SIOP-HRMB: An international prospective trial on clinically high-risk medulloblastoma (HR-MB) in patients older than 3 years.

Prior treatment

• Patients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and no other biological risk factors
• Patients previously treated for a brain tumour or any type of malignant disease
• Medical contraindication to radiotherapy or chemotherapy

Other illness

• Chang Stage M4 disease
• Known hypersensitivity to any of the treatments or excipients

Other

• Patients with proven or with high likelihood of germline TP53, APC, PTCH1, SUFU, PALB2, BRCA2 gene alteration or any other DNA repair defect.
• 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
• 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
• Brainstem or embryonal tumours in other sites

• Histologically proven (centrally reviewed) high-risk medulloblastoma, with any of the currently defined histological subtypes. High-risk disease is defined as patients with SHH or non-SHH/non-WNT (Groups 3 and 4) medulloblastoma, with at least one of the following high risk features: Metastatic disease- Chang Stage M1, M2 and M3, Large cell/anaplastic MB (as defined by WHO criteria 2016 [1]), Patients with MYC or MYCN amplified tumours (unless MYCN amplified non-WNT/non-SHH Group 4 without any other high risk factors), Patients with somatic SHH-TP53 mutant tumours, Patients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and other biological risk factors (as above)
• 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
• For Randomisation 2 ONLY: Patient entered into the SIOP-HRMB trial at diagnosis
• For Randomisation 2 ONLY: Patient treated with: Either Arm A (conventional radiotherapy) or Arm B (HART)
• 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: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome OR 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 ≥0.75 x 109/L; platelets ≥ 75 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 treatment