Precision Dosing of Busulfan in Children Undergoing HSCT (BuGenes01)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Allogeneic Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Autologous Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Genetic: GSTA1 genotyping

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 Type: Interventional
• Enrollment (Anticipated): 260
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marc Ansari, MD Prof; Phone Number: +41795536100; Email: research@cansearch.ch

Study Locations

• Switzerland
  • Geneva, Switzerland
    • Recruiting
    • Hopitaux Universitaires de Geneve
    • Contact: NAVA Tiago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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
Overall survival		12 months
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
Event-free survival	Considering as event aGVHD, SOS, relapse and death	12 months

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Publications and helpful links

General Publications

• 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.
• Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Huezo-Diaz Curtis P, Duval M, Theoret 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.
• Hassine KB, Nava T et al. 2021 (manuscript submitted).

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: March 12, 2021
• First Submitted That Met QC Criteria: March 29, 2021
• First Posted (Actual): March 30, 2021

Study Record Updates

• Last Update Posted (Actual): August 2, 2021
• Last Update Submitted That Met QC Criteria: July 30, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Adolescent; Children; Pharmacogenetics; HSCT; Busulfan; Precision dosing
• Other Study ID Numbers: BuGenes 01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No