Study of Thiotepa and TEPA Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients

Population Pharmacokinetics and Pharmacodynamics of Thiotepa and TEPA in Pediatric Patients Undergoing Hematopoietic Cell Transplantation (HCT).

Thiotepa is a chemotherapy drug used extensively in bone marrow transplantation. Thiotepa is a prodrug that undergoes metabolic conversion in the liver by CYP2B6 and CYP3A4 to its primary active metabolite, triethylene phosphoramide (TEPA). The goal of this study is to determine what causes some children to have different drug concentrations of thiotepa and TEPA 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 certain clinical and genetic factors cause changes in thiotepa and TEPA 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; Immune Deficiency; Nonmalignant Diseases; Genetic Inborn Errors of Metabolism
• Intervention / Treatment: Drug: Thiotepa

Detailed Description

Thiotepa is an alkylating agent with potent antitumor and immunosuppressive properties used in conditioning regimens of pediatric hematopoietic cell transplantation (HCT) to promote stem cell engraftment. Thiotepa is a prodrug that undergoes metabolic conversion in the liver by CYP2B6 and CYP3A4 to its primary active metabolite, TEPA.

This is a single-center, prospective, non-interventional pharmacokinetics (PK) study investigating the clinical pharmacology of thiotepa and TEPA in 60 children undergoing hematopoietic stem cell transplant (HCT) at University of California, San Francisco Benioff Children's Hospital. Patients would receive thiotepa regardless of whether or not they decide to consent to PK sampling.

Thiotepa 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 thiotepa and TEPA exposure in pediatric HCT recipients. Population PK methodologies support the use of sparse sampling and therefore allow the investigators to investigate drug levels in a pediatric population that would otherwise not be feasible using traditional intensive PK sampling.

Subjects will undergo PK sampling of plasma thiotepa and TEPA drug concentrations over the duration of thiotepa therapy (3 to 5 days).

To evaluate sources of variability impacting thiotepa and TEPA 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): 25

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

• Sampling Method: Non-Probability Sample

Study Population

The target population for the proposed study includes children 0-17 years of age undergoing autologous and allogeneic HCT for the treatment of malignant and nonmalignant disorders. Patients receiving thiotepa 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 thiotepa in a clinic or any other out-patient setting.

Description

Inclusion Criteria:

1. be between 0 to 17 years of age;
2. meet protocol specific eligibility criteria for autologous or allogeneic HCT
3. will be receiving thiotepa as part of their conditioning 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
Pediatric Hematopoietic Stem Cell Transplant Recipients; Children undergoing hematopoietic stem cell transplant (HCT) at University of California, San Francisco Benioff Children's Hospital	Drug: Thiotepa; Given IV; Other Names: Tepadina; Alkylating antineoplastic agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.	Area-under-the-curve (AUC) will be derived from the empirical Bayes estimates of individual clearance	2 hours post start of infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.	Area-under-the-curve (AUC) will be derived from the empirical Bayes estimates of individual clearance	4 hours post start of infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.	Area-under-the-curve (AUC) will be derived from the empirical Bayes estimates of individual clearance	6 hours post start of infusion
Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.	Area-under-the-curve (AUC) will be derived from the empirical Bayes estimates of individual clearance	24 hours post start of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival according to the AUC of thiotepa	Death due to any cause within 1 month post-transplant will be considered an event.	1 month post transplant
Event free survival according to the AUC of thiotepa	Death due to any cause within day 3 months post-transplant will be considered an event.	3 months post transplant
Event free survival according to the AUC of thiotepa	Death due to any cause within day 1 year post-transplant will be considered an event.	1 year post transplant

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Janel Long-Boyle, PharmD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2017
• Primary Completion (Actual): July 31, 2023
• Study Completion (Actual): July 31, 2023

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): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Pediatric; Thiotepa; Transplant; Hematopoietic; TEPA
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System 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; Immunologic Deficiency Syndromes; Anemia, Sickle Cell; Fanconi Anemia; Thalassemia; Metabolism, Inborn Errors; Hemoglobinopathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Alkylating Agents; Myeloablative Agonists; Thiotepa; Antineoplastic Agents; Antineoplastic Agents, Alkylating
• Other Study ID Numbers: 17-21994; 17087 (Other Identifier: 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