Study of Fludarabine Drug Exposure in Pediatric Bone Marrow Transplantation (HCT)

Population Pharmacokinetics of Fludarabine in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Hemoglobinopathies; Fanconi Anemia; Thalassemia; Hematologic Malignancies; Immunodeficiencies; Nonmalignant Diseases; Genetic Inborn Errors of Metabolism
• Intervention / Treatment: Drug: Fludarabine

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.

• Study Type: Observational
• Enrollment (Actual): 67

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Inpatient Pediatric Bone Marrow Transplant Recipients; 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; Given as injection; Other Names: Fludara

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Thrasher Research Fund
• Investigators: Principal Investigator: Janel R Long-Boyle, PharmD, PhD, University of California, San Francisco

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Actual): April 30, 2016
• Study Completion (Actual): April 30, 2016

Study Registration Dates

• First Submitted: March 14, 2011
• First Submitted That Met QC Criteria: March 14, 2011
• First Posted (Estimate): March 16, 2011

Study Record Updates

• Last Update Posted (Actual): October 4, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: pediatric; pharmacokinetics; fludarabine; hematopoietic cell transplantation; allogeneic
• Additional Relevant MeSH Terms: Metabolic Diseases; Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; DNA Repair-Deficiency Disorders; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Hematologic Neoplasms; Anemia, Sickle Cell; Fanconi Anemia; Thalassemia; Metabolism, Inborn Errors; Hemoglobinopathies; Antineoplastic Agents; Fludarabine
• Other Study ID Numbers: P0037192; 10081 (Registry Identifier: DAIDS ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No