SIOP-EP-II: An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma

Sponsor

Centre Leon Berard (Other)

Overall Status

Recruiting

CT.gov ID

NCT02265770

Collaborator

(none)

480

Enrollment

Locations

Arms

194

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 .

Condition or Disease	Intervention/Treatment	Phase
Childhood Ependymoma	Drug: 16 weeks of VEC + CDDP Drug: VEC + HD-MTX Drug: Chemotherapy + Valproate Radiation: Conformal radiotherapy Drug: VEC Drug: Chemotherapy Radiation: conformal radiotherapy +/- boost	Phase 2/Phase 3

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 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.

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.
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.
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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

480 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults With Ependymoma

Actual Study Start Date :

Jun 2, 2015

Anticipated Primary Completion Date :

Jun 1, 2028

Anticipated Study Completion Date :

Aug 1, 2031

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stratum 1 arm A Conformal radiotherapy followed by 16 weeks of VEC + CDDP.	Drug: 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. Other Names: Vincristine Etoposide Cyclophosphamide Cisplatin Radiation: Conformal radiotherapy Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Active Comparator: Stratum 1 arm B Conformal radiotherapy.	Radiation: Conformal radiotherapy Conformal radiotherapy: 59.4Gy (children <18 months or with risk factors: 54Gy). Daily fraction 1.8 Gy, 5 fractions / week.
Experimental: Stratum 2 arm A VEC + HD-MTX followed by conformal radiotherapy +/- boost	Drug: 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. Other Names: Vincristine Etoposide Cyclophosphamide Methotrexate Radiation: 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
Active Comparator: Stratum 2 arm B VEC followed by conformal radiotherapy +/- boost	Drug: 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 Other Names: Vincristine Etoposide Cyclophosphamide Radiation: 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
Experimental: Stratum 3 arm A Chemotherapy + Valproate.	Drug: 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. Other Names: Vincristine Carboplatin Methotrexate Cyclophosphamide Cisplatin Valproate
Active Comparator: Stratum 3 arm B Chemotherapy	Drug: 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. Other Names: Vincristine Carboplatin Methotrexate Cyclophosphamide Cisplatin

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 22 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 with an ependymoma WHO grade II and III, including ependymoma variants: papillary, clear-cell and tanycytic, RELA fusion positive or anaplastic ependymoma
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

Common inclusion criteria for Strata 1 and 2:

Age > 12 months and < 22 years at time of study entry
Histologically confirmed WHO Grade II-III ependymoma by central pathological review
No metastasis on spinal MRI and on CSF cytology assessments
No previous radiotherapy
No previous chemotherapy (except steroids)
No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy
No medical contraindication to radiotherapy and chemotherapy
No signs of infection
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
Histologically confirmed WHO Grade II-III ependymoma by central pathological review
Adequate bone marrow, liver and renal functions
No previous chemotherapy and radiotherapy
No contraindication to chemotherapy
No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy
No signs of infection. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of Graz-Department of Pediatrics and Adolescent Medicine	Graz		Austria	8036
2	CHR de la CITADELLE	Liege		Belgium	4000
3	University Hospital Brno	Brno		Czechia	61300
4	Aarhus University Hospital	Aarhus		Denmark	8200
5	CHRU STRASBOURG - Hôpital de Hautepierre	Strasbourg	Bas-Rhin	France	67098
6	AP-HM - Hôpital d'Enfants de La Timone	Marseille	Bouches-du-Rhône	France	13385
7	CHU Dijon - Hôpital des Enfants	Dijon	Côte d'Or	France	21079
8	CHRU BESANCON - Hôpital Jean Minjoz	Besançon	Doubs	France	25030
9	CHRU BREST - Hôpital Morvan	Brest	Finistère	France	29609
10	CHU de Bordeaux-Hôpital des enfants Pellegrin	Bordeaux	Gironde	France	33000
11	CHU de TOULOUSE - Hôpital des Enfants	Toulouse	Haute-Garonne	France	31059
12	CHRU MONTPELLIER - Hôpital Arnaud de Villeneuve	Montpellier	Herault	France	34295
13	Fondation Institut Curie	Paris	Ile-De-France	France	75005
14	Institut Gustave Roussy	Villejuif	Ile-de-France	France	94805
15	CHU de RENNES - Hôpital Sud	Rennes	Ille-et-Vilaine	France	35203
16	CHRU Tours - Hôpital Clocheville	Tours	Indre-et-Loire	France	37044
17	CHU GRENOBLE - Hôpital Couple-Enfant	La Tronche	Isère	France	38700
18	CHRU Saint-Etienne	Saint-Etienne	Loire	France	42055
19	Chu Angers	Angers	Maine-et-Loire	France	49100
20	CHU REIMS - American Memorial Hospital	Reims	Marne	France	51092
21	CHU NANCY - Brabois Hôpital d'Enfants	Vandoeuvre-les-Nancy	Meurthe-et-Moselle	France	54511
22	Centre OSCAR LAMBRET	Lille	Nord	France	59000
23	CHU Clermont- Ferrand - Hôpital Estaing	Clermont-Ferrand	Puy-de-Dôme	France	63003
24	Centre LEON BERARD	Lyon	Rhône	France	69473
25	CHU Rouen - Hôpital Charles Nicolle	Rouen	Seine Maritime	France	76031
26	CHU AMIENS-PICARDIE - Hôpital Nord	Amiens	Somme	France	80054
27	CHU POITIERS - Hôpital de la Milétrie	Poitiers	Vienne	France	86021
28	CHU Limoges	Limoges		France
29	CHU Nice - Hôpital de l'Archet 2	Nice		France	06202
30	CHU La Réunion	Saint-Denis		France	97400
31	University Medical Center Hamburg-Eppendorf	Hamburg		Germany	20246
32	Our Lady's Children's Hospital	Dublin		Ireland
33	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan		Italy	20133
34	Princess Maxima Center for pediatric oncology	Utrecht		Netherlands
35	Department of Paediatric, Haukeland University Hospital	Bergen		Norway	5021
36	University Medical Center Ljubljana	Ljubljana		Slovenia	1000
37	Hospitales Universitarios Virgen Macarena y Virgen del Rocío Avda	Sevilla		Spain	41071
38	Skåne University Hospital	Lund		Sweden	22185
39	University Children's Hospital	Zurich		Switzerland	8032
40	Queen's Medical Centre	Nottingham		United Kingdom