Polymorphisms and Busulfan Pharmacokinetic Study

NCT ID: NCT01257854

Last Updated: 2021-04-28

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2008-02-29
• Study Completion Date: 2023-12-31

Brief Summary

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

Detailed 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.

Conditions

Children Who Receive a Stem Cell Transplantation With Busulfan IV

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: OTHER

Study Groups

Busulfan, pharmacogenetic, pharmacokinetic, children

Children who receive Busulfan IV and have a pharmacokinetic of Busulfan

No interventions assigned to this group

Eligibility Criteria

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Society for Blood and Marrow Transplantation

NETWORK

Sponsor Role: collaborator

University Hospital, Geneva

OTHER

Sponsor Role: lead

Responsible Party

Marc Ansari

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marc Ansari, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hopital Cantonal de Genève, Switzerland

Locations

Alberta children's hospital

Calgary, Alberta, Canada

Site Status: ACTIVE_NOT_RECRUITING

Chu St Justine

Montreal, Quebec, Canada

Site Status: RECRUITING

Hopital Rebert Debré

Paris, , France

Site Status: ACTIVE_NOT_RECRUITING

Hopital Cantonal de Genève

Geneva, , Switzerland

Site Status: RECRUITING

Countries

Canada; France; Switzerland

Central Contacts

Marc Ansari, MD, PhD

Role: CONTACT

marc.ansari@hcuge.ch

+41223824589

Michel Duval, MD

Role: CONTACT

michel.duval@umontreal.ca

Facility Contacts

Henrique Bittencourt, MD, PhD

Role: primary

henrique.bittencourt.hsj@ssss.gouv.qc.ca

Michel Duval, MD

Role: backup

Marc Ansari, MD, PhD

Role: primary

marc.ansari@hcuge.ch

+41223824589

References

Ansari M, Lauzon-Joset JF, Vachon MF, Duval M, Theoret 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.

Reference Type: BACKGROUND

PMID: 19584821 (View on PubMed)

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. No abstract available.

Reference Type: BACKGROUND

PMID: 19891548 (View on PubMed)

Ansari M, Rezgui MA, Theoret 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 Group. Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients. Bone Marrow Transplant. 2013 Jul;48(7):939-46. doi: 10.1038/bmt.2012.265. Epub 2013 Jan 7.

Reference Type: RESULT

PMID: 23292236 (View on PubMed)

Ansari M, Theoret 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 outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Ther Drug Monit. 2014 Feb;36(1):93-9. doi: 10.1097/FTD.0b013e3182a04fc7.

Reference Type: RESULT

PMID: 24061446 (View on PubMed)

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):251-64. doi: 10.2174/1389200215666140202214012.

Reference Type: RESULT

PMID: 24524663 (View on PubMed)

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 in pediatric patients undergoing hematopoietic stem cell transplantation. Pharmacogenomics J. 2014 Jun;14(3):263-71. doi: 10.1038/tpj.2013.38. Epub 2013 Oct 29.

Reference Type: RESULT

PMID: 24165757 (View on PubMed)

Acosta-Martin AE, Antinori P, Uppugunduri CRS, Daali Y, Ansari M, Scherl A, Muller 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.

Reference Type: RESULT

PMID: 27599297 (View on PubMed)

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, Theoret Y, Duval M, Keizer RJ, Bittencourt H, Hassan M, Gungor T, Wynn RF, Veys P, Cuvelier GD, Marktel S, Chiesa R, Cowan MJ, Slatter MA, Stricherz MK, Jennissen C, Long-Boyle JR, Boelens JJ. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016 Nov;3(11):e526-e536. doi: 10.1016/S2352-3026(16)30114-4. Epub 2016 Oct 13.

Reference Type: RESULT

PMID: 27746112 (View on PubMed)

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 cyclophosphamide before hematopoietic stem cell transplantation. Pharmacogenomics J. 2018 Jan;18(1):64-69. doi: 10.1038/tpj.2016.65. Epub 2016 Oct 25.

Reference Type: RESULT

PMID: 27779248 (View on PubMed)

Ansari M, Curtis PH, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, Lesne L, Theoret 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. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget. 2017 Aug 27;8(53):90852-90867. doi: 10.18632/oncotarget.20310. eCollection 2017 Oct 31.

Reference Type: RESULT

PMID: 29207608 (View on PubMed)

Waespe N, Mlakar SJ, Dupanloup I, Rezgui MA, Bittencourt H, Krajinovic M, Kuehni CE, Nava T, Ansari M. A novel integrative multi-omics approach to unravel the genetic determinants of rare diseases with application in sinusoidal obstruction syndrome. PLoS One. 2023 Apr 5;18(4):e0281892. doi: 10.1371/journal.pone.0281892. eCollection 2023.

Reference Type: DERIVED

PMID: 37018234 (View on PubMed)

Jurkovic Mlakar S, Uppugunduri SCR, Nava T, Mlakar V, Golay H, Robin S, Waespe N, Rezgui MA, Chalandon Y, Boelens JJ, Bredius RGM, Dalle JH, Peters C, Corbacioglu S, Bittencourt H, Krajinovic M, Ansari M; paediatric diseases working party of the European society for blood and marrow transplantation. GSTM1 and GSTT1 double null genotypes determining cell fate and proliferation as potential risk factors of relapse in children with hematological malignancies after hematopoietic stem cell transplantation. J Cancer Res Clin Oncol. 2022 Jan;148(1):71-86. doi: 10.1007/s00432-021-03769-2. Epub 2021 Sep 9.

Reference Type: DERIVED

PMID: 34499222 (View on PubMed)

Uppugunduri CRS, Storelli F, Mlakar V, Huezo-Diaz Curtis P, Rezgui A, Theoret Y, Marino D, Doffey-Lazeyras F, Chalandon Y, Bader P, Daali Y, Bittencourt H, Krajinovic M, Ansari M. The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation. Front Pharmacol. 2017 Jul 11;8:451. doi: 10.3389/fphar.2017.00451. eCollection 2017.

Reference Type: DERIVED

PMID: 28744217 (View on PubMed)

Related Links

https://www.ebmt.org/working-parties/paediatric-diseases-working-party-pdwp

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

Other Identifiers

2009-018105-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2009-018105-41

Identifier Type: -

Identifier Source: org_study_id