Clinical trial NCT01095926: Pharmacokinetic Study of Doxorubicin in Children With Cancer
Official title: Phase II Pharmacokinetic Study to Assess the Age-dependency in the Clearance of Doxorubicin in Paediatric Patients With Solid Tumours and Leukaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Wilms Tumor
Neuroblastoma
Soft Tissue Sarcoma
Acute Lymphoblastic Leukemia
Keywords: pharmacokinetic
doxorubicin
cancer
troponin
natriuretic peptide
cardiotoxicity
anthracyclines
Ewing
ALL
Lead sponsor: University Hospital Muenster
Sponsor class: OTHER
First posted: 2010-03-30
Enrollment: 101
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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

Eligibility criteria: 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

Primary outcomes:
measure: Assess age-dependency in pharmacokinetics of doxorubicin in paediatric patients with solid tumours and leukaemia
timeFrame: 24h
Secondary outcomes:
measure: Assess interindividual, intraindividual and residual variability of PK parameters in children
timeFrame: 24h
measure: Assess relationship between PK parameters and patient characteristics
timeFrame: 24h
measure: Explore in a preliminary fashion genetic polymorphisms that may influence doxorubicin clearance
timeFrame: 5 years
measure: Evaluate the potential role of natriuretic peptides and troponin as indicators for subclinical cardiotoxicity
timeFrame: 1 month
Other outcomes:
Locations:
city: Lille
country: France
facility: Centre Oscar Lambret
city: Marseille
country: France
facility: CHU La Timone
city: Marseille
country: France
facility: MD Nicolas Andre, National Study Manager France
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Institut curie
city: Paris
country: France
facility: Institut Gustanve Roussy
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Kiel
country: Germany
facility: Universitätsklinikum Kiel
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Milan
country: Italy
facility: Prof. Maurizio D'Incalci, National Study Manager Italy
city: Monza
country: Italy
facility: Università degli Studi di Milano
city: Padova
country: Italy
facility: Clinica di Oncoematologia Pediatrica
city: Rome
country: Italy
facility: Università Cattolica di Roma
city: Birmingham
country: United Kingdom
facility: Birmingham Childrens Hospital
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Prof. Alan Boddy, National Study Manager UK
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary, Sir James Spence Institute of Child Health
Study officials:
affiliation: University Hospital Muenster
name: Joachim Boos, MD, Prof.
role: STUDY_CHAIR
References: