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| ID | Type | Description | Link |
|---|---|---|---|
| 2012/1908 | Other Identifier | CSET number |
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The trial includes i) the evaluation of the efficacy of a treatment strategy, designed as a phase II trial, and ii) a dose-finding part.
The Phase II trial is an open label, non-randomized, multicentre trial without control group. A Bayesian approach will be used to analyse the EFS, assuming a cure model. We will use three prior distributions of the EFS; (1) an enthusiastic prior distribution, (2) a pessimistic prior distribution, and (3) a non-informative prior distribution. As the patient outcomes in the trial will be recorded, the subsequent distribution of the outcome probability under experimental treatment will be computed by applying Bayes' theorem, which yields an estimated EFS probability with a 95% credibility interval (measure of Bayesian precision). Two interim analyses are planned to monitor the efficacy data (early stopping rules for futility or inefficacy).
The final analysis of efficacy will be made on an intention to treat basis, including all recruited patients, 3 years after recruitment of the last patient.
Due to the uncertainty on the dose of cyclophosphamide that can be given in combination with Busilvex for the last chemotherapy course in patients in complete response after intensification chemotherapy treatment, a dose-finding subtrial will be performed to address this issue (Phase I part). The dose escalation of cyclophosphamide will be performed using the Continual Reassessment Method in a Bayesian framework.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment | Experimental | Carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex. If insufficient response: TEMIRI + etoposide/radiotherapy + temozolomide |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Carboplatin + etoposide | Drug | Carboplatin 160 mg/m^2 Day 1 to day 5, as an intravenous infusion over 1 hour. Dilution in 5 % glucose saline or sodium chloride 9 mg/ml (0.9%). Etoposide 100 mg/m^2 D ay 1 to day 5, as an intravenous infusion over 1 hour. Dilution in physiological saline or 5 % glucose saline while not exceeding a concentration of 0.4 mg/ml etoposide in the infusion bottle. |
| Measure | Description | Time Frame |
|---|---|---|
| Phase I - Maximum Tolerated Dose | 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. | From inclusion to the Dose Limiting Toxicity up to 12 months |
| Phase II - Event Free Survival | 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. | From inclusion to Event up to 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Radiotherapy-free survival without event | From inclusion up to 3 years | |
| Overall Survival | From inclusion up to 3 years |
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Inclusion Criteria:
Histological diagnosis of medulloblastoma with no INI-1 loss
High risk medulloblastoma defined by at least one of the following conditions:
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-Common Toxicity Criteria v4.0 grading system)
No prior irradiation or chemotherapy (except Vepesid - CBP)
Written informed consent from parents or legal guardian
All patients must be affiliated to a social security regimen or be a beneficiary of the same in order to be included in the study.
Inclusion criteria for the Phase I part of the study:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christelle Dufour, MD | Gustave Roussy, Cancer Campus, Grand Paris | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Gustave Roussy | Villejuif | Val De Marne | 94805 | France | ||
| Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin |
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|
| Thiotepa | Drug | Thiotepa 200 mg/m² Day-3 to day-1, as an intravenously infusion over 1 hour dilution in 200 ml/m^2 of 5% glucose saline or sodium chloride 9 mg/ml (0.9%). |
|
| Cyclophosphamide + Busilvex | Drug | Cyclophosphamide:
Busilvex: < 9 kgs 0.8 mg/kg/dose -> 3.2 mg/kg/day; 9 à < 16 kgs 0.96 mg/kg/dose -> 3.84 mg/kg/day; 16 à 23 kgs 0.88 mg/kg/dose -> 3.52 mg/kg/day; > 23 à 34 kgs 0.76 mg/kg/dose -> 3.04 mg/kg/day; > 34 kgs -> 0.64 mg/kg/dose. |
|
| Temozolimide + Irinotecan | Drug | During 2 cycles of 21 days:
|
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| Etoposide + radiotherapy | Combination Product |
|
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| Temozolomide | Drug | 150 mg/m^2/day PO during 5 days, during 6 cycles of 21 days |
|
| Angers |
| 49055 |
| France |
| Centre Oscar Lambret | Lille | 59020 | France |
| Centre Léon Bérard | Lyon | 69373 | France |
| CHU La Timone | Marseille | 13385 | France |
| CHU Arnaud de Villeneuve | Montpellier | 34295 | France |
| CHU Nancy Brabois | Nancy | 54511 | France |
| CHU de Nice - Hôpital L'Archet 2 | Nice | 06202 | France |
| Institut Curie | Paris | 75248 | France |
| Hôpital Américain | Reims | 51092 | France |
| CHU Hôpital Sud | Rennes | 35203 | France |
| CHRU Hautepierre | Strasbourg | 67098 | France |
| Hôpital des enfants | Toulouse | 31059 | France |
| ID | Term |
|---|---|
| C098534 | EC regimen |
| D013852 | Thiotepa |
| D003520 | Cyclophosphamide |
| D002066 | Busulfan |
| D000077146 | Irinotecan |
| D005047 | Etoposide |
| D011878 | Radiotherapy |
| D000077204 | Temozolomide |
| ID | Term |
|---|---|
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D013721 | Triethylenephosphoramide |
| D001388 | Aziridines |
| D001389 | Azirines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
| D002166 | Camptothecin |
| D000470 | Alkaloids |
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D011083 | Polycyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D013812 | Therapeutics |
| D003606 | Dacarbazine |
| D014226 | Triazenes |
| D007093 | Imidazoles |
| D001393 | Azoles |
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