SIOP Ependymoma II: An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with ependymoma

Prior treatment

• All interventional strata : Concurrent treatment with any anti-tumour agents.
• All interventional strata : Inability to tolerate chemotherapy.
• Stratum 3 : Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial.

Other illness

• Stratum 3 : Family history of severe epilepsy in immediate family siblings.
• All interventional strata : Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion.

Lab values

• All interventional strata : 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.

Other

• Overall program : Patient with subependymomas and ependymoblastomas.
• All interventional strata : Unable to tolerate intravenous hydration.
• Stratum 1 and 2 : Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion.
• Stratum 3 : Pre-existing severe hepatic and/or renal damage.
• Stratum 3 : Elevated blood ammonium level ≥ 1.5 x upper limit of the normal.
• Stratum 3 : Elevated blood lactate level ≥ 1.5 x upper limit of the normal.
• Overall program : Primary diagnosis predating the activation of the SIOP Ependymoma II program (Apr 29th 2015).
• All interventional strata : Tumour entity other than primary intracranial ependymoma.
• All interventional strata : Patients with WHO grade I ependymoma including myxopapillary variant.
• All interventional strata : Patients with spinal cord location of the primary tumour.
• All interventional strata : Participation within a different trial for treatment of ependymoma.
• All interventional strata : Contraindication to one of the IMP used in the stratum according to the SmPCs (see protocol).

• Overall program : Main residence in one of the participating countries.
• All interventional strata : No previous chemotherapy (except steroids).
• All interventional strata : No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the patient unable to receive chemotherapy.
• All interventional strata : No signs of infection.
• All interventional strata : Adequate bone marrow, liver and renal function (detailed in protocol).
• All interventional strata : 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.
• All interventional strata : Written informed consent (specific to the stratum)
• Stratum 1 and 2 : Age ≥ 12 months and < 22 years at time of study entry.
• Stratum 1 and 2 : No metastasis on spinal MRI and on CSF cytology assessments.
• Stratum 1 and 2 : No medical contraindication to radiotherapy, and chemotherapy.
• Stratum 1 and 2 : Post-menarchal female not pregnant or nursing (breast feeding) and with a negative beta-HCG pregnancy test prior to commencing the trial.
• Overall program : Age < 22 years old at the diagnosis.
• Stratum 1 and 2 : Males and females of reproductive age and childbearing potential with highly effective contraception for the duration of their treatment and 6 months after the completion of their treatment.
• Stratum 1 : No residual measurable ependymoma based on the central neuro-radiological 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.
• Stratum 2 : Residual non reoperable measurable ependymoma based on central neuro-radiological 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).
• Stratum 3 : Children younger than 12 months at time of entry to study or any patient ineligible to receive radiotherapy due to age at diagnosis, tumour location or clinician / parent decision and according to national criteria.
• Stratum 3 : No medical contraindication to chemotherapy.
• Overall program : Histological diagnosis of intracranial or spinal, localized or metastatic, ependymoma according to local pathologist (all WHO grades).
• Overall program : Delivery to national referral pathology center of FFPE tumour tissue blocks (or at least twenty 4 µm sections on charged slides with sufficient interpretable material and at least ten 10 µm curls in an Eppendorf tube).
• Overall program : Written informed consent (specific to staging) for data and study biological samples collection.
• Overall program : 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.
• Overall program : Patients must be affiliated to a Social Security System in countries where this is mandatory.
• All interventional strata : Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
• All interventional strata : No previous radiotherapy.