Polymorphisms and Busulfan Pharmacokinetic Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Swiss Pediatric Oncology Group
Sponsor:
Collaborator:
European Group for Blood and Marrow Transplantation
Information provided by (Responsible Party):
Swiss Pediatric Oncology Group
ClinicalTrials.gov Identifier:
NCT01257854
First received: December 8, 2010
Last updated: June 5, 2013
Last verified: June 2013
  Purpose

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


Condition
Any Disease in Children Who Receive a Stem Cell Transplantation With Busulfan IV

Study Type: Observational
Study Design: Observational Model: Cohort
Official Title: Polymorphisms and Busulfan Pharmacokinetic Study in Pediatric Transplnatation

Resource links provided by NLM:


Further study details as provided by Swiss Pediatric Oncology Group:

Primary Outcome Measures:
  • polymorphisms in genes involved in Busulfan pathways correlation with pharmacokinetic [ Time Frame: 1 year post hematopoietic stem cell transplantation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • polymorphisms in genes involved in Busulfan pathways correlation with toxicity [ Time Frame: 1 year post hematopoietic stem cell transplantation ] [ Designated as safety issue: No ]
  • polymorphisms in genes involved in Busulfan pathways correlation with survival [ Time Frame: 1 year post stem cell transplantation ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

DNA from each patient are kept. Plasma from some centers are kept


Estimated Enrollment: 200
Study Start Date: February 2008
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
Busulfan, pharmacogenetic, pharmacokinetic, children
Children who receive Busulfan IV in the conditioning regimen before stem cell transplantation and have a pharmacokinetic of Busulfan

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.

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

primary care clinic of pediatric

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01257854

Contacts
Contact: Ansari Marc, MD +41223824589 marc.ansari@hcuge.ch
Contact: Duval Michel, MD michel.duval@umontreal.ca

Locations
Canada, Ontario
Hospital for Sick Children Completed
Toronto, Ontario, Canada, ON M5G 1X8
Canada, Quebec
Chu St Justine Recruiting
Montreal, Quebec, Canada, H3T1C5
Contact: Ansari Marc, MD         
Contact: Duval Michel, MD         
Principal Investigator: Ansari Marc, MD         
Canada
Alberta children's hospital Recruiting
Alberta, Canada
Contact: Lewis victor, MD         
Principal Investigator: lewis victor, MD         
Czech Republic
Charles University Motol Prague Recruiting
Prague, Czech Republic
Contact: Sedlacek Petr, MD       Petr.Sedlacek@fnmotol.cz   
Principal Investigator: Sedlacek Petr, MD         
France
Hopital Rebert de bré Recruiting
Paris, France
Contact: JH Dalle, PhD       jean-hugues.dalle@rdb.aphp.fr   
Principal Investigator: JH Dalle, MD, PhD         
Italy
San Raffaele Hospital Completed
San Raffaele, Italy
Netherlands
Ume Utrecht Completed
Utrecht, Netherlands
Switzerland
Hopital Cantonal de Genève Recruiting
Geneva, Switzerland, 1206
Contact: Ansari Marc, MD    +41223824589    marc.ansari@hcuge.ch   
Principal Investigator: Ansari Marc, MD         
Sub-Investigator: Krajinovic Maja         
Sponsors and Collaborators
Swiss Pediatric Oncology Group
European Group for Blood and Marrow Transplantation
Investigators
Principal Investigator: Ansari Marc, MD Hopital CAntonal de Genève, Switzerland
  More Information

Publications:
Responsible Party: Swiss Pediatric Oncology Group
ClinicalTrials.gov Identifier: NCT01257854     History of Changes
Other Study ID Numbers: 2009-018105-41, 2009-018105-41
Study First Received: December 8, 2010
Last Updated: June 5, 2013
Health Authority: Switzerland: Ethikkommission

Keywords provided by Swiss Pediatric Oncology Group:
busulfan
pharmacogenetic
pharmacokinetic
toxicity
survival

Additional relevant MeSH terms:
Busulfan
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014