Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation

Study Overview
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Brief Summary
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Fludarabine is a chemotherapy drug used extensively in bone marrow transplantation. The goal of this study is to determine what causes some children to have different drug concentrations of fludarabine in their bodies and if drug levels are related to whether or not a child experiences severe side-effects during their bone marrow transplant. The hypothesis is that clinical and genetic factors cause changes in fludarabine drug levels in pediatric bone marrow transplant patients and that high levels may cause severe side-effects.

Detailed Description
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Fludarabine is a nucleoside analog with potent antitumor and immunosuppressive properties used in conditioning regimens of pediatric allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment. This is a single-center, pharmacokinetic-pharmacodynamic (PK-PD) study investigating the clinical pharmacology of fludarabine in 45 children undergoing alloHCT at University of California, San Francisco Benioff Children's Hospital. Patients would receive fludarabine regardless of whether or not they decide to consent to PK sampling. Fludarabine doses will not be adjusted based on PK data. We will apply the combination of a D-optimality-based limited sampling strategy and population PK methodologies to determine specific factors influencing fludarabine exposure in pediatric alloHCT recipients and identify exposure-response relationships. Subjects will undergo PK sampling of plasma (f-ara-a) and intracellular (f-ara-ATP) drug concentrations over the duration of fludarabine therapy (3 to 5 days). To evaluate sources of variability impacting fludarabine exposure clinical data will be obtained from the patient's medical chart on each day of PK sampling. A single blood draw for the collection of DNA and genotyping of single nucleotide polymorphisms of genes involved in fludarabine activation, transport or elimination will occur in all patients. To assess exposure-response relationships neutrophil engraftment, treatment-related toxicity, and survival data will be collected through day 100 post-transplant.

Official Title
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Population Pharmacokinetics of Fludarabine in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Conditions
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Hematologic Malignancies, Nonmalignant Diseases, Immunodeficiencies, Hemoglobinopathies, Genetic Inborn Errors of Metabolism, Fanconi Anemia, Thalassemia, Sickle Cell Disease

Intervention / Treatment
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* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 0-17 years of age Undergoing alloHCT for the treatment of malignant or nonmalignant disorder Receiving fludarabine-based preparative regimen Exclusion Criteria: Any child 7-17 years of age unwilling to provide assent Parent or guardian unwilling to provide written consent

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Inpatient Pediatric Bone Marrow Transplant Recipients<br>All patients enrolled in this study will be located on the inpatient pediatric bone marrow transplant unit at University of California, San Francisco Benioff Children's Hospital. | Drug: Fludarabine<br>* Given as injection<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients. |  | 2hours post start of infusion | 
| Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients. |  | 3hours post start of infusion | 
| Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients. |  | 6hours post start of infusion | 
| Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients. |  | 24hours post start of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival according to the AUC of fludarabine |  | 1month post transplant | 
| Event free survival according to the AUC of fludarabine |  | 3months post transplant | 
| Event free survival according to the AUC of fludarabine |  | 1 year post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fludarabine, pharmacokinetics, pediatric, allogeneic, hematopoietic cell transplantation