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

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ClinicalTrials.gov Identifier: NCT03609840
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

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, 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.

Condition or disease
Hematologic Malignancies Nonmalignant Diseases Immune Deficiency Hemoglobinopathies Genetic Inborn Errors of Metabolism Fanconi Anemia Thalassemia Sickle Cell Disease

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 UCSF 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.

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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Population Pharmacokinetics and Pharmacodynamics of Thiotepa and TEPA in Pediatric Patients Undergoing Hematopoietic Cell Transplantation (HCT).
Actual Study Start Date : January 10, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : December 2021





Primary Outcome Measures :
  1. Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients. [ Time Frame: 2hours post start of infusion ]
  2. Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients. [ Time Frame: 4hours post start of infusion ]
  3. Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients. [ Time Frame: 6 hours post start of infusion ]
  4. Analysis of the Area under the Plasma Concentration versus Time Curve (AUC) of thiotepa for HCT in pediatric patients. [ Time Frame: 24hours post start of infusion ]

Secondary Outcome Measures :
  1. Evaluate the event free survival according to the AUC of thiotepa [ Time Frame: 1month post transplant ]
  2. Evaluate the event free survival according to the AUC of thiotepa [ Time Frame: 3 months post transplant ]
  3. Evaluate the event free survival according to the AUC of thiotepa [ Time Frame: 1 year post transplant ]

Biospecimen Retention:   Samples With DNA
Plasma


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
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.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03609840


Contacts
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Contact: Janel R Long-Boyle, PharmD 415-514-2746 long-boylej@pharmacy.ucsf.edu
Contact: Chris Dvorak, MD 415-476-0554 dvorakc@peds.ucsf.edu

Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Danna Chan, PharmD    415-596-4594    danna.chan@ucsf.edu   
Contact: Janel Long-Boyle, PharmD, PhD    415-514-2746    long-boylej@pharmacy.ucsf.edu   
Principal Investigator: Janel Long-Boyle, PharmD, PhD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Janel Long-Boyle, PharmD, PhD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03609840    
Other Study ID Numbers: 17-21994
First Posted: August 1, 2018    Key Record Dates
Last Update Posted: November 17, 2020
Last Verified: November 2020
Keywords provided by University of California, San Francisco:
Thiotepa
TEPA
Pediatric
Hematopoietic
Transplant
Additional relevant MeSH terms:
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Hematologic Neoplasms
Anemia, Sickle Cell
Thalassemia
Fanconi Anemia
Hemoglobinopathies
Metabolism, Inborn Errors
Immunologic Deficiency Syndromes
Neoplasms
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn
Neoplasms by Site
Immune System Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases