| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed with an intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary, myxopapillary, clear-cell and tanycytic) or anaplastic ependymoma. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014967 |
| E.1.2 | Term | Ependymoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
•Overall program
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?
•Stratum 1
To compare PFS in patients who receive 15 weeks chemotherapy with VEC+CDDP following complete surgical resection, with no residual disease, and radiotherapy when compared to those that undergo complete surgical resection, with no residual disease, and radiotherapy alone.
•Stratum 2
To evaluate the efficacy of 2 post-operative chemotherapy schedules with VEC or VEC+HD-MTX in patients who have incompletely resected tumour.
•Stratum3
To evaluate the PFS in children unable to receive radiation therapy and who receive valproate, as a HDCAI in addition to the primary chemotherapy strategy when compared to those that undergo chemotherapy without valproate. |
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| E.2.2 | Secondary objectives of the trial |
•Overall program
To evaluate second look surgery rates as compared to historical controls
To prospectively evaluate 1q copy-number status, Tenascin C, NELL2, LAMA 2, RELA-fusion and molecular subgroup as prognostic and predictive biomarkers in ependymoma within clinical trial setting
•Stratum 1
To evaluate whether OS is improved
To compare the neuropsychological and neuroendocrine morbidity
To compare the QoS
To determine the safety and the tolerance
•Stratum 2
To determine the safety and tolerability
To evaluate whether OS is improved
To evaluate whether PFS is improved
To evaluate the neuropsychological and neuroendocrine morbidity
To evaluate the QOS
To determine Safety of 8 Gy Boost radiotherapy
•Stratum 3
To evaluate whether OS is improved
To evaluate whether radiotherapy free survival is improved
To evaluate the Quality of Survival
To evaluate the neuropsychological and neuroendocrine morbidity
To determine the safety and tolerability of valproate |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Linked Biological Study:
This part of the program will be organised by the European Ependymoma biology consortium called “Biomarkers of Ependymomas in Children and Adolescents (BIOMECA)” throughout a cooperation agreement with the aim to identify informative prognostic biomarkers for assessment of disease status and predictive response to therapy. The SIOP Ependymoma Program II supports the identification of informative prognostic biomarkers within the collaborative BIOMECA study. This high priority initiative is an essential element of the overall program to improve future treatment of ependymoma.
Exploratory objectives:
•To test the hypothesis that key molecular events are predictive of clinical behaviour of ependymoma.
•To identify new biomarkers for Ependymoma clinical and biological behaviour (location, recurrence, chemo resistance, invasion, metastasis).
•To validate known biomarkers in the context of the new international prospective study for newly diagnosed Ependymoma
•To provide a new comprehensive grading scheme based on the histological, and immunohistochemical and/or biological criteria that could be used for newly diagnosed Ependymoma.
•To validate and compare the techniques to assess biomarkers for further use in the stratification of patients
•To select the best biomarker(s) and establish a prognostic signature for ependymoma.
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| E.3 | Principal inclusion criteria |
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 (histology confirmed by National Reference centre for Biology and Pathology review) meeting the following criteria will be enrolled into one of interventional strata:
•Main residence in one of the participating countries,
•Age below 22 years old at the diagnosis,
•Newly diagnosed with an ependymoma WHO grade II and III, including ependymoma variants: cellular, papillary, clear-cell and tanycytic 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 (see section 4.1.2.4 Definition of highly effective methods of contraception) for the duration of their treatment and 6 month after the completion of their treatment,
•Patients and/or their parents or legal guardians willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedure
Specific inclusion criteria have been defined for each stratum of the program.
Stratum 1:
•Age > 12 months and < 22 years at time of study entry
•No residual measurable ependymoma based on the central neuroradiological review (detailed in protocol)
•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 (e.g. renal, hematological) at the time of study entry
•No medical contraindication to radiotherapy and chemotherapy,
•No signs of infection
•Adequate bone marrow function(detailed in protocol)
•Adequate liver function (detailed in protocol)
•Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol)
Stratum 2:
•Age > 1 year and <22 years at time of entry to study
•Residual non reoperable measurable ependymoma based on central neuro-radiological review (detailed in protocol)
•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 (e.g. renal, hematological) at the time of study entry
•No medical contraindication to radiotherapy and chemotherapy,
•No signs of infection
•Adequate bone marrow function (detailed in protocol)
•Adequate liver function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol)
Stratum 3
•Children younger than 12 months at time of entry to study or any children ineligible to receive radiotherapy according to national criteria
•Histologically confirmed WHO Grade II-III ependymoma by central pathological review
•Adequate bone marrow function(detailed in protocol)
•Adequate liver function (detailed in protocol)
•Adequate renal function (In case of suspected compromised renal function, glomerular filtration should be measured by an isotope GFR method such as EDTA clearance or by creatinine clearance:detailed in protocol)
•No previous chemotherapy
•No previous 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 |
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| E.4 | Principal exclusion criteria |
All interventional stata
•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
•Age ≥ 22 years
•Contraindication to one of the IMP used in this stratum according to the SmPCs in appendix 4 of this protocol (SmPCs in appendixes are those from UK which were chosen for the assessment of the safety aspects of the study).
•Concurrent treatment with any anti-tumour agents
•Inability to tolerate chemotherapy
•Unable to tolerate intravenous hydration
•Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 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
•Pregnancy and breast feeding
Stratum 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 (liver) and/or renal (kidney) damage
Family history of severe epilepsy
•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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall program: Gross Total Resection (GTR) rate (Only descriptive statistics will be produced)
Stratum 1 Progression free survival from the date of randomisation to the date of event defined as progression or death due to any cause.
Stratum 2: Number of chemotherapy responders. Objective response to chemotherapy is measured based on SIOP-E Neuro Imaging guidelines.
Stratum 3: Progression free survival from the date of randomisation to the date of event defined as progression or death due to any cause.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stratum 1:The final analysis of trial data will be performed after 3 years follow-up of the last included patient.
Stratum 2:The first main analysis of trial data will take place 6 months after the final patient has been entered into the study, when response data from all patients will be available.
Stratum 3:
The first main analysis of trial data for primary outcome will take place 2.5 years after the final patient has been entered into the study. |
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| E.5.2 | Secondary end point(s) |
Overall program:
Second look surgery rate (Only descriptive statistics will be produced)
•Startum 1:
Overall survival measured from the date of randomisation to the date of death due to any cause.
Quality of survival (QoS)
Neuropsychological outcomes
Neuroendocrine outcomes (Neuroendocrine late effects)
Short and long term Safety: Adverse Events (CTCAE v4.03)
•Stratum 2:
Overall survival measured from the date of randomisation to the date of death due to any cause.
Progression Free Survival from the date of randomisation to the date of event defined as progression or death due to any cause.
Quality of survival (QoS)
Neuropsychological outcomes
Neuroendocrine outcomes (Neuroendocrine late effects)
Short and long term safety of frontline chemotherapy: Adverse Events (CTCAE v4.03)
Exploratory endpoint measure:
Toxicity will be monitored in the subgroup receiving radiotherapy boost.
Event Free survival for patients with boost of radiotherapy.
•Stratum 3:
Overall survival measured from the date of randomisation to the date of death due to any cause.
Radiotherapy free survival rate
Quality of survival (QoS)
Neuropsychological outcomes
Neuroendocrine outcomes (Neuroendocrine late effects)
Short and long term Safety and Toxicity of frontline chemotherapy based on proportion of patients experiencing Toxicity grade 3 to 4 (Adverse Events (CTCAE v4.03)).
Exploratory Endpoint measures (optional):
Pharmacokinetic modelling will be carried out using Valproate pharmacokinetic parameters in conjunction with patient characteristics and clinical parameters in order to investigate the key factors involved in determining individual valproate drug exposures within the patient population.
•Valproate pharmacodynamics will be followed throughout changes in histone H3 and H4 acetylation. Changes between baseline and time of steady state valproate will be correlated with valproate trough levels and clinical response.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stratum 1:
5 years after the last patient recruited has completed his treatment
Stratum 2:
5 years after the last patient recruited has completed his treatment
Stratum 3:
5 years after the last patient recruited has completed his treatment
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, quality of survival neuropshychological and neuroendocrine morbidity. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Stratum1:Observation/Stratum2:VEC alone/Stratum3:Standard alterned ±myelosuppressive chemotherapy |
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| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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