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

Study Overview
=================
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.

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

Conditions
-----------------
Hematologic Malignancies, Nonmalignant Diseases, Immune Deficiency, Hemoglobinopathies, Genetic Inborn Errors of Metabolism, Fanconi Anemia, Thalassemia, Sickle Cell Disease

Intervention / Treatment
-----------------
* Drug: Thiotepa


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: be between 0 to 17 years of age; meet protocol specific eligibility criteria for autologous or allogeneic HCT 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

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pediatric Hematopoietic Stem Cell Transplant Recipients<br>Children undergoing hematopoietic stem cell transplant (HCT) at University of California, San Francisco Benioff Children's Hospital | Drug: Thiotepa<br>* Given IV<br>* Other names: Tepadina;|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pediatric, Hematopoietic, Transplant, Thiotepa, TEPA