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Polymorphisms and Busulfan Pharmacokinetic Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01257854
Recruitment Status : Recruiting
First Posted : December 10, 2010
Last Update Posted : April 18, 2019
European Group for Blood and Marrow Transplantation
Information provided by (Responsible Party):
Marc Ansari, University Hospital, Geneva

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

Condition or disease
Children Who Receive a Stem Cell Transplantation With Busulfan IV

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.

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Polymorphisms and Busulfan Pharmacokinetic Study in Pediatric Transplnatation
Study Start Date : February 2008
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Busulfan

Busulfan, pharmacogenetic, pharmacokinetic, children
Children who receive Busulfan IV and have a pharmacokinetic of Busulfan

Primary Outcome Measures :
  1. polymorphisms in genes involved in Busulfan pathways correlation with pharmacokinetic [ Time Frame: 1 year post hematopoietic stem cell transplantation ]

Secondary Outcome Measures :
  1. polymorphisms in genes involved in Busulfan pathways correlation with toxicity [ Time Frame: 1 year post hematopoietic stem cell transplantation ]
  2. polymorphisms in genes involved in Busulfan pathways correlation with survival [ Time Frame: 1 year post stem cell transplantation ]

Biospecimen Retention:   Samples With DNA
DNA from each patient are kept. Plasma from some centers are kept

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
primary care clinic of pediatric

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01257854

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Contact: Marc Ansari, MD, PhD +41223824589
Contact: Michel Duval, MD

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Canada, Alberta
Alberta children's hospital Active, not recruiting
Calgary, Alberta, Canada
Canada, Quebec
Chu St Justine Recruiting
Montreal, Quebec, Canada, H3T1C5
Contact: Henrique Bittencourt, MD, PhD   
Contact: Michel Duval, MD         
Principal Investigator: Henrique Bittencourt, MD, PhD         
Hopital Rebert Debré Active, not recruiting
Paris, France
Hopital Cantonal de Genève Recruiting
Geneva, Switzerland, 1206
Contact: Marc Ansari, MD, PhD    +41223824589   
Principal Investigator: Marc Ansari, MD, PhD         
Sub-Investigator: Maja Krajinovic, MD, PhD         
Sponsors and Collaborators
University Hospital, Geneva
European Group for Blood and Marrow Transplantation
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Principal Investigator: Marc Ansari, MD, PhD Hopital Cantonal de Genève, Switzerland
Additional Information:
Publications of Results:

Other Publications:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Marc Ansari, MD, PhD, University Hospital, Geneva Identifier: NCT01257854    
Other Study ID Numbers: 2009-018105-41
2009-018105-41 ( EudraCT Number )
First Posted: December 10, 2010    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Keywords provided by Marc Ansari, University Hospital, Geneva: