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

NCT ID: NCT02025881

Last Updated: 2024-05-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-14
• Study Completion Date: 2020-10-25

Brief Summary

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.

Conditions

High-risk Medulloblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment

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

Group Type: EXPERIMENTAL

Carboplatin + etoposide

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: COMBINATION_PRODUCT

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

Temozolomide

Intervention Type: DRUG

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

Interventions

Carboplatin + etoposide

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.

Intervention Type: DRUG

Thiotepa

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%).

Intervention Type: DRUG

Cyclophosphamide + Busilvex

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.

Intervention Type: DRUG

Temozolimide + Irinotecan

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

Intervention Type: DRUG

Etoposide + radiotherapy

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

Intervention Type: COMBINATION_PRODUCT

Temozolomide

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

Intervention Type: DRUG

Eligibility Criteria

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.

• 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

• Maximum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gustave Roussy, Cancer Campus, Grand Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christelle Dufour, MD

Role: PRINCIPAL_INVESTIGATOR

Gustave Roussy, Cancer Campus, Grand Paris

Locations

Gustave Roussy

Villejuif, Val De Marne, France

Institut de Cancérologie de l'Ouest (ICO) - Site Paul Papin

Angers, , France

Centre Oscar Lambret

Lille, , France

Centre Léon Bérard

Lyon, , France

CHU La Timone

Marseille, , France

CHU Arnaud de Villeneuve

Montpellier, , France

CHU Nancy Brabois

Nancy, , France

CHU de Nice - Hôpital L'Archet 2

Nice, , France

Institut Curie

Paris, , France

Hôpital Américain

Reims, , France

CHU Hôpital Sud

Rennes, , France

CHRU Hautepierre

Strasbourg, , France

Hôpital des enfants

Toulouse, , France

Countries

France

Other Identifiers

2012/1908

Identifier Type: OTHER

Identifier Source: secondary_id

2012-004842-14

Identifier Type: -

Identifier Source: org_study_id