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

Population Pharmacokinetics of the Nucleoside Analogues Clofarabine and Fludarabine in Pediatric Patients Undergoing Hematopoietic Cell Transplantation (alloHCT)

Fludarabine and clofarabine are chemotherapy drugs used extensively in bone marrow transplantation. The goal of this study is to determine what causes some children to have different drug concentrations of clofarabine and 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 individual factors cause changes in clofarabine and 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; Thalassemia; Hematologic Malignancies; Immunodeficiencies; Fanconi's Anemia; Nonmalignant Diseases; Genetic Inborn Errors of Metabolism
• Intervention / Treatment: Drug: Clofarabine; Drug: Fludarabine Injection

Detailed Description

Fludarabine and clofarabine are nucleoside analogs 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, prospective, non-interventional pharmacokinetic (PK) study investigating the clinical pharmacology of combination nucleoside analogue therapy in 24 children undergoing alloHCT at University of California, San Francisco Benioff Children's Hospital.

Patients would receive clofarabine and fludarabine regardless of whether or not they decide to consent to PK sampling.

Clofarabine and fludarabine doses will not be adjusted based on PK data.

The investigators will apply the combination of a limited sampling strategy and population PK methodologies to determine specific factors influencing clofarabine and fludarabine exposure in pediatric alloHCT recipients and identify exposure-response relationships.

Subjects will undergo PK sampling of clofarabine and fludarabine drug concentrations over the duration of combination therapy (3 to 5 days).

To evaluate sources of variability impacting clofarabine and fludarabine exposure clinical data will be obtained from the patient's medical chart on each day of PK sampling.

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): 30

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 clofarabine and 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 clofarabine and 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 clofarabine and fludarabine-based preparative regimen

Exclusion Criteria:

• Any child 7-17 years of age unwilling to provide assent

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pediatric Bone Marrow Transplantation Recipients; Children undergoing alloHCT at UCSF Benioff Children's Hospital.	Drug: Clofarabine; Given IV; Drug: Fludarabine Injection; Given IV

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 and clofarabine dual therapy for HCT in pediatric patients.	2hours post start on infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine and clofarabine dual therapy for HCT in pediatric patients.	3hours post start of infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine and clofarabine dual therapy for HCT in pediatric patients.	6hours post start of infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of fludarabine and clofarabine dual therapy for HCT in pediatric patients.	24hours post start of infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluate the event free survival according to the AUC of fludarabine and clofarabine dual therapy	1month post transplant
Evaluate the event free survival according to the AUC of fludarabine and clofarabine dual therapy	3 months post transplant
Evaluate the event free survival according to the AUC of fludarabine and clofarabine dual therapy	1 year post transplant

Collaborators and Investigators

• Sponsor: University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 26, 2016
• Primary Completion (ACTUAL): June 30, 2020
• Study Completion (ACTUAL): June 30, 2020

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: July 24, 2018
• First Posted (ACTUAL): August 1, 2018

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; allogeneic; clofarabine
• 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; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Clofarabine; Fludarabine
• Other Study ID Numbers: P1518454; 19081 (OTHER: University of California, San Francisco)

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