Clinical trial NCT03609840: Study of Thiotepa and TEPA Drug Exposure in Pediatric Hematopoietic Stem Cell Transplant Patients
Official title: Population Pharmacokinetics and Pharmacodynamics of Thiotepa and TEPA in Pediatric Patients Undergoing Hematopoietic Cell Transplantation (HCT).
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hematologic Malignancies
Nonmalignant Diseases
Immune Deficiency
Hemoglobinopathies
Genetic Inborn Errors of Metabolism
Fanconi Anemia
Thalassemia
Sickle Cell Disease
Keywords: Thiotepa
TEPA
Pediatric
Hematopoietic
Transplant
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2018-08-01
Enrollment: 25
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 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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.
timeFrame: 2 hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.
timeFrame: 4 hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.
timeFrame: 6 hours post start of infusion
measure: Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients.
timeFrame: 24 hours post start of infusion
Secondary outcomes:
measure: Event free survival according to the AUC of thiotepa
timeFrame: 1 month post transplant
measure: Event free survival according to the AUC of thiotepa
timeFrame: 3 months post transplant
measure: Event free survival according to the AUC of thiotepa
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 Long-Boyle, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: