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

Conditions

• High-risk Medulloblastoma

Eligibility Criteria

Sex

ALL

Age

N/A - 5 Years

Healthy Volunteers

Not accepted

Interventions

• 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.
• 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: * 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.
• Temozolimide + Irinotecan — DRUG
  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
• Etoposide + radiotherapy — COMBINATION_PRODUCT
  * Etoposide: 35 mg/m\^2/day PO during 21days * Radiotherapy: 1.8 Gy/fraction/day (total dose: 54 Gy)
• Temozolomide — DRUG
  150 mg/m\^2/day PO during 5 days, during 6 cycles of 21 days

Study Details

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.

Key Dates

Start date

Sep 14, 2013

Status verified

May 2024

Primary completion

Oct 25, 2020

Completion

Oct 25, 2020

Study Design

Enrollment

29 participants (actual)

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Arms

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

Primary Outcome Measure

Phase I - Maximum Tolerated Dose [ Time Frame: From inclusion to the Dose Limiting Toxicity up to 12 months ]