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Inclusion criteria for trial entry and R1:
• Histologically proven (centrally reviewed) high-risk medulloblastoma, with
any of the currently defined histological subtypes. High-risk disease is
defined as patients with sonic hedgehog (SHH) or non-SHH/non-wingless-type
(WNT) (Groups 3 and 4) medulloblastoma, with at least one of the following high
risk features:
o Metastatic disease: Chang Stage M1, M2 and M3
o Large cell/anaplastic MB (as defined by World Health Organisation (WHO)
criteria 2016
o Patients with MYC or MYCN amplified tumours (unless MYCN amplified
non-WNT/non-SHH Group 4 without any other high risk factors)
o Patients with somatic SHH-TP53 mutant tumours .
o Patients with significant residual tumour (> 1.5 cm2) following surgical
resection of the primary tumour and other biological risk factors (as above)

• Age at diagnosis >=3 years. The date of diagnosis is the date on which initial
surgery is undertaken
• Submission of biological material, including fresh frozen tumour samples and
blood, in accordance with national and international schemes for molecular
genetic assessment of biological markers, and for associated biological studies
• No prior treatment for medulloblastoma, other than surgery, with the
exception of one cycle of induction chemotherapy with carboplatin and etoposide
may be given prior to trial entry and randomisation where there is clinical
urgency to start treatment
• Adequate hepatic function defined as:
o Total bilirubin <= 1.5 times upper limit of normal (ULN) for age, unless the
patient is known to have Gilbert*s syndrome
o ALT or AST < 2.5 X ULN for age
• Adequate renal function defined as creatinine < 1.5 x ULN
• Adequate haematological function defined as ANC >=1 x 109/L; platelets >= 100 x
109/L, prior to induction chemotherapy
• No significant hearing deficit in at least one ear (significant hearing
deficit defined as Chang grade 3 or above)
• Medically fit to receive protocol treatment
• Documented negative pregnancy test for female patients of childbearing
potential
• Patient agrees to use effective contraception whilst on treatment (patients
of childbearing potential)
• Written informed consent from the patient and/or parent/legal guardian

Inclusion criteria for Randomisation 2 (R2):
• Patient entered into the SIOP-HRMB trial at diagnosis
• Patient treated with:
o Either Arm A (conventional radiotherapy) or Arm B (HART)

Exclusion Criteria

Exclusion criteria for trial entry and R1:
• Patients with proven or with high likelihood of germline TP53, APC, PTCH1,
SUFU, PALB2, BRCA2 gene alteration or any other DNA repair defect
• Non-WNT/non-SHH Group 4 patients with MYCN amplification and no other
high-risk factor
• Patients with CTNNB1 mutation positive WNT medulloblastoma irrespective of
other risk factors
• Patients with significant residual tumour (> 1.5 cm2) following surgical
resection of the primary tumour and no other biological risk factors
• Chang Stage M4 disease
• Brainstem or embryonal tumours in other sites
• Patients previously treated for a brain tumour or any type of malignant
disease
• Medical contraindication to radiotherapy or chemotherapy
• Known hypersensitivity to any of the treatments or excipients
• Females who are pregnant or breastfeeding
• Patients who cannot be regularly followed up due to psychological, social,
family, geographical or other issues
• Patients for whom non-compliance with treatment, management guidelines or
monitoring is expected

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary outcome measure is event-free survival (EFS).</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary: Overall survival (OS), progression free survival (PFS), toxicity<br /><br>(including late<br /><br>effects), Quality of Survival (QoS).</p><br>

Updated 11/6/2023

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