Study of a Reduced-toxicity Myeloablative Conditioning Regimen Using Fludarabine and Full Doses of Intravenous Busulfan in Pediatric Patients Not Eligible for Standard Myeloablative Conditioning Regimens

Study Overview
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Brief Summary
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The purpose of this study is to assess transplant-related mortality (TRM) at one year after allogeneic hematopoietic stem cell transplantation (allo-HSCT) prepared by a reduced toxicity myeloablative conditioning regimen in young patients (children and adolescents) with hematologic malignancies.

Official Title
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Phase 2 Study of a Reduced-toxicity Myeloablative Conditionning Regimen Using Fludarabine and Full Doses of iv Busulfan in Pediatric Patients Not Eligible for Standard Myeloablative Conditioning Regimens

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Drug: Fludarabine IV- Busulfan IV (Busilvex®) - Anti-thymocyte globulines (Thymoglobuline®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Children and adolescents aged over 12 months and under 25 years Availability of an HLA identical family donor or an HLA-matched unrelated donor (10/10 or 9/10 if the mismatch level is at HLACw for an unrelated donor) or availability of an HLA matched cord blood (5/6 or 6/6) Informed consent signed by patients (18-25 years) and patient's legal representative, parent(s) or guardian (cf p13) Diagnosis of a hematologic malignancy which is a candidate for allo-HSCT, but not eligible for standard or conventional myeloablative conditioning regimens because of high risk for toxicity. Are considered as criteria of non-eligibility for standard or conventional myeloablative conditioning: a history of autologous or allogeneic stem cell transplantation comorbidities or medical history predictive of a prohibitive rate of TRM and toxicity with the use of standard high dose chemotherapy and / or radiotherapy. Exclusion Criteria: Patient has been administered any other systemic chemotherapeutic drug (including Gemtuzumab) within 21 days prior to trial enrollment and start of the conditioning regimen. Hydroxyurea is permitted if indicated to control induction refractory disease, and IT chemotherapy is allowed if indicated as maintenance treatment for previously diagnosed leptomeningeal disease, that has been in remission for at least 3 months prior to enrollment on this study. Active infection. Protocol PI will be final arbiter if there is uncertainty regarding whether a previous infection is resolved. Children and adolescents who are not older than 12 months and under 25 years A donor who is HLA mismatched at the level of more than one locus. Poor performance status (Lansky < 50%) Life expectancy is severely limited by concomitant illness and expected to be <12 weeks. Left ventricular ejection fraction < 30%. Uncontrolled arrhythmias or symptomatic cardiac disease. Symptomatic pulmonary disease. FEV1, FVC and DLCO <30% of expected corrected for hemoglobin. Creatinine clearance less than 30 mL/m per 1.73 m2 or requiring dialysis Evidence of chronic active hepatitis or cirrhosis. If positive hepatitis serology, discuss with Study Chairman and consider liver biopsy. Effusion or ascites >1L prior to drainage. HIV-positive. Female pregnancy Absence of effective contraception among boys and girls of childbearing potential (that contraception should be continued until 6 months after stopping treatment) Breastfeeding Patient's legal representative, parent(s) or guardian not able to sign informed consent. children's refusal Hypersensitivity to rabbit proteins, to the active substance or to any of the excipients of experimental products

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drugs<br>Fludarabine IV- Busulfan IV (Busilvex®) - Anti-thymocyte globulines (Thymoglobuline®) | Drug: Fludarabine IV- Busulfan IV (Busilvex®) - Anti-thymocyte globulines (Thymoglobuline®)<br>* IV fludarabine (30 mg/m²/day for 5 days) IV Busulfan (Busilvex 3.2 mg/kg/day for 4 days) (the Busulfan dose is to be adapted to the weight of the child according to the drug label) Anti-thymocyte globulines (Thymogolubuline, 2.5 mg/kg/day for 2 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-related mortality (TRM) | Evaluation of the cumulative incidence of TRM at 12 months after transplantation | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of engraftment | Incidence of engraftment defined as the first day of neutrophil (>500/μl for 3 consecutive days). Engraftment failure is defined as neutrophil <500/μl at day+42 after allo-SCT. | Day+42 | 
| Evaluation of overall (OS) and disease-free survival (DFS) | Evaluation of overall (OS) and disease-free survival (DFS) at 1 year after transplantation | 12 months | 
| Cumulative incidence of relapse, death from disease, and non-relapse mortality (NRM) | Cumulative incidence of relapse, death from disease, and non-relapse mortality (NRM) | 12 months | 
| Cumulative incidences and severity of acute and chronic Graft-versus-Host disease | Cumulative incidences and severity of acute and chronic Graft-versus-Host disease | 12 months | 
| Immune Recovery (to be determined in a subgroup of patients) | Immune Recovery parameters: blood counts, bone marrow aspiration with evaluation of morphological response. | 12 months |