Pharmacokinetic Study of Doxorubicin in Children With Cancer

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

Detailed Description
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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

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

Conditions
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Wilms Tumor, Neuroblastoma, Soft Tissue Sarcoma, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: doxorubicin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxorubicin<br> | Drug: doxorubicin<br>* blood sampling before, during and after doxorubicin administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Assess relationship between PK parameters and patient characteristics | Measure doxorubicin and doxorubicinol concentration in blood plasma. Collect samples at two different doxorubicin infusions. | 24h | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, doxorubicin, cancer, troponin, natriuretic peptide, cardiotoxicity, anthracyclines, Ewing, ALL