SIOP HR-Medulloblastoma

Primary objectives

• To evaluate whether the outcome in children, young people and adults with HR-MB is improved over standard therapy i.e. conventional (once a day) radiotherapy (RT) (standard therapy),for those treated with: hyperfractionated-accelerated radiotherapy (HART), or high-dose therapy (HDT) with thiotepa followed by conventional RT.
• To evaluate whether the outcome in HR-MB is different for those treated with two different maintenance chemotherapy therapies.

Secondary objectives

• To study the late effects of treatment, and their impact on quality of survival (QoS), including neurocognitive function, neurological impairment, endocrine impairment, audiological function and secondary tumours.
• To conduct comprehensive prospective biological studies in SIOP-HRMB, with the aims of (1) understanding the biological basis of HR-MB, (1a) identification and validation of diagnostic and prognostic biomarkers, and (1b) identification and validation of molecular targets with therapeutic potential and associated predictive biomarkers
• To conduct prospective QoS, toxicity and pharmacogenomic studies with the aim of exploring clinical, host and tumour factors, and genetic variants, that relate to early and late side-effects of treatment and survival parameters.

All arms

Two cycles of post-surgery induction therapy (Carboplatin/Etoposide) over 6 weeks.

Randomisation 1

Arm A (Randomisation 1):
Conventional radiotherapy (control arm), start 3-4 weeks after the second cycle Carbo/eto induction therapy:
Craniospinal irradiation: 36 Gy in 20 fractions
Primary tumour site boost: 18 Gy in 10 fractions
Total dose to the primary site: 54 Gy in 30 fractions

Arm B (Randomisation 1):
Hyperfractionated-Accelerated Radiotherapy HART, start 3-4 weeks after the second cycle Carbo/eto induction therapy:
Craniospinal irradiation: 39 Gy, 2 fractions/day, 15 treatment days
Primary tumour site boost: 20,8 Gy, 2 fractions/ day, 8 treatment days
Gesamtdosis: Primärtumor 59,8 Gy in 46 Fraktionen

Arm C (Randomisation 1):
Highdose chemotherapy, start earliest 3 weeks after the secon cycle inductuion therapy: 2 cycles of Thiotepa rfollowed by peripheral stem cell re-infusion. Duration ca. 4-6 weeks. Followed by:
Conventional radiotherapy (control arm), start 3-4 weeks after the second cycle Carbo/eto induction therapy:
Craniospinal irradiation: 36 Gy in 20 fractions
Primary tumour site boost: 18 Gy in 10 fractions
Total dose to the primary site: 54 Gy in 30 fractions

Randomisation 2

Arm D (Randomisation 2):
Standard maintenance therapy with VCR/CCNU/Cisp starts 6 (maximal 12) weeks nafter radiation therapy. A total of 8 blocks will be administered alternately with regimen A and regimen B. (Regimen A: cisplatin, CCNU, VCR; regimen B: cyclophosphamide, VCR). Total duration: 36 weeks.

Arm E (Randomisation 2): temozolomide maintenance chemotherapy:
Patients randomised to Arm C HD chemotherapy followed by conventional radiotherapy will not be eligible for R2 randomisation and will all be treated with Arm E.
Temozolomide maintenance chemotherapy starts 4 (max. 12) weeks weeks after radiation therapy. Temozolomide will be given on days 1-5 at the dose of 150 mg/m²/day, as a 28 day cycle for a total of 6 cycles.

Inclusion criteria for trial entry and randomisation 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-WNT-type (Groups 3 and 4) medulloblastoma, with at least one of the following high risk features:
• a) Metastatic disease: Chang Stage M1, M2 and M3*, b) Large cell/anaplastic MB (as defined by World Health Organisation (WHO) criteria 2016), c)Patients with MYC or MYCN amplified tumours (unless MYCN amplified non-WNT/non-SHH-Group 4 without any other high risk factors), d) Patients with somatic SHH-TP53 mutant tumours, e) 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. (See Section 18.1.4).
• 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; ALT or AST under 2.5 X ULN for age
• Adequate renal function defined as creatinine under 1.5 x ULN
• Adequate haematological function defined as ANC at least 0.75 x 109/L; plateletsat least 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 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: Either Arm A (conventional radiotherapy) or Arm B (HART)

• 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 (over 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.