International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

• Register: ClinicalTrials.gov
• Last refreshed on: 25 April 2022
• Main ID: NCT02066220
• Date of registration: 07/02/2014
• Prospective Registration: Yes
• Primary sponsor: Universitätsklinikum Hamburg-Eppendorf
• Public title: International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
• Scientific title: AN INTERNATIONAL PROSPECTIVE TRIAL ON MEDULLOBLASTOMA (MB) IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH WNT BIOLOGICAL PROFILE (PNET 5 MB - LR and PNET 5 MB - WNT-HR), AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR), OR TP53 MUTATION, AND REGISTRY FOR MB OCCURRING IN THE CONTEXT OF GENETIC PREDISPOSITION
• Date of first enrolment: June 2014
• Target sample size: 360
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/show/NCT02066220
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2/Phase 3

Countries of recruitment

Austria, Belgium, Czech Republic, Czechia, Denmark, France, Germany, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Francois Doz, Prof. Dr.
• Affiliation: Institut Curie Paris, France

• Name: Till Milde, Dr. med.
• Affiliation: Hopp Children´s Tumor Center at the NCT (KiTZ) and German Cancer Research Center

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22
years (LR-arm: less than 16 years). The date of diagnosis is the date on which surgery
is undertaken.

2. Histologically proven medulloblastoma, including the following subtypes, as defined in
the WHO classification (2007): classic medulloblastoma, desmoplastic/nodular
medulloblastoma. Pre-treatment central pathology review is considered mandatory.

3. Standard-risk medulloblastoma, defined as;

- total or near total surgical resection with less than or equal to 1.5 cm2
(measured on axial plane) of residual tumour on early post-operative MRI, without
and with contrast, on central review;

- no central nervous system (CNS) metastasis on MRI (cranial and spinal) on central
review;

- no tumour cells on the cytospin of lumbar CSF

- no clinical evidence of extra-CNS metastasis; Patients with a reduction of
postoperative residual tumor through second surgery to less than or equal to 1.5
cm2 are eligible, if if timeline for start of radiotherapy can be kept.

4. Submission of high quality biological material including fresh frozen tumor samples
for the molecular assessment of biological markers (such as the assessment of
myelocytomatosis oncogene (MYC) copy number status) in national biological reference
centers. Submission of blood is mandatory for all patients, who agree on germline DNA
studies. Submission of CSF is recommended.

5. No amplification of MYC or MYCN (determined by FISH).

6. For LR-arm: Low-risk biological profile, defined as WNT subgroup positivity. The WNT
subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or
(ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin
mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional
testing).

For SR-arm: average-risk biological profile, defined as ß-catenin nuclear
immuno-negativity by IHC (mandatory) and mutation analysis (optional).

7. No prior therapy for medulloblastoma other than surgery.

8. Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability
to start radiotherapy within 40 days after surgery renders patients ineligible for the
study.

9. Screening for the compliance with eligibility criteria should be completed, and
patient should be included into the study within 28 days after first surgery (in case
of second surgery within 35 days after first surgery). Inclusion of patients is not
possible later than 40 days after first tumour surgery, or after start of
radiotherapy.

10. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function

11. no significant sensorineural hearing deficit as defined by pure tone audiometry with
bone conduction or air conduction and normal tympanogram showing no impairment = 20
decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is not
possible postoperatively, normal otoacoustic emissions are acceptable, if there is no
history for hearing deficit.

12. No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA
breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome
or other reasons as defined by patient's clinician.

13. No identified Turcot and Li Fraumeni syndrome.

14. Written informed consent (and patient assent where appropriate) for therapy according
to the laws of each participating country. Information must be provided to the patient
on biological studies (tumour and germline), and written informed consent obtained of
agreement for participation.

15. National and local ethical committee approval according to the laws of each
participating country (to include approval for biological studies).

Exclusion Criteria:

1. One of the inclusion criteria is lacking.

2. Brainstem or supratentorial primitive neuro-ectodermal tumour.

3. Atypical teratoid rhabdoid tumour.

4. Medulloepithelioma; Ependymoblastoma

5. Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with
extensive nodularity (MBEN), centrally confirmed.

6. Unfavourable or undeterminable biological profile, defined as amplification of MYC or
MYCN, or MYC or MYCN or WNT subgroup status not determinable.

7. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative
lumbar CSF).

8. Patient previously treated for a brain tumour or any type of malignant disease.

9. DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or
identified Gorlin,Turcot, or Li Fraumeni syndrome.

10. Patients who are pregnant.

11. Female patients who are sexually active and not taking reliable contraception.

12. Patients who cannot be regularly followed up due to psychological, social, familial or
geographic reasons.

13. Patients in whom non-compliance with toxicity management guidelines can be expected.



Age minimum: 3 Years
Age maximum: 21 Years
Gender: All

Health Condition(s) or Problem(s) studied

Brain Tumors

Intervention(s)

Drug: Induction Chemotherapy

Radiation: Radiotherapy without Carboplatin

Radiation: WNT-HR < 16 years

Radiation: WNT-HR >= 16 years

Drug: Vinblastin Maintenance

Radiation: Radiotherapy with Carboplatin

Drug: Reduced-intensity maintenance chemotherapy

Radiation: SHH-TP53 (somatic)

Drug: Maintenance chemotherapy

Radiation: SHH-TP53 M+ (germline)

Radiation: SHH-TP53 M0

Primary Outcome(s)

3-year Event-Free Survival (EFS) [Time Frame: LR-arm after 9 years, SR-arm after 105 events (approx. 10 years)]

Secondary Outcome(s)

Late effects of therapy on endocrine function [Time Frame: 10 years]

Progression-free survival [Time Frame: 10 years]

Residual tumor [Time Frame: 6 years]

Feasibility of carboplatin treatment [Time Frame: approx. 7 years]

Pattern of relapse [Time Frame: 10 years]

Late effects of therapy on quality of survival [Time Frame: 10 years]

Leukoencephalopathy grading [Time Frame: 8 years]

Overall survival [Time Frame: 10 years]

Late effects of therapy on audiology [Time Frame: 8 years]

Late effects of therapy on neurology [Time Frame: 10 years]

Secondary ID(s)

SIOP PNET 5 MB

2011-004868-30

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Deutsche Kinderkrebsstiftung