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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Jun 2015 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-512222-28-00

EudraCT number

2013-002766-39

ClinicalTrials.gov

NCT02265770

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Diagnosis, Others, Therapy

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 progression-free survival (PFS) in patients who receive 16 weeks of chemotherapy (VEC+CDDP) following complete surgical resection and radiotherapy to those who undergo complete surgical resection 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.
Stratum 3:
To evaluate the progression free survival in children unable to receive radiation therapy and who receive valproate, as a histone deacetylase inhibitor in addition to the primary chemotherapy strategy when compared to those that undergo chemotherapy without valproate.

Secondary objectives 10

1. Overall program : To evaluate second look surgery rates as compared to historical controls.
2. All interventional strata : To describe in both study arms, the efficacy in each molecular sub-group.
3. All interventional strata : To evaluate whether overall survival (OS) is improved in patients in the experimental arm when compared to those in the standard arm.
4. All interventional strata : To compare the neuroendocrine morbidity in each treatment arm.
5. All interventional strata : To evaluate the neuropsychological morbidity in each treatment arm.
6. All interventional strata : To evaluate the quality of survival (QoS) in each treatment arm.
7. All interventional strata : To determine the safety and the tolerance of patients in the experimental arm when compared to those in the standard arm.
8. Stratum 2 : To describe the concordance between central and local radiological assessment of the efficacy of post-operative chemotherapy.
9. Stratum 2 : To evaluate whether progression-free survival (PFS) is improved in patients with VEC+HD-MTX Dose following surgical resection when compared to those who receive VEC alone
10. Stratum 3 : to evaluate whether radiotherapy- and progression- free survival are improved in patients who receive valproate added to a primary chemotherapy when compared to those who receive primary chemotherapy only

Conditions and MedDRA coding

Newly diagnosed with an intracranial or spinal ependymoma (all WHO grades) including ependymoma variants: cellular, papillary, myxopapillary, clear-cell and tanycytic or anaplastic ependymoma.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 24

1. Overall program : Main residence in one of the participating countries.
2. Overall program : Age < 22 years old at the diagnosis.
3. Overall program : Histological diagnosis of intracranial or spinal, localized or metastatic, ependymoma according to local pathologist (all WHO grades).
4. 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).
5. Overall program : Written informed consent (specific to staging) for data and study biological samples collection.
6. 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.
7. Overall program : Patients must be affiliated to a Social Security System in countries where this is mandatory.
8. All interventional strata : Newly diagnosed intracranial ependymoma of WHO grade II-III confirmed by central pathological review.
9. All interventional strata : No previous radiotherapy.
10. All interventional strata : No previous chemotherapy (except steroids).
11. 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.
12. All interventional strata : No signs of infection.
13. All interventional strata : Adequate bone marrow, liver and renal function (detailed in protocol).
14. 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.
15. All interventional strata : Written informed consent (specific to the stratum)
16. Stratum 1 and 2 : Age ≥ 12 months and < 22 years at time of study entry.
17. Stratum 1 and 2 : No metastasis on spinal MRI and on CSF cytology assessments.
18. Stratum 1 and 2 : No medical contraindication to radiotherapy, and chemotherapy.
19. 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.
20. 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.
21. 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.
22. 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).
23. 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.
24. Stratum 3 : No medical contraindication to chemotherapy.

Exclusion criteria 18

1. Overall program : Patient with subependymomas and ependymoblastomas.
2. Overall program : Primary diagnosis predating the activation of the SIOP Ependymoma II program (Apr 29th 2015).
3. All interventional strata : Tumour entity other than primary intracranial ependymoma.
4. All interventional strata : Patients with WHO grade I ependymoma including myxopapillary variant.
5. All interventional strata : Patients with spinal cord location of the primary tumour.
6. 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.
7. All interventional strata : Participation within a different trial for treatment of ependymoma.
8. All interventional strata : Pre-existing mucositis, peptic ulcer, inflammatory bowel disease, ascites, or pleural effusion.
9. All interventional strata : Contraindication to one of the IMP used in the stratum according to the SmPCs (see protocol).
10. All interventional strata : Concurrent treatment with any anti-tumour agents.
11. All interventional strata : Unable to tolerate intravenous hydration.
12. All interventional strata : Inability to tolerate chemotherapy.
13. Stratum 1 and 2 : Patient for whom imaging remains RX despite all effort to clarify the MRI conclusion.
14. Stratum 3 : Pre-existing severe hepatic and/or renal damage.
15. Stratum 3 : Family history of severe epilepsy in immediate family siblings.
16. Stratum 3 : Presence of previously undiagnosed mitochondrial disorder detected by screening as part of trial.
17. Stratum 3 : Elevated blood ammonium level ≥ 1.5 x upper limit of the normal.
18. Stratum 3 : Elevated blood lactate level ≥ 1.5 x upper limit of the normal.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Overall program : Gross Total Resection (GTR) rate
2. Stratum 1 and 3 : Progression Free Survival (PFS)
3. Stratum 2 : Number of treatment responders (according to central radiological review)

Secondary endpoints 10

1. Overall program : Second look surgery rate
2. All interventional strata : Efficacy in each molecular sub-group in terms of PFS and OS
3. All interventional strata : Overall Survival
4. All interventional strata : Neuroendocrine outcomes
5. All interventional strata : Neuropsychological outcomes
6. All interventional strata : Quality of Survival
7. All interventional strata : Adverse events (CTCAE v4.03)
8. Stratum 2 : The concordance rate between central and local radiological reviews will be described as the proportion of patients in whom the result of the central radiological review confirms the local review.
9. Stratum 2 : Progression Free Survival
10. Stratum 3 : Radiotherapy-free survival rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Dr Pierre LEBLOND

Public contact point

Organisation

Centre Leon Berard

Contact name

Dr Pierre LEBLOND

Third parties 1

Locations

13 EU/EEA countries · 144 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 655 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications