SIOP Ependymoma II

Ependymoma

Prospective, international, randomized, unblinded phase II and III trial

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 with completely removed intra cranial ependymoma.

Stratum 2:

• To compare the activity of 2 post-operative chemotherapy schedules, VEC or VEC+HD-MTX in patients who have incompletely resected tumour.
• To determine safety of 8 Gy boost radiotherapy in patients with residual disease despite frontline chemotherapy and after 59.4 Gy conformal radiotherapy

Stratum 3:

• To evaluate the progression free survival in children unable to receive radiation therapy and who receive valproate, as a histone deacetylase inhibitor in addition to the primary chemotherapy strategy when compared to those that undergo chemotherapy without valproate.

All Strata:

• To determine whether the assessment of residual disease can be improved by a centralized review of post-operative MRI and whether such review increases the rate of complete resection compared to historical controls.
• Does central neurosurgical and radiological review increase resection rates?

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. After surgery and central review of imaging and pathology, patients will be offered the opportunity to undergo second look surgery, if possible.

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 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.

Observational study: After staging phase, 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.

• 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
• Delivery to national referral pathology center of formalin-fixed paraffin embedded (FFPE) tumour tissue blocks (or at least twenty 5 μm sections on charged slides with sufficient interpretable material and at least ten 10 μm curls in an Eppendorf tube)  Written informed consent (staging) for collection and transfer of biological samples.
• 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.

Additional Inclusion criteria have been defined for each stratum of the program!

• 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

Additional exclusion criteria have been defined for each stratum of the program!