: Bas-Rhin
city: Marseille
country: France
facility: AP-HM - Hôpital d'Enfants de La Timone
state: Bouches-du-Rhône
city: Dijon
country: France
facility: CHU Dijon - Hôpital des Enfants
state: Côte d'Or
city: Besançon
country: France
facility: CHRU BESANCON - Hôpital Jean Minjoz
state: Doubs
city: Brest
country: France
facility: CHRU BREST - Hôpital Morvan
state: Finistère
city: Bordeaux
country: France
facility: CHU de Bordeaux-Hôpital des enfants Pellegrin
state: Gironde
city: Toulouse
country: France
facility: CHU de TOULOUSE - Hôpital des Enfants
state: Haute-Garonne
city: Montpellier
country: France
facility: CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve
state: Herault
city: Paris
country: France
facility: Fondation Institut Curie
state: Ile-De-France
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Ile-de-France
city: Rennes
country: France
facility: CHU de RENNES - Hôpital Sud
state: Ille-et-Vilaine
city: Tours
country: France
facility: CHRU Tours - Hôpital Clocheville
state: Indre-et-Loire
city: La Tronche
country: France
facility: CHU GRENOBLE - Hôpital Couple-Enfant
state: Isère
city: Saint-Etienne
country: France
facility: CHRU Saint-Etienne
state: Loire
city: Angers
country: France
facility: Chu Angers
state: Maine-et-Loire
city: Reims
country: France
facility: CHU REIMS - American Memorial Hospital
state: Marne
city: Vandoeuvre-les-Nancy
country: France
facility: CHU NANCY - Brabois Hôpital d'Enfants
state: Meurthe-et-Moselle
city: Lille
country: France
facility: Centre OSCAR LAMBRET
state: Nord
city: Clermont-Ferrand
country: France
facility: CHU Clermont- Ferrand - Hôpital Estaing
state: Puy-de-Dôme
city: Lyon
country: France
facility: Centre LEON BERARD
state: Rhône
city: Rouen
country: France
facility: CHU Rouen - Hôpital Charles Nicolle
state: Seine Maritime
city: Amiens
country: France
facility: CHU AMIENS-PICARDIE - Hôpital Nord
state: Somme
city: Poitiers
country: France
facility: CHU POITIERS - Hôpital de la Milétrie
state: Vienne
city: Limoges
country: France
facility: CHU Limoges
city: Nice
country: France
facility: CHU Nice - Hôpital de l'Archet 2
city: Saint-Denis
country: France
facility: CHU La Réunion
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Dublin
country: Ireland
facility: Our Lady's Children's Hospital
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Utrecht
country: Netherlands
facility: Princess Maxima Center for pediatric oncology
city: Bergen
country: Norway
facility: Department of Paediatric, Haukeland University Hospital
city: Ljubljana
country: Slovenia
facility: University Medical Center Ljubljana
city: Sevilla
country: Spain
facility: Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Zurich
country: Switzerland
facility: University Children's Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
Study officials:
affiliation: IHOP
name: Pierre LEBLOND, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.