Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma

Inclusion Criteria:

* Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma (WNT M0-1, SHH M0-1 (p53wt), Group 4 M0-1)
* Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1
* Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA)
* Adult (18 years and above): in WNT-activated and Group 4 medulloblastoma
* Post-pubertal, defined as females with a bone age of at least 15 years and males with a bone age of at least 17 years, or adult (greater than 18 y of age) (see appendix N) in SHH-activated and TP53-wildtype medulloblastoma
* Availability of prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
* Availability of paraffin embedded tumour tissue (FFPE) (1 block or 30 unstained slides) and whole blood sample (10 ml) for central review
* For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH, SUFU, BRCA2 and PALB2 if known before randomization
* Clinical status within 2 weeks of randomization: Karnofsky 50-100. NANO-score 0 to 9 (allowing full-blown cerebellar symptoms)
* Clinically standard-risk (centrally assessed MRI review) defined as: total or near total surgical resection with less than or equal to 1.5 cm2 (measured in axial plane) of residual tumour on early post-operative MRI, without and with contrast; no CNS metastasis on MRI (cranial and spinal); Chang stage M0-1 with no clinical evidence of extra-CNS metastasis
* Full recovery from surgery or any post-surgical complication (e.g. Bleeding, infections etc)
* Pre-surgery and/or post-surgery MRI available.
* Baseline brain MRI and spinal MRI available within 2 weeks of randomization.
* Normal liver, renal and haematological function within 2 weeks of randomization.
* WBC greater than or equal to 3×10\^9/L
* ANC greater than or equal to 1.5×10\^9/L
* Platelet count of greater than or equal to 100×10\^9/L independent of transfusion
* Hemoglobin greater than or equal to 10 g/dl
* Total Bilirubin less than or equal to 1.5 ULN
* ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) less than or equal to 2.5 × ULN
* Serum creatinine less than 1.5 x ULN or creatinine clearance (CrCl) greater than 30 mL/min (using the Cockcroft-Gault formula)
* Negative serum or urine pregnancy test within 7 days of randomization for WOCBP.
* Patients of childbearing / reproductive potential (WOCBP) must use two methods of adequate birth control, including a highly effective method and a barrier method during the study treatment period and for at least 20 months after the last study treatment is mandatory for the patients that received sonidegib, for all other patients this period is at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Male patients even those who have had a vasectomy must always use a condom during treatment and for 6 months after last treatment. Men should not donate semen during treatment and for at least 6 months after ending treatment (donation of semen for the semen analyses of the fertility project 1 b is allowed). Appendix H.
* Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 20 months after the last study treatment.
* Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. For patients less than 18 years of age, consent has to be obtained from the parent(s) or legal representative.

Exclusion Criteria:

* Prior treatment for medulloblastoma
* Unavailability of central review pathology results.
* Inability to start radiotherapy within 43 days of surgery
* Significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing impairment greater than or equal to 20 dB at 1-3 kHz
* Any medical contraindication to radiotherapy or chemotherapy.
* Hypersensitivity to contrast medium for MRI.
* Hypersensitivity towards the active substance of any of study drugs or their excipients
* Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or statins
* Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
* Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score less than or equal to 6 and PSA less than 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance as per ESMO guidelines. Other cancers for which the subject has completed potentially curative treatment more than 5 years prior to diagnosis of medulloblastoma study entry are allowed
* Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV RNA \[qualitative\] is detected)
* Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive HIV-1/2 antibodies)
* Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.