Clinical trial NCT04822532: Precision Dosing of Busulfan in Children Undergoing HSCT
Official title: Implementing Pharmacogenetics in the Busulfan Dosing Method for Children Undergoing Hematopoietic Stem-cell Transplantation: a Prospective, Multicentric, Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hematopoietic Stem Cell Transplantation
Allogeneic Hematopoietic Stem Cell Transplantation
Autologous Hematopoietic Stem Cell Transplantation
Keywords: Precision dosing
Pharmacogenetics
Children
Adolescent
Busulfan
HSCT
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2021-03-30
Enrollment: 260
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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)

Primary outcomes:
measure: Accuracy of the first-dose Bu area under the curve (AUC) prediction
timeFrame: 1 month
measure: Accuracy of the Bu Clearance prediction
timeFrame: 1 month
measure: Dose adjustment requirement
timeFrame: 1 month
Secondary outcomes:
measure: Time to deliver the personalized dose
timeFrame: 1 week
measure: Incidence of treatment-related toxicities (TRTs)
timeFrame: 12 months
measure: Incidence and severity of sinusoidal obstruction syndrome (SOS)
timeFrame: 12 months
measure: Incidence of primary and secondary graft failure
timeFrame: 12 months
measure: Incidence and severity of acute graft-versus-host disease (aGVHD)
timeFrame: 12 months
measure: Overall survival
timeFrame: 12 months
measure: Event-free survival
timeFrame: 12 months
Other outcomes:
Locations:
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève
Study officials:
References:
citation: 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.
citation: 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.
citation: Hassine KB, Nava T et al. 2021 (manuscript submitted).