| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children with medulloblastoma of standard risk. Medulloblastoma is a highly cellular malignant embryonal neoplasm classified as a Primitive Neuro-ectodermal Tumour [PNET] |
| bambini di età superiore a 3 anni affetti da medulloblastoma a rischio basso o intermendio |
|
| E.1.1.1 | Medical condition in easily understood language |
| Medulloblastoma is a type of brain tumour that mainly affects children |
| Il medulloblastoma è un tumore cerebrale che si presenta principalmente nei bembini |
|
| 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 | 16.1 |
| 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 Arm- LR
- to confirm that the 3-year Event-Free Survival rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when patients are treated with 23.4 Gy neuraxis irradiation plus boost to the primary tumor, and reduced-intensity chemotherapy
Treatment Arm - SR
- to test whether the Event-Free Survival 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 (23.4 Gy neuraxis irradiation plus boost to the primary tumor) followed by a modified maintenance chemotherapy.
|
| Pazienti a basso rischio. Dimostrare, nel gruppo di pazienti a basso rischio biologico, un tasso di soprevvivenza libera da malattia (EFS), a 3 anni, superiore all'80% nonostante una chemioterapia di mantenimento di intensitò ridotta rispetto al passato; pazienti a rischio intermendio: sarà di verificare se la sopravvivenza liberada eventi nei bambini e negli adolescenti affetti da medulloblastoma a rischio standard con profilo biologico di rischio maggiore cambia a seconda che i pazienti vengano trattati con o senza la somministrazione di carboplatino concomitante alla radioterapia, seguita da un regime modificati di chemioterapia di mantenimento. |
|
| E.2.2 | Secondary objectives of the trial |
Treatment Arm - LR
- Overall Survival rate, and pattern of relapse
- late effects of the reduced-dose approach
- to conduct comprehensive studies in a prospective fashion on the biological basis of WNT-subgroup medulloblastoma, with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in this disease subgroup.
Treatment Arm - SR
- Overall Survival Rate, Progression-free survival rates, and pattern of relapse
- to test the feasibility of carboplatin treatment concomitantly with radiotherapy
- late effects in the randomized treatment arms
- to conduct comprehensive studies in a prospective fashion on the biological basis of standard-risk medulloblastoma with the aim of identification, investigation and validation of biomarkers and drug targets with therapeutic potential in this disease subgroup. |
| pazienti a basso rischio: valutazione del tasso di sopravvivenza globale, degli effetti a lungo termine del trattamento e della qualità di vita dei pazienti; pazienti a rischio intermedio: valutazione degli effetti a lungo termine del trattamento e della qualità di vita dei pazienti; |
|
| 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. |
| Sottostudi saranno effettuati esclusivamente in Germania |
|
| E.3 | Principal inclusion criteria |
a) Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years.
The date of diagnosis is the date on which first surgery/biopsy is undertaken.
b) Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007):
classic medulloblastoma desmoplastic/nodular medulloblastoma Pre-treatment central pathology review is considered mandatory.
c) Standard risk medulloblastoma, defined as:
- total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual
tumour on early postoperative MRI, without and with contrast, on central review;
- no CNS metastasis on MRI (cranial and spinal) on central review; )
- no tumour cells on the cytospin samples of lumbar CSF (see chapter 8.1.2. Post-operative Period, page 4,),
according to national regulations a CSF review might me required.
- no clinical evidence of extra-CNS metastasis.
In patients with significant residual tumor (> 1.5 cm2) after first surgery, secondary surgery should be considered. Patients whith a reduction of postoperative residual tumor through second surgery to less than or equal to 1.5 cm2 are eligible, if second surgery is performed within 14 days after first surgery.
d) Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centers.
e) No amplification of MYC or MYCN (determined by FISH).
f)
Treatment Arm - LR, low-risk biological profile, defined as ß-catenin nuclear immuno-positivity by IHC (mandatory) and / or mutation analysis (optional).For PNET 5 MB - SR, average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC (mandatory) and mutation analysis (optional)
Treatment Arm- SR, average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC (mandatory) and mutation analysis (optional) .
g) No prior therapy for medulloblastoma other than surgery.
h) Radiotherapy aiming to start no more than 28 days after surgery. Failure to start radiotherapy within 40 days after surgery renders patients ineligible for the study.
i) CTC grades < 2 for liver, renal, and haematological function.
j) no significant sensineural hearing deficit as defined by pure tone audiomentry with bone conduction or air conduction and normal tympanogram shows no impairement ≥ 20 dB at 1-3 kHz. If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history of hearing deficit.
k) No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Njimwegen breakage syndrome) Gorlin Syndrome or other reasons as defined by patient’s clinician;
l) No identified Turcot and Li Fraumeni syndrome.
m) Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country.
n) National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).
|
| età compresa tra 3 e 22 anni, diagnosi istologica di medulloblastoma, classificazione in base al profilo di beta-catenina in pazienti a basso rischio e a rischio intermedio, invio di materiale fresco per le valutazioni molecolari dei marcatori biologici, assenza di sindromi di Turcot e Li Fraumeni, nessuna terapia precedente (eccetto la chirurgia) per il medulloblastoma, firma del consenso informato. |
|
| E.4 | Principal exclusion criteria |
a) One of the inclusion criteria is lacking.
b) Brainstem or supratentorial primitive neuro-ectodermal tumour.
c) Atypical teratoid rhabdoid tumour.
d) Medulloepithelioma.
e) Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), centrally confirmed.
f) Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or not determinable MYC or MYCN or ß-catenin.
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) DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin, Turcot, or Li Fraumeni syndrome.
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.
|
| diagnosi diversa da medulloblastoma (variante classica, desmoplastica, nodulare), profili biologici sfavorevoli definiti come l’amplificazione di MYC o MYCN o stato non determinabile di MYC, MYCN o beta-catenina, malattia metastatica, precedenti trattamenti per tumore cerebrale o altro tumore, sindromi genetiche, pazienti femmine in gravidanza. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is event-free survival (EFSOP) for the treatment arm SR and 3-years EFS rate for the treatment arm LR |
| prima progressione di malattia, prima recidiva, diagnosi di secondo tumore, morte. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| not applicable |
| non applicabile |
|
| 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
|
| sopravvivenza libera da eventi, sopravvivenza globale (dal primo intervento e dal termine della chemioterapia), sopravvivenza libera da progressione, fattibilità del trattamento con carboplatino concomitante alla radioterapia, misure indirette della valutazione della qualità della vita, ototossicità, valutazione della funzione endocrina, funzioni neurologiche. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| not applicable |
| non applicabile |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| valutazione sequele a lungo termine e qualità della vita |
| valutazione sequele a lungo termine e qualità della vita |
|
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
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