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

• Register: EUCTR
• Last refreshed on: 4 March 2024
• Main ID: EUCTR2013-002766-39-NL
• Date of registration: 16/12/2019
• Prospective Registration: Yes
• Primary sponsor: CENTRE LEON BERARD
• Public title: SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma
• Scientific title: SIOP Ependymoma II - An International Clinical Program for the diagnosis and treatment of children, adolescents and young adults with Ependymoma - SIOP Ependymoma II
• Date of first enrolment: 05/02/2020
• Target sample size: 536
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002766-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Stratum1: Observation/Stratum2:VEC alone/Stratum3:Standard alterned ±myelosuppressive chemotherapy Number of treatment arms in the trial: 6
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, Finland, Germany, Greece, Ireland, Italy, Netherlands, Norway, Spain, Sweden, Switzerland

Contacts

• Name: DRCI-PROMOTION
• Affiliation: CENTRE LEON BERARD

• Name: DRCI-PROMOTION
• Affiliation: CENTRE LEON BERARD

Key inclusion & exclusion criteria

Inclusion criteria:
OVERALL PROGRAM:
• 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 ependymoma.
• Delivery to national referral pathology center of FFPE tumour tissue blocks.
• Written informed consent (staging).
• 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.

STRATUM I:
• Age>12 months and < 22 years at time of study entry.
• No residual measurable ependymoma based on the central neuroradiological 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.
• Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
• No metastasis on spinal MRI and on CSF cytology assessments.
• No previous radiotherapy.
• No previous chemotherapy.
• No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy.
• No medical contraindication to radiotherapy, and chemotherapy.
• No signs of infection.
• Adequate bone marrow, liver and renal function (detailled in protocol).
• 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.
• 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 (stratum 1).

STRATUM 2:
• Age > 12 months and < 22 years at time of study entry.
• No residual measurable ependymoma based on the central neuroradiological 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).
• Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
• No metastasis on spinal MRI and on CSF cytology assessments.
• No previous radiotherapy.
• No previous chemotherapy.
• No co-existent unrelated disease at the time of study entry that would render the patient unable to receive chemotherapy.
• No medical contraindication to radiotherapy, and chemotherapy.
• No signs of infection.
• Adequate bone marrow, liver and renal functions (detailled in protocol).
• 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.
• Patients and/or their parents or legal guardians must be willing and able to comply with
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.
• 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 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.
• 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.
• Inable 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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Histological diagnosis of intracranial localized ependymoma, including ependymoma variants: myxopapillary ependymoma, ependymoma (papillary, clear-cell, tanycytic), ependymoma RELA-fusion positive or anaplastic.
MedDRA version: 20.0 Level: PT Classification code 10014967 Term: Ependymoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: Vincristine
Product Code: VCR
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: VINCRISTINE
CAS Number: 57-22-7
Current Sponsor code: VCR
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Etoposide
Product Code: VP16
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETOPOSIDE
CAS Number: 33419-42-0
Other descriptive name: ETOPOSIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Product Name: CYCLOPHOSPHAMIDE
Product Code: CPM
Pharmaceutical Form: Powder for infusion
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Current Sponsor code: CPM
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 500-1000

Product Name: CISPLATIN
Product Code: CDDP
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATIN
CAS Number: 15663-27-1
Current Sponsor code: CDDP
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: CARBOPLATIN
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CARBOPLATIN
CAS Number: 41575-94-4
Other descriptive name: CARBOPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: SODIUM VALPROATE
Product Code: VPA
Pharmaceutical Form:
INN or Proposed INN: SODIUM VALPROATE
CAS Number: 1069-66-5
Current Sponsor code: VPA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: up to
Concentration number: 40-

Product Name: METHOTREXATE
Product Code: MTX
Pharmaceutical Form: Concentrate for solution for

Primary Outcome(s)

Secondary Objective: •Overall program
To evaluate second look surgery rates as compared to historical controls

•Stratum 1
To describe in both study arms, the efficacy in each molecular sub-group
(stratum 2 and 3)
To evaluate whether OS is improved
To compare neuroendocrine morbidity
To evaluate the QoS
To evaluate the neuropsychological morbidity
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 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 neuropsychological morbidity
To determine the safety and tolerability of valproate

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.

Main Objective: •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.

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.

Secondary Outcome(s)

Secondary end point(s): Overall program:
Second look surgery rate (Only descriptive statistics will be produced)
Stratum 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.

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.

Secondary ID(s)

NCT02265770

2013-002766-39-SE

ET13-002

Source(s) of Monetary Support

Koppie-Au Foundation

PHRC 2012

SFCE

Ethics review

Status: Approved
Approval date: 05/02/2020
Contact: