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 PREDISPOSITIO

Phase 3

Recruiting

Conditions: brain tumour
medulloblastoma
10029211

Registration Number: NL-OMON55597

Lead Sponsor: niversity Medical Centre Hamburg-Eppendorf

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 30

Inclusion Criteria

GENERAL INCLUSION CRITERIA ALL STUDIES
1. Submission of high quality biological material incl. fresh frozen tumour
samples and blood
2. CTC grades < 2 for liver, renal, haematological function
3. Central pathology review, central molecular diagnosis of genetically defined
subgroup, and central MRI mandatory
4. Cytospin of lumbar CSF
5. Written informed consent
6. National and local ethical committee approval
COMMON INCLUSION CRITERIA FOR LR, SR AND WNT-HR
1. No prior therapy for medulloblastoma (MB) other than surgery
2. 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. Inclusion of patients is not possible later than 40
days after first tumour surgery, or after start of radiotherapy
3. No significant sensineural hearing deficit
4. No identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene
alteration. No unrefuted clinical suspect for patient or familial
APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li
Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary
condition that affects tolerance of antitumour treatment, or may prone to
secondary tumours
5. No other medical contraindication to radiotherapy or chemotherapySPECIFIC
INCLUSION CRITERIA LR-STUDY
1. Age at diagnosis > 3-5 and < 16 years
2. MB, WNT-activated; histologic subtypes: MB, classic and desmoplastic/nodular
3. Clinically standard -risk MB, defined as total or near total surgical
resection with less than or equal to 1.5 cm2 of residual tumour on early
post-operative MRI, without and with contrast, on central review; no CNS
metastasis on MRI 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 tumour through second surgery to less than or equal to
1.5 cm2 are eligible, if timeline for start of radiotherapy can be kept
4. No amplification of MYC or MYCN
5. Low-risk biological profile, defined as presence of β-catenin mutation
resulting in WNT activation
SPECIFIC INCLUSION CRITERIA SR-STUDY
1. Age at diagnosis >3-5 and <22 years
2. MB, SHH-activated and TP53-wildtype; MB, non-WNT/non-SHH; MB, group 3; MB,
group 4; Histologic subtype: MB, classic and desmoplastic/nodular
3. Clinically standard-risk, defined as total or near total surgical resection
with less than or equal to 1.5 cm2 of residual tumour on early post-operative
MRI, without and with contrast, on central review; no CNS metastasis on MRI 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 tumour through second surgery to less than or equal to 1.5 cm2 are
eligible, if timeline for start of radiotherapy can be kept
4. No amplification of MYC or MYCN; MYCN amplification allowed for patients
with group 4 MB
5. WNT-subgroup negativity is prerequisite: WNT-negative tumours are defined by
β-catenin nuclear immuno-negativity by immunohistochemistry (IHC), and the
absence of β-catenin mutation
6. For patients with SHH activated tumours: exclusion of germline alteration of
TP53, PTCH and SUFU is required. Exclusion of somatic m

Exclusion Criteria

EXCLUSION CRITERIA PNET-5 MB - LR and PNET-5 MB - SR:
Exclusion criteria LR
1. One of the inclusion criteria is lacking;
2. Brainstem or supratentorial embryonal tumour;
3. Atypical teratoid rhabdoid tumour;
4. Medulloepithelioma, embryonal tumour with multi-layered rosettes.
5. Large cell/anaplastic medulloblastoma, or medulloblastoma with extensive
nodularity (MBEN), confirmed on central pathological review.
6. Unfavourable or undeterminable biological profile, defined as amplification
of 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. identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration.
Unrefuted clinical suspect for patient or familial APC-associated polyposis
conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin
Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance
of antitumour treatment, or may prone to secondary tumours;
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.

Exclusion criteria SR
1. One of the inclusion criteria is lacking;
2. Brainstem or supratentorial embryonal tumour;
3. Atypical teratoid rhabdoid tumour;
4. Medulloepithelioma, embryonal tumour with multi-layered rosettes;
5. Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma
with extensive nodularity (MBEN), confirmed on central pathological review;
6. Unfavourable or undeterminable biological profile, defined as amplification
of MYC or MYCN, or WNT subgroup status not determinable, MYCN amplification
allowed for patients with group 4 medulloblastoma;
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. identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration.
Unrefuted clinical suspect for patient or familial APC-associated polyposis
conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin
Snydrome, Fanconi anemia, or other hereditary condition that affects tolerance
of antitumour treatment, or may prone to secondary tumours
10. identified somatic TP53 mutation in SHH activated tumours
11. Patients who are pregnant;
12. Female patients who are sexually active and not taking reliable
contraception;
13. Patients who cannot be regularly followed up due to psychological, social,
familial or geographic reasons;
14. Patients in whom non-compliance with toxicity management guidelines can be
expected.

Exclusion criteria WNT-HR
1. One of the inclusion criteria is lacking.
2. Brainstem or supratentorial embryonal tumour.
3. Atypical teratoid/rhabdoid tumour.
4. Medulloepithelioma, embryonal tumour with multi-layered rosettes.
5. Undeterminable biological profile, defined as WNT subgroup status not
determinable.
6. Patient previously treated for a brain tumo

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>PNET 5 MB-LR:<br /><br>-3 year event-free survival (EFS)<br /><br><br /><br>PNET 5 MB-SR:<br /><br>-Event-free survival (EFS)<br /><br><br /><br>PNET 5 MB WNT-HR:<br /><br>-Event-free survival (EFS)<br /><br><br /><br>PNET 5 MB SHH-TP53<br /><br>-Event-free survival (EFS)</p><br>

Secondary Outcome Measures