Clinical trial NCT01316549: Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation
Official title: Population Pharmacokinetics of Fludarabine in Pediatric Patients Undergoing Hematopoietic Cell Transplantation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hematologic Malignancies
Nonmalignant Diseases
Immunodeficiencies
Hemoglobinopathies
Genetic Inborn Errors of Metabolism
Fanconi Anemia
Thalassemia
Sickle Cell Disease
Keywords: fludarabine
pharmacokinetics
pediatric
allogeneic
hematopoietic cell transplantation
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2011-03-16
Enrollment: 67
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The target population for the proposed study includes children 0-17 years of age undergoing alloHCT for the treatment of malignant and nonmalignant disorders.

Patients receiving fludarabine over 3 to 5 days are eligible to participate.

All patients enrolled in this study will undergo PK sampling on the inpatient pediatric BMT unit at UCSF Benioff Children's Hospital. The proposed research will not study any patients receiving fludarabine in a clinic or any other out-patient setting.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients.
timeFrame: 2hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients.
timeFrame: 3hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients.
timeFrame: 6hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine for HCT in pediatric patients.
timeFrame: 24hours post start of infusion
Secondary outcomes:
measure: Event free survival according to the AUC of fludarabine
timeFrame: 1month post transplant
measure: Event free survival according to the AUC of fludarabine
timeFrame: 3months post transplant
measure: Event free survival according to the AUC of fludarabine
timeFrame: 1 year post transplant
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Janel R Long-Boyle, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ivaturi V, Dvorak CC, Chan D, Liu T, Cowan MJ, Wahlstrom J, Stricherz M, Jennissen C, Orchard PJ, Tolar J, Pai SY, Huang L, Aweeka F, Long-Boyle J. Pharmacokinetics and Model-Based Dosing to Optimize Fludarabine Therapy in Pediatric Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant. 2017 Oct;23(10):1701-1713. doi: 10.1016/j.bbmt.2017.06.021. Epub 2017 Jul 3.