Polymorphisms and Busulfan Pharmacokinetic Study

Children Who Receive a Stem Cell Transplantation With Busulfan IV Clinical Trial

Official title:

Polymorphisms and Busulfan Pharmacokinetic Study in Pediatric Transplnatation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01257854
• Other study ID #: 2009-018105-41
• Secondary ID: 2009-018105-41
• Status: Recruiting
• Start date: February 2008
• Est. completion date: December 2023

Study information

• Verified date: April 2021
• Source: University Hospital, Geneva
• Contact: Marc Ansari, MD, PhD
• Phone: +41223824589
• Email: marc.ansari[@]hcuge.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Test the correlations between the pharmacogenetic and pharmacokinetic of Busulfan IV in children receiving hematopoietic stem cell transplantation.

Description:

Most of the drugs used to treat cancer are metabolized by hepatic enzymes such as cytochrome P450 or Glutathion-S-Transferase (GST). These enzymatic pathways can be more or less active in the drug's metabolism according to the given polymorphism of each patient (pharmacogenomics).

The current hypothesis is that some functional polymorphisms of genes, which control important enzymes in Busulfan metabolism, contribute to the observed interindividual variability in PK of this drug. This variability can hence predict the resistance as well as the toxicity from a drug in patients who have cancer. The pharmacokinetic profile of different drugs, which have a hepatic metabolism, can be dramatically modified by these polymorphisms. Busulfan is a major drug used in the conditioning regimen before hematopoietic stem cell transplantation, particularly in children in whom total body irradiation has to be avoided. This drug has a narrow therapeutic index. At a lower systemic exposure than the targeted one, Busulfan has insufficient activity and hence an increased risk of transplant rejection and leukemic relapse.

At higher systemic exposures, the toxicity risk increases dramatically with an elevated incidence of hepatic veno-occlusive disease (VOD). Pharmacokinetic monitoring of Busulfan allows optimal dosing. The recommended doses are based on the weight, body surface area or age. Nevertheless, a majority of patients will still need an adjustment of the dose administered after their first dose: this will result in a cumulative systemic exposure that will be over or under therapeutic. Busulfan is metabolized principally by the GSTA1, as well as by other GST enzymes like the GSTM1 and GSTP1. These enzymes are present in the liver as well as in the intestinal cells and are up regulated in the digestive system of young children.With this study we will look for the polymorphism in GST genes, look at the Busulfan IV pharmacokinetics and finally look at the GST alpha enzyme activity and see if there is a correlation with clinical end points. This study will also study any correlation with other genes (repair DNA genes, CYP etc..) that could be correlated with Busulfan and/or cyclophosphamide. This study will also allow to do some DNA banking for future studies in genetics. This multicentric study is sponsor by the Swiss pediatric Oncology Group and is a European Bone and Marrow Transplantation study open in 6 countries (Switzerland, Canada, Italy, Holland, Tscèque republic, ). Pilot study are first analyze with St. Justine Hospital then with the other center at a later stage.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

• Patients must be = than 18 years of age at study entry on this protocol

• The patient must receive iv Busulfan as part of his hematopoietic stem cell transplant conditioning regimen.

• Each participating center has to go through a PK cross validation

• All patients (or their legal guardians) must sign a document of informed consent that has been approved by the Institutional Human Review Committee.

• Each center has to do his own PK of BU

Related Conditions & MeSH terms

• Children Who Receive a Stem Cell Transplantation With Busulfan IV

Locations

Country	Name	City	State
Canada	Alberta children's hospital	Calgary	Alberta
Canada	Chu St Justine	Montreal	Quebec
France	Hopital Rebert Debré	Paris
Switzerland	Hopital Cantonal de Genève	Geneva

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Geneva	European Group for Blood and Marrow Transplantation

Countries where clinical trial is conducted

Canada,  France,  Switzerland, 

References & Publications (10)

Acosta-Martin AE, Antinori P, Uppugunduri CRS, Daali Y, Ansari M, Scherl A, Müller M, Lescuyer P. Detection of busulfan adducts on proteins. Rapid Commun Mass Spectrom. 2016 Dec 15;30(23):2517-2528. doi: 10.1002/rcm.7730. — View Citation

Ansari M, Curtis PH, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, Lesne L, Théoret Y, Chalandon Y, Dupuis LL, Schechter T, Bartelink IH, Boelens JJ, Bredius R, Dalle JH, Azarnoush S, Sedlacek P, Lewis V, Champagne M, Peters C, Bittencourt H, Krajinovic M — View Citation

Ansari M, Krajinovic M. Can the pharmacogenetics of GST gene polymorphisms predict the dose of busulfan in pediatric hematopoietic stem cell transplantation? Pharmacogenomics. 2009 Nov;10(11):1729-32. doi: 10.2217/pgs.09.135. — View Citation

Ansari M, Lauzon-Joset JF, Vachon MF, Duval M, Théoret Y, Champagne MA, Krajinovic M. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. Bone Marrow Transplant. 2010 Feb;45(2):261-7. doi: 10.1038/bmt.2009.143. Epub 2009 Jul 6. — View Citation

Ansari M, Rezgui MA, Théoret Y, Uppugunduri CR, Mezziani S, Vachon MF, Desjean C, Rousseau J, Labuda M, Przybyla C, Duval M, Champagne M, Peters C, Bittencourt H, Krajinovic M; Pediatric Disease Working Parties of the European Blood and Marrow Transplant — View Citation

Ansari M, Théoret Y, Rezgui MA, Peters C, Mezziani S, Desjean C, Vachon MF, Champagne MA, Duval M, Krajinovic M, Bittencourt H; Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group. Association between busulfan exposure and — View Citation

Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, Bredius RG, Egberts AC, Bierings M, Kletzel M, Shaw PJ, Nath CE, Hempel G, Ansari M, Krajinovic M, Théorêt Y, Duval M, Keizer RJ, Bittencourt H, Hassan M, Güngör T, Wynn RF, Veys P — View Citation

Huezo-Diaz Curtis P, Uppugunduri CRS, Muthukumaran J, Rezgui MA, Peters C, Bader P, Duval M, Bittencourt H, Krajinovic M, Ansari M. Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophospha — View Citation

Huezo-Diaz P, Uppugunduri CR, Tyagi AK, Krajinovic M, Ansari M. Pharmacogenetic aspects of drug metabolizing enzymes in busulfan based conditioning prior to allogenic hematopoietic stem cell transplantation in children. Curr Drug Metab. 2014 Mar;15(3):251 — View Citation

Uppugunduri CR, Rezgui MA, Diaz PH, Tyagi AK, Rousseau J, Daali Y, Duval M, Bittencourt H, Krajinovic M, Ansari M. The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	polymorphisms in genes involved in Busulfan pathways correlation with pharmacokinetic		1 year post hematopoietic stem cell transplantation
Secondary	polymorphisms in genes involved in Busulfan pathways correlation with toxicity		1 year post hematopoietic stem cell transplantation
Secondary	polymorphisms in genes involved in Busulfan pathways correlation with survival		1 year post stem cell transplantation

External Links

•   European Society for Blood and Marrow Transplantation (EBMT) - Pediatric Diseases Working Party