Precision Dosing of Busulfan in Children Undergoing HSCT

Study Overview
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Brief Summary
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The objective of this clinical trial is to evaluate the personalization the conditioning regimen prior to the hematopoietic stem cell transplant (HSCT) in children and adolescents, to improve HSCT efficacy while reducing conditioning-related toxicities. Namely, we are going to compare the accuracy of two methods for determining the first dose of busulfan, one of the medicines used during the conditioning regimen. First doses will be determined based either only on anthropometric information such as age and weight or by adding a genetic factor that influences the individual ability of busulfan metabolization.

Detailed Description
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Participants will be randomly assigned (1:1 ratio, stratified by conditioning regimen - the presence of fludarabine) to receive their first dose of busulfan according to: the most performing method based on age and weight - McCune's model (control arm) a method that also considers a pharmacogenetic factor (variants occurring in the promoter region of the GSTA1 gene) in association with the co-administered chemotherapeutic agent fludarabine in the dose personalization (experimental arm) This is an international study being carried out in five countries (Canada, Italy, Switzerland, France, and Denmark).

Official Title
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Implementing Pharmacogenetics in the Busulfan Dosing Method for Children Undergoing Hematopoietic Stem-cell Transplantation: a Prospective, Multicentric, Randomized Clinical Trial

Conditions
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Hematopoietic Stem Cell Transplantation, Allogeneic Hematopoietic Stem Cell Transplantation, Autologous Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Genetic: GSTA1 genotyping


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be aged from 0-18 years old on entry to the study; Clinical indication of allogeneic or autologous hematopoietic stem cell transplantation; The conditioning protocol must include IV Bu formulations, Busulfex® (Otsuka Pharmaceutical), Busilvex® (Pierre Fabre Pharma) or other European Medicines Agency (EMA) or Food and Drugs Administration (FDA) approved generic formulations regardless of the administration schedule (q6h, q12h, or q24h) The expected length of time from recruitment to starting the conditioning regimen must be superior to 10 days; Informed written consent to participate in the study signed by the participant/parent Exclusion Criteria: • At least one of the drugs listed below scheduled to be administered in the Bu administration days up to 24h after the last dose of Bu, whenever a washout is not possible: Metronidazol (required washout: 7 days) Nalidixic acid (required washout: 7 days) Phenytoin (required washout: 21 days) Itraconazole (required washout: 14 days) Ketoconazole (required washout: 7 days) Voriconazole (required washout: 7 days) Deferasirox (required washout: 7 days)

Ages Eligible for Study
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Maximum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacogenetic based-model (GSTA1)<br> | Genetic: GSTA1 genotyping<br>* Diplotype determination based on 4 single-nucleotide polymorphisms (SNPs) occurring in the promoter region of the GSTA1 gene<br>|
| Active Comparator: The most performing method based on age and weight - McCune's model<br> | Genetic: GSTA1 genotyping<br>* Diplotype determination based on 4 single-nucleotide polymorphisms (SNPs) occurring in the promoter region of the GSTA1 gene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy of the first-dose Bu area under the curve (AUC) prediction | Proportion of the first doses which result in AUCs within the therapeutic target range defined by the prescriber | 1 month | 
| Accuracy of the Bu Clearance prediction | Absolute prediction error between the predicted and measured Bu clearance of the first dose | 1 month | 
| Dose adjustment requirement | Change in percentage between the first dose administered and the next time-wise adjustable dose: 2nd (Bu q24h), 3rd (Bu q12h), or 5th (Bu q6h) doses | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to deliver the personalized dose | Proportion of personalized doses delivered within the optimal delivery time (to be determined during the first year of the trial) | 1 week | 
| Incidence of treatment-related toxicities (TRTs) |  | 12 months | 
| Incidence and severity of sinusoidal obstruction syndrome (SOS) |  | 12 months | 
| Incidence of primary and secondary graft failure |  | 12 months | 
| Incidence and severity of acute graft-versus-host disease (aGVHD) |  | 12 months | 
| Overall survival |  | 12 months | 
| Event-free survival | Considering as event aGVHD, SOS, relapse and death | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Precision dosing, Pharmacogenetics, Children, Adolescent, Busulfan, HSCT