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

NCT02025881 | Terminated Phase 1 DMC

• 2 other identifiers: 2012-004842-142012/1908
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 13

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Radiotherapy-free survival without event

  From inclusion up to 3 years

• Overall Survival

  From inclusion up to 3 years

Study Arms (1)

Treatment

EXPERIMENTAL

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

Drug: Carboplatin + etoposide; Drug: Thiotepa; Drug: Cyclophosphamide + Busilvex; Drug: Temozolimide + Irinotecan; Combination Product: Etoposide + radiotherapy; Drug: Temozolomide

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.

Treatment

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%).

Treatment

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.

Treatment

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

Treatment

Etoposide + radiotherapy COMBINATION_PRODUCT

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

Treatment

Temozolomide DRUG

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

Treatment

Eligibility Criteria

• Age: Up to 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• Desmoplastic medulloblastoma
• Atypical Teratoid rhabdoid tumour
• Uncontrolled active or symptomatic intracranial hypertension
• Patient incapable of undergoing medical follow-up
• Relapse of medulloblastoma

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (13)

Gustave Roussy

Villejuif, Val De Marne, 94805, France

Location

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

Angers, 49055, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

CHU La Timone

Marseille, 13385, France

Location

CHU Arnaud de Villeneuve

Montpellier, 34295, France

Location

CHU Nancy Brabois

Nancy, 54511, France

Location

CHU de Nice - Hôpital L'Archet 2

Nice, 06202, France

Location

Institut Curie

Paris, 75248, France

Location

Hôpital Américain

Reims, 51092, France

Location

CHU Hôpital Sud

Rennes, 35203, France

Location

CHRU Hautepierre

Strasbourg, 67098, France

Location

Hôpital des enfants

Toulouse, 31059, France

Location

MeSH Terms

Interventions

EC regimen; Thiotepa; Cyclophosphamide; Busulfan; Irinotecan; Etoposide; Radiotherapy; Temozolomide

Intervention Hierarchy (Ancestors)

Phosphoramides; Organophosphorus Compounds; Organic Chemicals; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Camptothecin; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Therapeutics; Dacarbazine; Triazenes; Imidazoles; Azoles

Study Officials

• Christelle Dufour, MD

  Gustave Roussy, Cancer Campus, Grand Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 30, 2013
• First Posted: January 1, 2014
• Study Start: September 14, 2013
• Primary Completion: October 25, 2020
• Study Completion: October 25, 2020
• Last Updated: May 24, 2024

Record last verified: 2024-05

Locations

FR (13)