Clinical Trial Finder

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

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.#46;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.

Arms

Experimental: Stratum 1 arm A

Conformal radiotherapy followed by 16 weeks of VEC + CDDP.

Active Comparator: Stratum 1 arm B

Conformal radiotherapy.

Experimental: Stratum 2 arm A

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

Active Comparator: Stratum 2 arm B

VEC followed by conformal radiotherapy +/- boost

Experimental: Stratum 3 arm A

Chemotherapy + Valproate.

Active Comparator: Stratum 3 arm B

Chemotherapy

Interventions

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.

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.

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.

Radiation: - Conformal radiotherapy

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

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

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.

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