Histologically proven 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 additional high risk feature MedDRA version: 20.0 Level: PT Classification code 10027107 Term: Medulloblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
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: r
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
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: o Metastatic disease: Chang Stage M1, M2 and M3. o Large cell/Anaplastic MB (as defined by World Health Organisation (WHO) criteria 2016 o Patients with significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and other biological risk factors o Patients with MYC or MYCN amplified tumours (unless MYCN amplified Group 4 without any other high risk factors) o Patients 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: o Total bilirubin = 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome o ALT or AST =65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
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 ß-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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To evaluate whether outcome in children, young people and adults with high risk medulloblastoma (HR-MB) is improved over standard therapy for those treated with;(i) conventional (once a day) radiotherapy(ii) hyperfractionated-accelerated radiotherapy (HART), or (iii) high dose chemotherapy with thiotepa followed by conventional radiotherapy. • To evaluate whether outcome in HR-MB is different for those treated with two different maintenance chemotherapy therapies (standard four-drug combination given as 8 cycles, alternating between cisplatin, lomustine and vincristine; and cyclophosphamide and vincristine; vs single agent oral temozolomide over 6 cycles) ;Secondary Objective: • 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 HR-MB, with the aims of (i) understanding the biological basis of HR-MB, (ii) identification and validation of diagnostic and prognostic biomarkers, and (iii) 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. ;Primary end point(s): The primary outcome measure is event-free survival (EFS). An “event” is considered to be any progression or relapse of disease, any deaths, and any occurrence of a secondary neoplasm. “Relapse” is defined as the appearance of local disease, metastasis, or both following documented complete resection, or previous complete response. “Progression” is defined as tumour growth > 25% (based on the three-dimensional measurement on the MRI) in the case of residual tumour. “Secondary | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Overall survival (OS) and progression-free survival (PFS) are secondary outcome measures. Pattern of relapse Indirect and direct measures of Quality of Survival (QoS) Audiological toxicity Endocrine function Neurological function Biological tumour markers;Timepoint(s) of evaluation of this end point: Overall survival and progression free survival are defined as the time from the date of randomisation to the date of death, relapse or progression for PFS or to date of death for OS; patients will be censored at date last seen if lost to follow-up. Pattern of relapse is defined as the time from the date of surgery and ends on the date of appearance of relapse/progression Indirect and direct measures of Quality of Survival will be assessed throughout the trial. Audiological toxicity, Endocrine function and Neurological function will be assessed throughout the trial. Biological tumour markers will be evaluated from pre-treatment samples. | — |
Countries
Austria, Belgium, Czechia, Czech Republic, Denmark, Finland, France, Germany, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom
Contacts
Public ContactEileen Grimes
University of Birmingham
Outcome results
None listed