E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High-risk medulloblastoma |
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E.1.1.1 | Medical condition in easily understood language |
High-risk medulloblastoma |
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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 | 16.0 |
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 |
Phase II: To assess the efficacy in terms of Event Free Survival (EFS) of the strategy intended to treat children younger than 5 years of age suffering from high-risk medulloblastoma with sequential high-dose chemotherapy without radiotherapy.
Phase I: To determine the Maximum Tolerated Dose (MTD) of cyclophosphamide in combination with a fixed dose of Busilvex in children with high-risk medulloblastoma who are in complete response after the intensification phase.
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E.2.2 | Secondary objectives of the trial |
To assess feasibility and efficacy of a strategy without radiotherapy by estimating the rate of patients alive free of disease without having received radiation therapy
To assess efficacy of this strategy in terms of Overall Survival
To assess the proportion of radiological tumour response of VP16-Carboplatin courses
To assess the proportion of patients achieving complete response after 2 courses of VP16-carboplatine followed by 2 courses of thiotepa
To characterize the pharmacokinetics of cyclophosphamide – Busilvex combination (Phase I)
To assess efficacy, feasibility and tolerance of salvage treatment
To evaluate the acute toxicity of this therapeutic strategy, overall and by treatment phase (induction / intensification / consolidation)
To evaluate the prognostic value of some immunohistochemical markers on the risk of relapse or progression
To evaluate neurocognitive development of patients within 10 years after the end of treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histological diagnosis of medulloblastoma with no INI-1 loss
- High risk medulloblastoma defined by at least one of the following conditions:
Newly diagnosed classical metastatic medulloblastoma
Newly diagnosed anaplastic/large cell medulloblastoma
Newly diagnosed medulloblastoma with amplification of c-myc or N-myc
- Age at initial biopsy less or equal than 5 years
- Weight compatible with leukapheresis
- Ability to comply with requirements for submission of materials for central review
- Nutritional and general status compatible with this therapy, Lansky play score ≥ 30%
- Estimated life expectancy ≥3 months
- No organ toxicity other than neurological symptoms (grade >2 according to NCI-CTC v4.0 grading system)
- No prior irradiation or chemotherapy (except VP16 – CBP)
- Written informed consent from parents or legal guardian
Inclusion criteria for the Phase I part of the study:
- Complete response after intensification phase confirmed by central review
- Adequate hepatic and renal function |
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E.4 | Principal exclusion criteria |
- Desmoplastic medulloblastoma
- Atypical Teratoid rhabdoid tumour
- Uncontrolled active or symptomatic intracranial hypertension
- Patient incapable of undergoing medical follow-up
- Relapse of medulloblastoma |
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E.5 End points |
E.5.1 | Primary end point(s) |
For the whole study :
Event Free Survival
For the Phase I part of the study :
Dose Limiting Toxicity |
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E.5.2 | Secondary end point(s) |
- Radiotherapy-free survival without event ;
- Overall survival ;
- Response (complete and partial response) to conventional chemotherapy assessed after the first two courses ;
- Complete response to induction and intensification phases assessed after the two courses of thiotepa ;
- Toxicity according to NCI-CTC v4.0 grading system, in particular after the course of cyclophosphamide in combination with Busilvex to estimate the maximum tolerated dose of cyclophosphamide in this setting (phase I part) ;
- Pharmacokinetics of cyclophosphamide and Busilvex ;
- Response to salvage treatment ;
- Cognitive assessments ;
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 35 |
E.8.5 | The trial involves multiple Member States | No |
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
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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 | 9 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |