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SNCTP000003045 | EUCTR2013-002766-39 | BASEC2018-01421
Alternative entry: NCT02265770

Ein internationales klinisches Therapieoptimierungsstudien-Programm für die Diagnose und Behandlung von Kindern, Jugendlichen und jungen Erwachsenen mit Ependymomen.

Data source: BASEC (Imported from 27.01.2022), WHO (Imported from 18.01.2022)
Changed: 05.10.2021
Disease category: Head and Neck Cancer, Other Cancer

Brief description of trial (Data source: BASEC)

Das Ependymom gehört zu den häufigsten bösartigen Hirntumoren bei Kindern und Jugendlichen. Meistens werden Patienten zuerst operiert, um den Tumor zu entfernen. Danach erhalten sie als Nachbehandlung eine Strahlentherapie und eine Chemotherapie (eine Therapie mit Medikamenten). Leider können so noch nicht alle Patienten geheilt werden und die Behandlung kann zu starken Nebenwirkungen führen.
Das Ziel dieser Studie ist es, die Diagnose und die Behandlung von Ependymom Patienten zu verbessern. Für alle Patienten soll eine spezifischere Therapie gefunden werden, die die Überlebensprognose und die Lebensqualität steigert. Die Studie wird untersuchen, ob bei Patienten mit guten Heilungschancen die Therapie ohne Nachteile verringert werden kann. So wären die Patienten schwächeren Nebenwirkungen ausgesetzt und die Therapie wäre weniger belastend. Bei Patienten mit weniger guten Heilungschancen werden vielversprechende neue Therapieansätze mit der heutigen Standardtherapie verglichen.

Health conditions investigated (Data source: BASEC)

Ependymom bei Kindern, Jugendlichen und jungen Erwachsenen.

Health conditions (Data source: WHO)

Histological diagnosis of intracranial localized ependymoma, including ependymoma variants: myxopapillary ependymoma, ependymoma (papillary, clear-cell, tanycytic), ependymoma RELA-fusion positive or anaplastic .
MedDRA version: 20.0Level: PTClassification code 10014967Term: EpendymomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]

Rare disease (Data source: BASEC)

Yes

Intervention investigated (e.g. drug, therapy or campaign) (Data source: BASEC)

Das Forschungsprogramm besteht aus drei Teilen. Im ersten Teil wird der Tumor bei einer Operation weit möglichst entfernt und Proben davon in einem Labor untersucht. Bei Patienten, bei denen eine weitgehende Entfernung während der ersten Operation nicht möglich war, analysiert eine nationale Gruppe von Neurochirurgen und Neuroonkologen die Bilder und die Operations- und anderen Arztberichte und macht darauf basierend eine Empfehlung an die behandelnde Klinik, ob der Patient noch einmal operiert werden soll. Diese Empfehlung ist jedoch nicht bindend. Die Patienten werden danach, in drei Behandlungsgruppen eingeteilt. Patienten in jeder Gruppe erhalten nach Zufallsprinzip eine von zwei Behandlungen. Die drei Gruppen sind:
1) Falls der Tumor vollständig entfernt werden konnte, untersucht die Studie ob eine Strahlentherapie als Nachbehandlung ausreicht oder zusätzlich zur Strahlentherapie eine Chemotherapie nötig ist. Die Gruppeneinteilung, mit oder ohne Chemotherapie, wird durch das Zufallsprinzip vorgenommen (Randomisierung).
2) Fall der Tumor nicht vollständig entfernt werden konnte, wird zuerst bei allen Patienten eine Chemotherapie durchgeführt. Dazu wird durch eine Randomisierung entschieden, ob die Chemotherapie ohne oder mit zusätzlichem Methotrexat durchgeführt wird. Danach wird eine Strahlentherapie durchgeführt, gefolgt von einer weiteren Chemotherapie.
3) Bei Patienten unter 12 Monaten, sowie Patienten die aus anderen Gründen nicht für eine Strahlentherapie in Frage kommen, wird eine intensive Chemotherapie durchgeführt. Die Hälfte der Patienten (Randomisierung) erhält zusätzlich das Medikament Valproat.
Der dritte Teil des Forschungsprogramms ist eine Beobachtungsstudie. Die Proben der Patienten werden direkt nach der Operation zusätzlich in spezialisierte Labore geschickt und dort nochmals untersucht. Durch diese Untersuchungen kontrollieren Expertengruppen die Diagnose und Therapieeinteilung der Patienten. Zusätzlich sollen durch den Einsatz moderner Labormethoden molekulare Gewebeeigenschaften bestimmt werden, die zum einen die Diagnose noch sicherer machen, zum anderen auch Auskunft über den zu erwarteten Krankheitsverlauf geben können. So kann das Wissen über Ependymome erweitert werden und zu einer noch besseren Behandlung zukünftiger Patienten führen.

Interventions (Data source: WHO)


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
Current Sponsor code: VP16
Other descriptive name: ETOPOSIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

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
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Methotrexate
Product Code: MTX
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Current Sponsor code: MTX
Other descriptive name: METHOTREXATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Product Name: Sodium Valproate
Product Code: VPA
Pharmaceutical Form: Oral solution
INN or Proposed INN: SODIUM VALPROATE
CAS Number: 1069-66-5
Current Sponsor code: VPA
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-

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: Cyclophosphamide

Criteria for participation in trial (Data source: BASEC)

Diagnose eines Ependymoms
Patienten unter 22 Jahren
Hauptwohnort in einem der teilnehmenden Länder

Exclusion criteria (Data source: BASEC)

Erste Diagnose vor offizieller Eröffnung der Studie
Vorgängige Behandlung mit Anti-Tumor Medikamenten
Teilnahme an einer anderen Ependymom Studie

Inclusion/Exclusion Criteria (Data source: WHO)

Inclusion criteria:
OVERALL PROGRAM:
•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,
•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 1:
•Age>12 months and < 22 years at time of study entry,
•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
•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 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)
•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 scheduled visits, treatment plan, laborator
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,
• nable 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.

Further information on the trial in WHO primary registry

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002766-39

Further information on the trial from WHO database (ICTRP)

https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-002766-39-GR

Further information on trial

Date trial registered

11.03.2021

Incorporation of the first participant

01.04.2021

Recruitment status

Authorised-recruitment may be ongoing or finished

Academic title (Data source: WHO)

An international clinical program for the diagnosis and treatment of children, adolescents and young adults with ependymoma. - SIOP EP II

Type of trial (Data source: WHO)

Interventional clinical trial of medicinal product

Design of the trial (Data source: WHO)

Controlled: yes
Randomised: yes
Open: yes
Single blind: no
Double blind: no
Parallel group: yes
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: yes
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 (Data source: WHO)

Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): yesTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no

Primary end point (Data source: WHO)

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.;Secondary Objective: 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 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;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.;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.

Secundary end point (Data source: WHO)

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

Contact information (Data source: WHO)

Floga- Parents association of Children with Cancer;PHRC 2012;SFCE;Koppie-Au Foundation

Trial results (Data source: WHO)

Results summary

An international clinical program for the diagnosis and treatment of children, adolescents and young adults with ependymoma.

Link to the results in the primary register

no information available yet

Information on the availability of individual participant data

no information available yet

Trial sites

Trial sites in Switzerland (Data source: BASEC)

Aarau, Basel, Bellinzona, Bern, Geneva, Lausanne, Luzern, St. Gallen, Zurich

Countries (Data source: WHO)

Switzerland might not appear as site of trial if it has not yet been entered as such in the WHO primary registry.
Austria, Belgium, Czech Republic, Denmark, Finland, Germany, Greece, Ireland, Italy, Netherlands, Norway, Spain, Sweden

Contact for further information on the trial

Details of contact in Switzerland (Data source: BASEC)

Dr. med. Nicolas Gerber
+41 44 266 74 55
nicolas.gerber@kispi.uzh.ch

Contact for general information (Data source: WHO)

National Coordinating Site
8, Levadias str.
Hellenic society of Pediatric Haematology-Oncology
302106800125
contact@eepao.gr

Contact for scientific information (Data source: WHO)

National Coordinating Site
8, Levadias str.
Hellenic society of Pediatric Haematology-Oncology
302106800125
contact@eepao.gr

Principal Sponsor/Investigator

Principal sponsor (Data source: WHO)

Centre Léon Bérard

Authorisation by the ethics committee (Data source: BASEC)

Name of the authorising ethics committee (for multicentre studies only the lead committee)

Kantonale Ethikkommission Zürich

Date of authorisation by the ethics committee

06.11.2018

Further trial identification numbers

Trial identification number of the ethics committee (BASEC-ID) (Data source: BASEC)

2018-01421

Secondary ID (Data source: WHO)

ET-13-002
NCT02265770
VHP 201385
2013-002766-39-SE