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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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High-risk Medulloblastoma

Intervention / Treatment
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* Drug: Carboplatin + etoposide
* Drug: Thiotepa
* Drug: Cyclophosphamide + Busilvex


Participation Criteria
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Eligibility Criteria
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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: Newly diagnosed classical metastatic medulloblastoma Newly diagnosed anaplastic/large cell medulloblastoma or other unfavourable histology confirmed by review and coordinating investigator 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-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: Complete response after intensification phase confirmed by central review Adequate hepatic and renal function Exclusion Criteria: Desmoplastic medulloblastoma Atypical Teratoid rhabdoid tumour Uncontrolled active or symptomatic intracranial hypertension Patient incapable of undergoing medical follow-up Relapse of medulloblastoma

Ages Eligible for Study
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Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex | Drug: Carboplatin + etoposide<br>* Carboplatin 160 mg/m2 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/m2 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.<br>Drug: Thiotepa<br>* Thiotepa 200 mg/m² Day-3 to day-1 As an intravenously infusion over 1 hour dilution in 200 ml/m² of 5% glucose saline or sodium chloride 9 mg/ml (0.9%)<br>Drug: Cyclophosphamide + Busilvex<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiotherapy-free survival without event |  | From inclusion up to 3 years | 
| Overall Survival |  | From inclusion up to 3 years |