Pharmacokinetic Study of Doxorubicin in Children With Cancer

Acute Lymphoblastic Leukemia Clinical Trial

— Doxo  

Official title:

Phase II Pharmacokinetic Study to Assess the Age-dependency in the Clearance of Doxorubicin in Paediatric Patients With Solid Tumours and Leukaemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01095926
• Other study ID #: EPOC-MS-001
• Secondary ID: 2009-011454-17
• Status: Completed
• Phase: Phase 2
• First received: March 22, 2010
• Last updated: June 27, 2013
• Start date: May 2010
• Est. completion date: May 2013

Study information

• Verified date: March 2010
• Source: University Hospital Muenster
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical DevicesUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Analyze pharmacokinetics of doxorubicin in children with cancer. Furthermore investigate the predictive role of troponin and natriuretic peptides for anthracycline-induced cardiotoxicity .

Description:

• Paediatric patients up to the age of 17 years will be included. Number and time points of PK sampling will depend on age and tumour type.

• PK samples will be collected from two doxorubicin administrations. Analyzing samples from two doxorubicin administrations will allow distinguishing between interindividual, intraindividual and residual variability.

• Doxorubicin and its major metabolite doxorubicinol will be measured in plasma using HPLC

• In addition, the natriuretic peptide BNP and the precursors NT-pro ANP and NT-proBNP as well as troponin T will be measured in plasma up to 28 days after doxorubicin administration to evaluate their use as clinical markers for cardiotoxicity.

• A data set of max 5 samples (3 +2 (in the 1st + 2nd Doxorubicin sampling periods)) will be collected in the younger children (< 3 years) and a data set of max. 8 samples ( 5 + 3) will be collected in the older children. Samples will be taken at predefined time points/ time intervals.

• An additional DNA sample will be taken and analyzed for genetic polymorphisms. The influence of genotype on pharmacokinetics and metabolism will be investigated by appropriate statistical methods, including population pharmacokinetic analyses. Genes to study would include MDR1 and SLC22A16, both involved in the transport of doxorubicin and AKR1A1 and CBR1, both involved in the reduction of doxorubicin to doxorubicinol. Selected genotypes will be incorporated as covariates into the population pharmacokinetic models developed. The potential impact of genetic variation will be evaluated in the context of other sources of variability such as age, weight, gender etc

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: May 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 17 Years

Eligibility

Inclusion Criteria:

• patients = 17 years of age

• plan to receive at least two cycles of doxorubicin

• must be enrolled in a national or European protocol for treatment of Wilms Tumours, Neuroblastoma, Soft tissue sarcoma, Ewing Sarcoma or Acute lymphoblastic leukaemia and must be treated with doxorubicin according to that protocol Or Patients < 3 years enrolled or listed in any national or European study protocol for any paediatric malignancy. Treatment with doxorubicin has to be according to that protocol.

• Parents or legal representative(s) must provide written informed consent to participate in the trial according to national regulations. Patients that are able to understand should provide assent to participate in the trial.

• Life expectancy of at least 3 month

• Karnofsky performance status of = 70%

• Additional blood withdrawal is acceptable for the patient. The decision is left to the investigator

Exclusion Criteria:

• prior cardiac problems

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia, Lymphoid
• Neuroblastoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Sarcoma
• Soft Tissue Sarcoma
• Wilms Tumor

Intervention

Drug:
• doxorubicin
blood sampling before, during and after doxorubicin administration

Locations

Country	Name	City	State
France	Centre Oscar Lambret	Lille
France	CHU La Timone	Marseille
France	MD Nicolas Andre, National Study Manager France	Marseille
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	Institut curie	Paris
France	Institut Gustanve Roussy	Paris
Germany	Universitätsklinikum Essen	Essen
Germany	Universitätsklinikum Frankfurt	Frankfurt
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Kiel	Kiel
Germany	Universitätsklinikum Münster	Münster
Germany	Klinikum Stuttgart	Stuttgart
Italy	Prof. Maurizio D'Incalci, National Study Manager Italy	Milan
Italy	Università degli Studi di Milano	Monza
Italy	Clinica di Oncoematologia Pediatrica	Padova
Italy	Università Cattolica di Roma	Rome
United Kingdom	Birmingham Childrens Hospital	Birmingham
United Kingdom	St James's University Hospital	Leeds
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United Kingdom	Prof. Alan Boddy, National Study Manager UK	Newcastle upon Tyne
United Kingdom	Royal Victoria Infirmary, Sir James Spence Institute of Child Health	Newcastle upon Tyne

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Muenster

Countries where clinical trial is conducted

France,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assess age-dependency in pharmacokinetics of doxorubicin in paediatric patients with solid tumours and leukaemia	Measure doxorubicin and doxorubicinol concentration in blood plasma. Collect samples at two different doxorubicin infusions.	24h	No
Secondary	Assess interindividual, intraindividual and residual variability of PK parameters in children	Measure doxorubicin and doxorubicinol concentration in blood plasma. Collect samples at two different doxorubicin infusions.	24h	No
Secondary	Assess relationship between PK parameters and patient characteristics	Measure doxorubicin and doxorubicinol concentration in blood plasma. Collect samples at two different doxorubicin infusions.	24h	No
Secondary	Explore in a preliminary fashion genetic polymorphisms that may influence doxorubicin clearance	Obtain one whole blood sample per patient, if separate consent was given.	5 years	No
Secondary	Evaluate the potential role of natriuretic peptides and troponin as indicators for subclinical cardiotoxicity	Measure troponin T, troponin I, BNP, NT-proBNP, NT-proANP. Collect samples at two different doxorubicin infusions before and up to 1month after doxorubicin administration.	1 month	Yes