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

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.

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