Ein internationales klinisches Therapieoptimierungsstudien-Programm für die Diagnose und Behandlung von Kindern, Jugendlichen und jungen Erwachsenen mit Ependymomen.

Product Name: Vincristine
Product Code: VCR
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: VINCRISTINE
CAS Number: 57-22-7
Current Sponsor code: VCR
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Etoposide
Product Code: VP16
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETOPOSIDE
CAS Number: 33419-42-0
Other descriptive name: ETOPOSIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Product Name: CYCLOPHOSPHAMIDE
Product Code: CPM
Pharmaceutical Form: Powder for infusion
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Current Sponsor code: CPM
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 500-1000

Product Name: CISPLATIN
Product Code: CDDP
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATIN
CAS Number: 15663-27-1
Current Sponsor code: CDDP
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: CARBOPLATIN
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CARBOPLATIN
CAS Number: 41575-94-4
Other descriptive name: CARBOPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: SODIUM VALPROATE
Product Code: VPA
Pharmaceutical Form:
INN or Proposed INN: SODIUM VALPROATE
CAS Number: 1069-66-5
Current Sponsor code: VPA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: up to
Concentration number: 40-

Product Name: METHOTREXATE
Product Code: MTX
Pharmaceutical Form: Concentrate for solution for

Gender:
Female: yes
Male: yes

Inclusion criteria:
OVERALL PROGRAM:
? Main residence in one of the participating countries.
? Age < 22 years old at diagnosis.
? Histological diagnosis of intracranial or spinal, localized or metastatic, ependymoma according to local pathologist (all WHO grades) including: myxopapillary ependymoma, ependymoma (papillary, clear-cell, tanycytic), ependymoma RELA-fusion positive or anaplastic ependymoma.
? Delivery to national referral pathology center of FFPE tumour tissue blocks.
? Written informed consent (staging).
? All patients and/or their parents or legal guardians willing and able to comply with protocol schedule and agree to sign a written informed consent.
? Patients must be affiliated to a Social Security System in countries where this is mandatory.

STRATUM I:
? Age>12 months and < 22 years at time of study entry.
? No residual measurable ependymoma based on the central neuroradiological review This includes:
R0: No residual tumour on postoperative MRI in accordance with the neurosurgical report.
R1: No residual tumour on MRI but description of a small residual tumour by the neurosurgeon.
R2: Small residual tumour on MRI with the maximum diameter below 5mm in any direction.
? Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
? No metastasis on spinal MRI and on CSF cytology assessments.
? No previous radiotherapy.
? No previous chemotherapy.
? 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 function (detailled in protocol).
? 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.
? Patients and/or their parents or legal guardians must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures of the stratum 1.
? Written informed consent (stratum 1).

STRATUM 2:
? Age > 12 months and < 22 years at time of study entry.
? No residual measurable ependymoma based on the central neuroradiological review. This includes:
R3: Residual tumour that can be measured in 3 planes.
R4: Size of the residual tumour not differing from the preoperative status (e.g. after biopsy).
? Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
? No metastasis on spinal MRI and on CSF cytology assessments.
? No previous radiotherapy.
? No previous chemotherapy.
? 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 (detailled in protocol).
? 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.
? Patients and/or their parents or legal guardians must be willing and able to comply with
Exclusion criteria:
OVERALL PROGRAM
? Patient with subependymomas and ependymoblastomas.
? Primary diagnosis predating the activation of the SIOP Ependymoma II program (Apr 29th 2015).

STRATUM 1
? Tumour entity other than primary intracranial ependymoma.
? Patients with WHO grade I ependymoma including myxopapillary variant.
? Patients with spinal cord location of the primary tumour.
? Participation within a different trial for treatment of ependymoma.
? Concurrent treatment with any anti-tumour agents.
? Inability to tolerate chemotherapy.
? Unable to tolerate intravenous hydration.
? Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator.
? Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion.
? Contraindication to one of the IMP used in the stratum 1 according to the SmPCs.
? Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion.

STRATUM 2
? Tumour entity other than primary intracranial ependymoma.
? Patients with WHO grade I ependymoma including myxopapillary variant.
? Patients with spinal cord location of the primary tumour.
? Participation within a different trial for treatment of ependymoma.
? Concurrent treatment with any anti-tumour agents.
? Inability to tolerate chemotherapy.
? Unable to tolerate intravenous hydration.
? Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator.
? Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion.
? Contraindication to one of the IMP used in the stratum 2 according to the SmPCs.
? Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion.

STRATUM 3:
? Tumour entity other than primary intracranial ependymoma.
? Patients with WHO grade I ependymoma including myxopapillary variant.
? Patients with spinal cord location of the primary tumour.
? Participation within a different trial for treatment of ependymoma.
? Concurrent treatment with any anti-tumour agents.
? Inability to tolerate chemotherapy.
? Inable to tolerate intravenous hydration.
? Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results in the judgment of the investigator.
? Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion.
? Pre-existing severe hepatic and/or renal damage.
? Family history of severe epilepsy in immediate family siblings.
? Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial.
? Elevated blood ammonium level = 1.5 x upper limit of the normal.
? Elevated blood lactate level = 1.5 x upper limit of the normal.
? Contraindication to one of the IMP used in the stratum 3 according to the SmPCs.