Precision Dosing of Busulfan in Children Undergoing HSCT

Not Applicable

Recruiting

• Conditions: Allogeneic Hematopoietic Stem Cell Transplantation; Autologous Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation
• Interventions: Genetic: GSTA1 genotyping

• Registration Number: NCT04822532
• Lead Sponsor: University Hospital, Geneva

Brief Summary

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

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:

1. the most performing method based on age and weight - McCune's model (control arm)

2. 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).

Study Timeline

• Status Verified: 2021-03
• Study First Submitted: 2021-03-12
• Study First Submitted QC: 2021-03-29
• Study First Posted: 2021-03-30
• Study Start: 2021-06-15
• Last Update Submitted: 2021-07-30
• Last Update Posted: 2021-08-02
• Primary Completion: 2025-06
• Study Completion: 2025-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 260

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pharmacogenetic based-model (GSTA1)	GSTA1 genotyping	-
The most performing method based on age and weight - McCune's model	GSTA1 genotyping	-

Primary Outcome Measures

Name	Time	Method
Accuracy of the first-dose Bu area under the curve (AUC) prediction	1 month	Proportion of the first doses which result in AUCs within the therapeutic target range defined by the prescriber
Dose adjustment requirement	1 month	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
Accuracy of the Bu Clearance prediction	1 month	Absolute prediction error between the predicted and measured Bu clearance of the first dose

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Hôpitaux Universitaires de Genève; 🇨🇭 Geneva, Switzerland