Children with medulloblastoma. Medulloblastoma is a highly cellular malignant embryonal neoplasm. 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
Sponsors
University Medical Center Hamburg-Eppendorf
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: General inclusion criteria all studies Submission of high quality biological material incl. fresh frozen tumour samples and blood CTC grades 3-5 and 3-5 and <22 years MB, SHH-activated and TP53-wildtype; MB, non-WNT/non-SHH; MB, group 3; MB, group 4; Histologic subtype: MB, classic and desmoplastic/nodular Clinically standard-risk, defined as total or near total surgical resection with less than or equal to 1.5 cm2 of residual tumour on early post-operative MRI, without and with contrast, on central review; no CNS metastasis on MRI on central review; no tumour cells on the cytospin of lumbar CSF; no clinical evidence of extra-CNS metastasis; Patients with a reduction of postoperative residual tumour through second surgery to less than or equal to 1.5 cm2 are eligible, if timeline for start of radiotherapy can be kept No amplification of MYC or MYCN; MYCN amplification allowed for patients with group 4 MB WNT-subgroup negativity is prerequisite: WNT-negative tumours are defined by ß-catenin nuclear immuno-negativity by IHC, and the absence of ß-catenin mutation For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH and SUFU is required. Exclusion of somatic mutation is sufficient for enrolment of the patient. In case of somatic alteration, urgent diagnostic evaluation for germline alteration after appropriate consent is necessary. Patients with germline TP53, PTCH, SUFU, BRCA2, or PALB2 alteration are not eligible for the study
Exclusion criteria
Exclusion criteria: Exclusion criteria LR a) One of the inclusion criteria is lacking; b) Brainstem or supratentorial embryonal tumour; c) Atypical teratoid rhabdoid tumour; d) Medulloepithelioma, embryonal tumour with multi-layered rosettes. e) Large cell/anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review. f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable. g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF); h) Patient previously treated for a brain tumour or any type of malignant disease; i) identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration. Unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours; j) Patients who are pregnant; k) Female patients who are sexually active and not taking reliable contraception; l) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons; m) Patients in whom non-compliance with toxicity management guidelines can be expected. Exclusion criteria SR a) One of the inclusion criteria is lacking; b) Brainstem or supratentorial embryonal tumour; c) Atypical teratoid rhabdoid tumour; d) Medulloepithelioma, embryonal tumour with multi-layered rosettes; e) Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review; f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable, MYCN amplification allowed for patients with group 4 medulloblastoma; g) Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF); h) Patient previously treated for a brain tumour or any type of malignant disease; i) identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration. Unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours j) identified somatic TP53 mutation in SHH activated tumours k) Patients who are pregnant; l) Female patients who are sexually active and not taking reliable contraception; m) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons; n) Patients in whom non-compliance with toxicity management guidelines can be expected. Exclusion criteria WNT-HR a) One of the inclusion criteria is lacking. b) Brainstem or supratentorial embryonal tumour. c) Atypical teratoid/rhabdoid tumour. d) Medulloepithelioma, embryonal tumour with multi-layered rosettes. e) Undeterminable biological profile, defined as WNT subgroup status not determinable. f) Patient previously treated for a brain tumour or any type of malignant disease. g) Identified germline APC, BRCA2, PALB2, PTCH, SUFU, or TP53 gene alteration. Unrefuted clinical suspect for biallelic mismatch repair syndrome, Fanconi anaemia, Gorlin syndrome, Li-Fraumeni syndro
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Treatment Study-LR -to confirm that the 3-year Event-Free Survival (EFS) rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80%. Treatment Study-SR -to test whether the Event-Free Survival (EFS) in children and adolescents with standard-risk medulloblastoma having an average-risk biological profile is different for patients treated with or without carboplatin concomitantly with radiotherapy. Treatment Study-WNT-HR -to confirm the 3-year event-free survival (EFS) of rate of 80 % in children and adolescents with high-risk medulloblastoma having a low-risk biological profile . Treatment Study SHH-TP53 -to determine the superiority of EFS in MB SHH-TP53-mutant patients receiving treatment adapted to presence of somatic or germline TP53 mutation in comparison to historic MB SHH TP53mut cohort.;Secondary Objective: Treatment Studies LR, SR, WNT-HR, and SHH-TP53 -Overall Survival rate, and pattern of relapse -Late effects focusing on Hearing, endocrine/neurologic function, health Status, executive function, behavioural outcome, situation,QoL -to conduct comprehensive studies in a prospective fashion on the biological basis of these subgroup medulloblastoma, with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in these disease subgroups. Treatment Study-SR -Progession-free survival rates (PFS) - to test the feasibility of carboplatin treatment concomitantly with radiotherapy Treatment Study SHH-TP53 -response after 1 and 2 cycles chemotherapy -response after RT -frequency of second malignancies after treatment -detection of increased treatment toxicity -to study late effects focusing on second malignancy -prospective studies with the aim to evaluate germline-somatic correlations, correlations of genotype and phenotype;Primary end point(s): The primary endpoint is event-free survival (EFSOP) for the treatment study SR | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Event-free survival (EFSend) 2) Overall survival (OSOP) 3) Overall survival (OSend) 4) Progression-free survival (PFSOP) 5) Feasibility of carboplatin treatment 6) Residual tumor (<1.5 cm2) will be estimated by central MRI review postoperatively 7) Relapse pattern will be evaluated at the end of therapy 8) Indirect measures for quality of survival 9) Ototoxicites 10) Endocrine function 11) Neurologic function 12) Biological tumour markers 13) Leukoencephalopathy (LEP) 14) Audit of compliance with protocol defined therapy Additional in SHH-TP53: a) Reponse Rate (RR) b) Duration of response (DOR) c) Incidence of secondary malignancies d) Incidence of local, metastastatic and combined relapses in relation to radiation field (inside or outside of radiation field) e) Incidence of somatic, germline, and mosaic TP53 mutations;Timepoint(s) of evaluation of this end point: After an estimated follow-up time of 3 years after last patient in | — |
Countries
Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom
Contacts
Public ContactStefan Rutkowski
University Medical Center Hamburg-Eppendorf
Outcome results
None listed