Precision Dosing of Busulfan in Children Undergoing HSCT

Hematopoietic Stem Cell Transplantation Clinical Trial

— BuGenes01  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04822532
• Other study ID #: BuGenes 01
• Status: Recruiting
• Phase: N/A
• Start date: June 15, 2021
• Est. completion date: June 2025

Study information

• Verified date: March 2021
• Source: University Hospital, Geneva
• Contact: Marc Ansari, MD Prof
• Phone: +41795536100
• Email: research[@]cansearch.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 260
• Est. completion date: June 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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)

Related Conditions & MeSH terms

• Allogeneic Hematopoietic Stem Cell Transplantation
• Autologous Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cell Transplantation

Intervention

Genetic:
• GSTA1 genotyping
Diplotype determination based on 4 single-nucleotide polymorphisms (SNPs) occurring in the promoter region of the GSTA1 gene

Locations

Country	Name	City	State
Switzerland	Hôpitaux Universitaires de Genève	Geneva

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Geneva

Country where clinical trial is conducted

Switzerland, 

References & Publications (3)

Hassine KB, Nava T et al. 2021 (manuscript submitted).

McCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NH. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res. 2014 Feb 1;20(3):754-63. doi: 10.1158/1078-0432.CCR-13-1960. Epub 2013 Nov 11. — View Citation

Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Huezo-Diaz Curtis P, Duval M, Théoret Y, Daudt LE, Litalien C, Ansari M, Krajinovic M, Bittencourt H. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. Br J Clin Pharmacol. 2018 Jul;84(7):1494-1504. doi: 10.1111/bcp.13566. Epub 2018 Apr 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Accuracy of the Bu Clearance prediction	Absolute prediction error between the predicted and measured Bu clearance of the first dose	1 month
Primary	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	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
Secondary	Incidence of treatment-related toxicities (TRTs)		12 months
Secondary	Incidence and severity of sinusoidal obstruction syndrome (SOS)		12 months
Secondary	Incidence of primary and secondary graft failure		12 months
Secondary	Incidence and severity of acute graft-versus-host disease (aGVHD)		12 months
Secondary	Overall survival		12 months
Secondary	Event-free survival	Considering as event aGVHD, SOS, relapse and death	12 months