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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: High-risk Medulloblastoma
• Intervention / Treatment: Drug: Carboplatin + etoposide; Drug: Thiotepa; Drug: Cyclophosphamide + Busilvex

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Val De Marne
    • Villejuif, Val De Marne, France, 94805
      • Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment; carboplatin + etoposide then thiotepa then Cyclophosphamide + Busilvex

Drug: Carboplatin + etoposide; 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.; Drug: Thiotepa; 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%); 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
Radiotherapy-free survival without event	From inclusion up to 3 years
Overall Survival	From inclusion up to 3 years

Collaborators and Investigators

• Sponsor: Gustave Roussy, Cancer Campus, Grand Paris
• Investigators: Principal Investigator: Christelle Dufour, MD, Gustave Roussy, Cancer Campus, Grand Paris

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2013
• Primary Completion (Actual): April 10, 2017
• Study Completion (Anticipated): April 1, 2021

Study Registration Dates

• First Submitted: December 30, 2013
• First Submitted That Met QC Criteria: December 30, 2013
• First Posted (Estimate): January 1, 2014

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 23, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Medulloblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Carboplatin; Etoposide; Thiotepa
• Other Study ID Numbers: 2012-004842-14; 2012/1908 (Other Identifier: CSET number)