Internationale Studie für Patientinnen und Patienten mit Hochrisiko-Medulloblastom

Product Name: Thiotepa
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Thiotepa
CAS Number: 52-24-4
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 15-100

Product Name: Vincristine
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Vincristine
CAS Number: 57-22-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Cyclophosphamide
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Cyclophosphamide
CAS Number: 50-18-0
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 500-2000

Product Name: Temozolomide
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Temozolomide
CAS Number: 85622-93-1
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 5-250

Product Name: Carboplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: carboplatin
CAS Number: 41575-94-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: Cisplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: cisplatin
CAS Number: 15663-27-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Lomustine
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Lomustine
CAS Number: 13010-47-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Gender:
Female: yes
Male: yes

Inclusion criteria:
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) subgroup or non-SHH/non-wingless-type (WNT) (Groups 3 and 4) medulloblastoma, with at least one of the following high risk features:
oMetastatic disease: Chang Stage M1, M2 and M3.
oLarge cell/Anaplastic MB (as defined by World Health Organisation (WHO) criteria 2016
oPatients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and other biological risk factors
oPatients with MYC or MYCN amplified tumours (unless MYCN amplified Group 4 without any other high risk factors)
oPatients with SHH subgroup tumours harbouring somatic TP53 mutations.
?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 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:
oTotal bilirubin = 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert?s syndrome
oALT 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
?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:
oEither Arm A (conventional radiotherapy) or Arm B (HART) as part of R1


Are the trial subjects under 18? yes
Number of subjects for this age range: 750
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 99
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1

Exclusion criteria:
Exclusion criteria for trial entry and randomisation 1:
?Patients with proven or with high likelihood of Germline TP53, APC, PTCH, SUFU, PALB2, BRCA2 gene alteration or any other DNA repair defect.
?Group 4 patients with MYCN amplification and no other high-risk factor
?Patients with ?-catenin 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.