| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007):
classic medulloblastoma
desmoplastic/nodular medulloblastoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To confirm that the 3-year Event-Free Survival (EFS) rate in children and adolescents with standard-risk medulloblastoma and a low-risk biological profile remains in excess of 80% when patients are treated with reduced-intensity chemotherapy and radiotherapy, and to test whether the Event-Free Survival (EFS) in children and adolescents with standard-risk medulloblastoma and an average-risk biological profile is different for patients treated with or without carboplatin concomitantly with radiotherapy followed by a modified maintenance chemotherapy. |
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| E.2.2 | Secondary objectives of the trial |
For Low Risk group patients the secondary objectives are:
- to investigate the Overall Survival (OS) rate, Progression Free Survival (PFS) rate and the pattern of relapse.
For Standard Risk group patients the secondary objectives are:
- to investigate the Overall Survival rates (OS), the Progression-free survival rates, and the pattern of relapse in the randomized treatment arms.
- to test the feasibility of carboplatin treatment concomitantly with radiotherapy
For both groups:
- to study late effects focusing on hearing, endocrine, and neurologic function, and standardized, patients/ parents rated measurements of health status, executive function, behavioural outcome, and quality of life.
- to conduct prospective studies on medulloblastoma, with the aim of identifying biomarkers and drug targets.
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| 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 |
Biological Investigation: prospective biological study to undertake a detailed characterisation of the established clinical molecular & histological disease features of medulloblastoma.
To identify characterise & validate novel molecular disease features.
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| E.3 | Principal inclusion criteria |
Inclusion Criteria
Note: with the exception of criterion f), the Inclusion Criteria are the same for PNET 5 MB - LR and PNET 5 MB - SR.
To be eligible for inclusion in either study, patients must meet all of the following criteria:
a) Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 16.0 years (LR-arm) or 22.0 years (SR-arm).
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 58), according to national regulations a CSF review might me required.
• no clinical evidence of extra-CNS metastasis.
In patients with significant residual tumour (> 1.5 cm2) after first surgery, secondary surgery should be considered. 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.
d) Submission of high quality biological material including fresh frozen tumour samples for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centers. Submission of blood is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended.
e) No amplification of MYC or MYCN (determined by FISH).
f) For PNET 5 MB - LR, low-risk biological profile, defined as WNT subgroup positivity, in patients aged <16.0 years at diagnosis. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).
For PNET 5 MB - SR, average-risk biological profile, defined as WNT subgroup negativity. WNT-negative tumours are defined by (i) ß-catenin nuclear immuno-negativity by IHC (mandatory testing), and the absence of ß-catenin mutation (mandatory testing) and monosomy 6 (optional testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) in the absence of ß-catenin mutation and monosomy 6, or (iii) monosomy 6 in the absence of ß-catenin nuclear immuno-positivity by IHC or ß-catenin mutation.
OR
WNT subgroup positive tumours arising in patients age ≥16.0 years at diagnosis. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).
g) No prior therapy for medulloblastoma other than surgery.
h) 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.
i) Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy.
j) CTC grades < 2 for liver, renal, and haematological function.
k) 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.
l) 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;
m) No identified Turcot and Li Fraumeni syndrome.
n) Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation.
o) National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
Note: the Exclusion Criteria are the same for PNET 5 MB - LR and PNET 5 MB - SR.
To be eligible for inclusion in either study, patients must meet none of the following criteria:
a) One of the inclusion criteria is lacking.
b) Brainstem or supratentorial primitive neuro-ectodermal tumour.
c) Atypical teratoid rhabdoid tumour.
d) Medulloepithelioma Ependymoblastoma.
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 WNT subgroup status.
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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure is the rate of 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 neoplasm” is defined as any diagnosed neoplasm that was distinct from
medulloblastoma.
The percentage of patients in whom no event has occurred at 36 months of follow-up will be the measure for EFS. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Event Free Survival will be evaluated 36 months after completion of treatment. |
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| E.5.2 | Secondary end point(s) |
Secondary end points are:
the rate of overall survival (OS), and progression free survival (PFS), estimated by the Kaplan-Meier method,
Pattern of relapse,
Feasibility of carboplatin treatment concomitantly to radiotherapy,
Quality of survival (QoS),
Audiological toxicity,
Endocrine function,
Neurological function,
The prognostic value of biological tumour markers |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS and PFS evaluated after 36 months follow up.
Pattern of relapse timepoint is date of apperance of relapse/progression.
Carboplatin feasibility will be evaluated throughout and summarised at end of trial.
QoS timepoints; after surgery/before radiotherapy, 2 years after diagnosis, 5 years after diagnosis, and at 18 years of age.
Audiological toxicity evaluated 2 years after diagnosis.
Endocrine function evaluated 2 and 5 years from diagnosis/surgery and at 18 years of age.
Neurological function evaluated 6 weeks after radiotherapy, before each chemo course, 6 weeks after last cycle of maintenance chemo, every 4 months in Yr 1, every 6 months in Yr 2, once a year in Yrs 3-5 post treatment.
The prognostic value of bio-markers will be evaluated at end of trial. |
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| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| 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 | 1 |
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