| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children with medulloblastoma. Medulloblastoma is a highly cellular malignant embryonal neoplasm. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Medulloblastoma is a type of brain tumour that mainly affects children |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027107 |
| E.1.2 | Term | Medulloblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Substudies will only be conducted in Germany. |
- Begleitstudie Neuropsychologische Basisdiagnostik
- Molekulare Begleitstudie DKFZ
- Begleitstudie zur Apoptoseinduktion |
|
| E.3 | Principal inclusion criteria |
General inclusion criteria all studies
Submission of high quality biological material incl. fresh frozen tumour samples and blood
CTC grades < 2 for liver, renal, haematological function
Central pathology review, central molecular diagnosis of genetically defined subgroup, and central MRI mandatory
Cytospin of lumbar CSF
Written informed consent
National and local ethical committee approval
Common inclusion criteria LR, SR, WNT-HR
No prior therapy for medulloblastoma (MB) other than surgery
Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study
Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy
No significant sensineural hearing deficit
No identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration. No 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
No other medical contraindication to radiotherapy or chemotherapy
Specific inclusion criteria LR
Age at diagnosis >3-5 and <16 years
MB, WNT-activated; histologic subtypes: MB, classic and desmoplastic/nodular
Clinically standard -risk MB, 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
Low-risk biological profile, defined as presence of β-catenin mutation resulting in WNT activation
Specific inclusion criteria SR-study
Age at diagnosis >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 β-catenin nuclear immuno-negativity by IHC, and the absence of β-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
Specific inclusion criteria WNT-HR-study
Age at diagnosis >3-5 years
MB, WNT-activated; Histologic subtype: MB, classic, desmoplastic/nodular, and large-cell/anaplastic
Low-risk biological profile, defined as WNT-subgroup positivity. The WNT-subgroup is defined by the presence of: β-catenin mutation or β-catenin nuclear immuno-positivity by IHC and β-catenin mutation or β-catenin nuclear immuno-positivity by IHC and monosomy 6
Clinical high risk features, defined as: age ≥ 16 years, or incomplete surgical resection with more than 1.5 cm2 of residual tumour on early post-operative MRI, or Large cell/anaplastic histology, or CNS metastasis on MRI on central review, or tumour cells on the cytospin of lumbar CSF
Specific inclusion criteria SHH-TP53-study
Age at diagnosis >3-5 years
Histologically proven MB, SHH-activated TP53 mutant
All histological subtype of MB (AMB, DMB, CMB, LCMB, MBEN allowed) and evidence of MYC/N amplification
Patients with germline TP53 mutation, TP53 mosaicism and/ or somatic TP53 mutation are eligible.
Diagnosis of SHH-activated TP53-mutant MB as first or secondary malignancy.
Start of postoperative chemotherapy within 28 days (max. 40 days) after surgery. Foreseeable inability to start therapy within 40 days after surgery renders patients ineligible for the study.
Patients with clinical high-risk features may be registered after initiation of the first cycle of chemotherapy.
No other contraindication to protocol therapy
|
|
| E.4 | Principal 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) identified somatic TP53 mutation
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 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
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 syndrome, patient or familial APC-associated polyposis conditions or other hereditary condition, which affects tolerance of antitumour treatment, or may prone to secondary tumours
h) identified somatic TP53 mutation
i) Patients, who are pregnant.
j) Patients, who are sexually active and are not taking reliable contraception measures.
k) Patients, who cannot be regularly followed up due to psychological, social, familial or geographic reasons.
l) Patients, in whom non-compliance with toxicity management guidelines can be expected.
Exclusion criteria SHH-TP53
a) One of the inclusion criteria is lacking.
b) Patients who refuse testing for germline TP53-mutations, since this is relevant for stratification to therapy.
c) Patients who are pregnant.
d) heterosexually active patients, who refuse reliable contraception.
e) Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons.
f) Patients in whom non-compliance with toxicity management guidelines can be expected. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is event-free survival (EFSOP) for the treatment study SR and 3-years EFS rate for the treatment studies LR, WNT-HR, and SHH-TP53.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
LR, WNT-HR, and SHH-TP53-studies: 3 years after last patient in
SR-study: after 105 events (relapse) or after an estimated follow-up time of 4 years after last patient in |
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After an estimated follow-up time of 3 years after last patient in |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| SR-arm: group with carboplatin concomitant to radiotherapy compared to group without carboplatin |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 190 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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