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 OCURRING IN THE CONTEXT OF GENETIC PREDISPOSITIO

Phase 1

• Conditions: Children with medulloblastoma. Medulloblastoma is a highly cellular malignant embryonal neoplasm.; MedDRA version: 20.0Level: PTClassification code 10027107Term: MedulloblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-004868-30-AT
• Lead Sponsor: niversity Medical Center Hamburg-Eppendorf

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-03-09
• Last Update Posted: 10 May 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 410

Inclusion Criteria

General inclusion criteria all studies
Submission of high quality biological material incl. fresh frozen tumour samples and blood
CTC grades < 2 for liver, renal, haematological function
Central pathology review, central molecular diagnosis of genetically defined subgroup, and central MRI mandatory
Cytospin of lumbar CSF
Written informed consent
National and local ethical committee approval

Common inclusion criteria LR, SR, WNT-HR
No prior therapy for medulloblastoma (MB) other than surgery
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
No significant sensineural hearing deficit
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
No other medical contraindication to radiotherapy or chemotherapy

Specific inclusion criteria LR
Age at diagnosis >3-5 and <16 years
MB, WNT-activated; histologic subtypes: MB, classic and desmoplastic/nodular
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
No amplification of MYC or MYCN
Low-risk biological profile, defined as presence of ß-catenin mutation resulting in WNT activation

Specific inclusion criteria SR-study
Age at diagnosis >3-5 and <22 years
MB, SHH-activated and TP53-wildtype; MB, non-WNT/non-SHH; MB, group 3; MB, group 4; Histologic subtype: MB, classic and desmoplastic/nodular
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
No amplification of MYC or MYCN; MYCN amplification allowed for patients with group 4 MB
WNT-subgroup negativity is prerequisite: WNT-negative tumours are defined by ß-catenin nuclear immuno-negativity by IHC, and the absence of ß-catenin mutation
For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH and SUFU is required. Exclusion of somatic mutation is sufficient for enrolment of the patient. In case of somatic alteration, urgent diagnostic evaluation for germline alteration after appropriate consent is necessary. Patients with germline TP53, PTCH, SUFU, BRCA2, or PALB2 alteration are not eligible for the study

Exclusion Criteria

Exclusion criteria LR
a) One of the inclusion criteria is lacking;
b) Brainstem or supratentorial embryonal tumour;
c) Atypical teratoid rhabdoid tumour;
d) Medulloepithelioma, embryonal tumour with multi-layered rosettes.
e) Large cell/anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review.
f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable.
g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF);
h) Patient previously treated for a brain tumour or any type of malignant disease;
i) 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;
j) Patients who are pregnant;
k) Female patients who are sexually active and not taking reliable contraception;
l) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons;
m) Patients in whom non-compliance with toxicity management guidelines can be expected.

Exclusion criteria SR
a) One of the inclusion criteria is lacking;
b) Brainstem or supratentorial embryonal tumour;
c) Atypical teratoid rhabdoid tumour;
d) Medulloepithelioma, embryonal tumour with multi-layered rosettes;
e) Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review;
f) 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;
g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF);
h) Patient previously treated for a brain tumour or any type of malignant disease;
i) 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
j) identified somatic TP53 mutation in SHH activated tumours
k) Patients who are pregnant;
l) Female patients who are sexually active and not taking reliable contraception;
m) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons;
n) Patients in whom non-compliance with toxicity management guidelines can be expected.

Exclusion criteria WNT-HR
a) One of the inclusion criteria is lacking.
b) Brainstem or supratentorial embryonal tumour.
c) Atypical teratoid/rhabdoid tumour.
d) Medulloepithelioma, embryonal tumour with multi-layered rosettes.
e) Undeterminable biological profile, defined as WNT subgroup status not determinable.
f) Patient previously treated for a brain tumour or any type of malignant disease.
g) Identified germline APC, BRCA2, PALB2, PTCH, SUFU, or TP53 gene alteration.
Unrefuted clinical suspect for biallelic mismatch repair syndrome, Fanconi anaemia, Gorlin syndrome, Li-Fraumeni syndro

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified