- 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 (>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
- Full recovery from surgery or any post-surgical complication (e.g. Bleeding,
- 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 ≥ 3×10^9/L
- ANC ≥ 1.5×10^9/L
- Platelet count of ≥ 100×10^9/L independent of transfusion
- Hemoglobin ≥ 10 g/dl
- Total Bilirubin ≤ 1.5 ULN
- ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) ≤ 2.5 × ULN
- Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 30 mL/min (using the
- 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 < 18 years of age,
consent has to be obtained from the parent(s) or legal representative.
- 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 ≥ 20 dB at 1-3
- 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
- Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or
- 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 ≤ 6 and PSA < 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
- 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
- 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.