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Study of Sequential High-dose Chemotherapy in Children With High Risk Medulloblastoma (HR MB-5)

Primary Purpose

High-risk Medulloblastoma

Status

Unknown status

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Carboplatin + etoposide

Thiotepa

Cyclophosphamide + Busilvex

About this trial

This is an interventional treatment trial for High-risk Medulloblastoma

Eligibility Criteria

undefined - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Gustave Roussy

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

Radiotherapy-free survival without event

Overall Survival

Full Information

NCT ID

NCT02025881

First Posted

December 30, 2013

Last Updated

February 23, 2021

Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

1. Study Identification

Unique Protocol Identification Number

NCT02025881

Brief Title

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

Acronym

HR MB-5

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Unknown status

Study Start Date

September 14, 2013 (Actual)

Primary Completion Date

April 10, 2017 (Actual)

Study Completion Date

April 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

High-risk Medulloblastoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

29 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex

Intervention Type

Drug

Intervention Name(s)

Carboplatin + etoposide

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Thiotepa

Intervention Description

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%)

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide + Busilvex

Intervention Description

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

Primary Outcome Measure Information:

Title

Phase I - Maximum Tolerated Dose

Description

Time Frame

From inclusion to the Dose Limiting Toxicity up to 12 months

Title

Phase II - Event Free Survival

Description

Time Frame

From inclusion to Event up to 3 years

Secondary Outcome Measure Information:

Title

Radiotherapy-free survival without event

Time Frame

From inclusion up to 3 years

Title

Overall Survival

Time Frame

From inclusion up to 3 years

10. Eligibility

Sex

All

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

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. 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christelle Dufour, MD

Organizational Affiliation

Gustave Roussy, Cancer Campus, Grand Paris

Official's Role

Principal Investigator

Facility Information:

Facility Name

Gustave Roussy

City

Villejuif

State/Province

Val De Marne

ZIP/Postal Code

94805

Country

France

12. IPD Sharing Statement

Learn more about this trial

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

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