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Carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex. If insufficient response: TEMIRI + etoposide/radiotherapy + temozolomide

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.

Carboplatin + etoposide

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:

* Level 1 20 mg/kg/day
* Level 2 30 mg/kg/day
* Level 3 40 mg/kg/day
* Level 4 50 mg/kg/day

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.

Cyclophosphamide + Busilvex

During 2 cycles of 21 days:

* Temozolomide: 100 mg/m\^2/day PO from Day 1 to Day 5;
* Irinotecan: 10 mg/m\^2/day IV from Day 1 to Day 5 + from Day 8 to Day 12

Temozolimide + Irinotecan

* Etoposide: 35 mg/m\^2/day PO during 21days
* Radiotherapy: 1.8 Gy/fraction/day (total dose: 54 Gy)

Etoposide + radiotherapy

150 mg/m\^2/day PO during 5 days, during 6 cycles of 21 days

Christelle Dufour, MD

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.

Study of Sequential High-dose Chemotherapy in Children With High Risk Medulloblastoma

Phase I / II Study of Sequential High-dose Chemotherapy With Stem Cell Support in Children Younger Than 5 Years of Age With High-risk Medulloblastoma

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Sequential High-dose Chemotherapy in Children With High Risk Medulloblastoma	NCT02025881	High-risk Medul...	Carboplatin + e... Thiotepa Cyclophosphamid... Temozolimide + ... Etoposide + rad... Temozolomide	- 5 Years	Gustave Roussy, Cancer Campus, Grand Paris
Study of Sequential High-dose Chemotherapy in Children With High Risk Medulloblastoma	NCT02025881	High-risk Medul...	Carboplatin + e... Thiotepa Cyclophosphamid... Temozolimide + ... Etoposide + rad... Temozolomide	- 5 Years	Gustave Roussy, Cancer Campus, Grand Paris

Spots Global Cancer Trial Database for etoposide + radiotherapy