Polymorphisms and Busulfan Pharmacokinetic Study

April 27, 2021 updated by: Marc Ansari, University Hospital, Geneva

Polymorphisms and Busulfan Pharmacokinetic Study in Pediatric Transplnatation

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

Study Overview

Status

Recruiting

Conditions

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.

Study Type

Observational

Enrollment (Anticipated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada
        • Active, not recruiting
        • Alberta Children's Hospital
    • Quebec
      • Montreal, Quebec, Canada, H3T1C5
  • France
      • Paris, France
        • Active, not recruiting
        • Hopital Rebert Debré
  • Switzerland
      • Geneva, Switzerland, 1206
        • Recruiting
        • Hopital Cantonal de Geneve
        • Contact:
        • Principal Investigator:
          • Marc Ansari, MD, PhD
        • Sub-Investigator:
          • Maja Krajinovic, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

primary care clinic of pediatric

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
polymorphisms in genes involved in Busulfan pathways correlation with pharmacokinetic
Time Frame: 1 year post hematopoietic stem cell transplantation
1 year post hematopoietic stem cell transplantation

Secondary Outcome Measures

Outcome Measure
Time Frame
polymorphisms in genes involved in Busulfan pathways correlation with toxicity
Time Frame: 1 year post hematopoietic stem cell transplantation
1 year post hematopoietic stem cell transplantation
polymorphisms in genes involved in Busulfan pathways correlation with survival
Time Frame: 1 year post stem cell transplantation
1 year post stem cell transplantation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Geneva

Collaborators

European Society for Blood and Marrow Transplantation

Investigators

  • Principal Investigator: Marc Ansari, MD, PhD, Hopital Cantonal de Genève, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2008

Primary Completion (Anticipated)

December 1, 2023

Study Completion (Anticipated)

December 1, 2023

Study Registration Dates

First Submitted

December 8, 2010

First Submitted That Met QC Criteria

December 8, 2010

First Posted (Estimate)

December 10, 2010

Study Record Updates

Last Update Posted (Actual)

April 28, 2021

Last Update Submitted That Met QC Criteria

April 27, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 2009-018105-41 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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