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 | 20.0 |
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 16 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 compare the activity 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
•Stratum 1
To evaluate whether OS is improved
To compare the neuroendocrine morbidity
To evaluate the QoS
To evaluate the neurophychological morbidity
To determine the safety and tolerance
•Stratum 2
To determine the safety and tolerability
To evaluate whether OS is improved
To evaluate whether PFS is improved
To compare neuroendocrine morbidity
To evaluate the QOS
To evaluate the neuropsychological morbidity
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 compare the neuroendocrine morbidity
To evaluate the Quality of Survival
To evaluate the neuropsychologica 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 |
Integrated 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.
To prospectively evaluate 1q copy - number status, Tenascin C, NELL 2, LAMA 2, RELA - fusion and molecular subgroup as prognostica and prtedictive biomarkers in ependymoma within Clinical trial setting. |
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E.3 | Principal inclusion criteria |
OVERALL PROGRAM (staging phase):
- Main residence in one of the participating countries
- Age < 22 years old at the 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 (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 (specific to staging) for data and study biological samples collection,
- 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
Inclusion criteria applying to ALL 3 stratum (1, 2 and 3).
- Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review
- No previous radiotherapy
- No previous chemotherapy (except steroids)
- No co-existent unrelated disease (e.g. renal, hematological) at the time of study entry that would render the patient unable to receive chemotherapy
- No signs of infection
- Adequate bone marrow function (details see protcol)
- Adequate liver function (details see protocol)
- Adequate renal function: < 1.5 x Normal serum creatinine as adjusted for age (details see protocol)
- Patients must be affiliated to a Social Security System in countries where this is mandatory
STRATUM 1 inclusion criteria in addition to those listed above applying to all 3 stratum.
- Age > 12 months and < 22 years at time of study entry
- No residual measurable ependymoma based on the central neuro-radiological review (please refer to radiological assessment: section Definitions of residual tumour detailed in protocol)
- No metastasis on spinal MRI and on CSF cytology assessments (see section Mandatory Lumbar puncture)
- No medical contraindication to radiotherapy, and chemotherapy
- 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 (details see protocol)
- 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 (specific to stratum 1) from patients and/or their parents or legal guardian(s) obtained for study participation, data acquisition and transfer, collection and transfer of biological samples. Assent, of the child, when appropriate, will be obtained according to institutional guidelines
STRATUM 2 inclusion criteria in addition to those listed above applying to all stratum:
- Age > 12 months and < 22 years at time of study entry,
- Residual non reoperable measurable ependymoma based on central neuro-radiological Review (details see protocol)
- No metastasis on spinal MRI and on CSF cytology assessments (see section Mandatory Lumbar puncture)
-- 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 (details see protocol)
- 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 2
- Written informed consent (specific to stratum 2) from patients and/or their parents or legal guardian(s) obtained for study participation, data acquisition and transfer, collection and transfer of biological samples. Assent, of the child, when appropriate, will be obtained according to institutional guidelines
STRATUM 3 inclusion criteria in addition to those listed above applying to all stratum:
- 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
- No medical contraindication to chemotherapy
- Patients and/or their parents or legal guardians must be willing and able to comply withscheduled visits, treatment plan, laboratory tests and other study procedures of the stratum 3
- Written informed consent (specific to stratum 3) from parents or legal guardian(s) obtained for study participation, data acquisition and transfer, collection and transfer of biological samples. Assent, of the child, when appropriate, will be obtained according to institutional
guidelines
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E.4 | Principal 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 in appendix 4 of this protocol (SmPCs in appendix are those from UK which were chosen for the assessment of the safety aspects of the study)
- 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 productadministration, 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 in appendix 4 of this protocol (SmPCs in appendix are those from UK which were chosen for the assessment of
the safety aspects of the study)
- 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
- 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
- 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 in appendix 4 of this protocol (SmPCs in appendix are those from UK which were chosen for the assessment of the safety aspects of the study) |
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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 |