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Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant (HCT)

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ClinicalTrials.gov Identifier: NCT04645667
Recruitment Status : Recruiting
First Posted : November 27, 2020
Last Update Posted : March 1, 2021
Sponsor:
Collaborator:
University of North Carolina, Chapel Hill
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:
The purpose of this research study is to evaluate tacrolimus plasma concentrations in patients who will undergo an allogeneic hematopoietic stem cell transplant (HCT). The study aims to identify associations between plasma concentrations, baseline demographic characteristics, clinical lab parameters, and genetic factors. These associations will help clinicians determine the best starting dose for tacrolimus in order to minimize risks of aGVHD and tacrolimus-induced toxicities.

Condition or disease Intervention/treatment
Acute GVHD Drug: Tacrolimus

Detailed Description:
This study aims to evaluate tacrolimus concentration-time data to characterize tacrolimus inter-individual pharmacokinetic (PK) variability in adult patients who will receive HCT, and to associate concentration-time data, exposure and clearance data with important clinical endpoints such as acute graft-versus-host disease (aGVHD) and tacrolimus-induced toxicities. This study proposes to enroll 50 patients at University of North Carolina Medical Center (UNCMC) who will undergo allogeneic HCT, who will receive tacrolimus starting the third day prior to allogeneic HCT (Day -3) for aGVHD prophylaxis. This will be an observational study, and its goal will be to ideally collect baseline clinical and demographic data, concentration-time data for tacrolimus on Day -3 (3 days before the transplant), Day -2 (2 days before the transplant), Day -1 (one day before the transplant), and Day 0 (the day of the allogeneic HCT) for a full pharmacokinetic profile. A medical chart review will be conducted to extract data on tacrolimus-induced toxicities (i.e., acute kidney injury [AKI], hypertension, metabolic panel changes, etc.) and aGVHD incidence rate up to Day +100 (100 days post-allogeneic HCT). Blood will also be collected for genotyping and will also be collected after the transplant to obtain information for surrogate PD biomarkers of tacrolimus efficacy, such as interleukin 2 (IL2) production and quantifiable nuclear localization of the dephosphorylated nuclear-activated T cells (NFAT). These data will aid in the development of a population-based PK/pharmacodynamic (PD) model that will serve as the foundation for a proposed precision dosing approach to optimize tacrolimus dosing. One of the secondary endpoints will be time to aGVHD, which will be defined as the duration from D0 until the first occurrence of aGVHD, censored at 100 days post-allogeneic HCT (Day +100). In the case of haplo-transplant patients, they will receive tacrolimus starting on Day +5 (as opposed to on Day -3 in non-haplo-transplant recipients). Per standard of care, haplo-transplant patients are initiated on Day +5 (5 days after the transplant). Therefore, in these patients, serial blood draws will be collected on a similar timeline as the non-haplo-transplant patients, but in this case Day +5, Day +6 (6 days after the transplant), Day +7 (7 days after the transplant), and Day +8 (8 days after the transplant; Day +8 is when they reach steady-state). For the PD biomarker studies in haplo-transplant patients, blood draws will occur on Day +9 (9 days after the transplant), Day +16 (16 days after the transplant), and Day +23 (23 days after the transplant) (Figure 2). All other procedures will remain the same.

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Study Type : Observational
Estimated Enrollment : 50 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Development of a Population Pharmacokinetic Model to Optimize Tacrolimus Dosing in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplant.
Actual Study Start Date : February 1, 2021
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Group/Cohort Intervention/treatment
Adult patients of allogeneic hematopoietic HCT
Patients who receive their first allogeneic HCT transplant and who receive tacrolimus for aGVHD prophylaxis per standard of care.
Drug: Tacrolimus
Patients will be enrolled into this group if they receive tacrolimus per standard of care. This is an observational study and no interventions will be made.
Other Name: Prograf




Primary Outcome Measures :
  1. Tacrolimus clearance [ Time Frame: Day +1 of tacrolimus administration to Day +4 of tacrolimus administration ]
    Patient's clearance calculated after the first day on tacrolimus and patient's clearance calculated after 5-6 doses of tacrolimus after they reach steady-state


Secondary Outcome Measures :
  1. Incidence and severity of aGVHD [ Time Frame: Day +21 to Day +100 from HCT ]
    The duration from the day of transplant to the first occurrence of aGVHD, censored at 100 days post-HCT.

  2. Incidence of tacrolimus-induced toxicities [ Time Frame: Day -3 to Day +100 from HCT ]
    The duration from the day of transplant to the first occurrence of tacrolimus-induced toxicities (AKI, hypertension, and metabolic abnormalities)

  3. Time to aGVHD [ Time Frame: Day +21 to Day +100 from HCT ]
    The duration from the day of transplant to the first occurrence of aGVHD, censored at 100 days post-HCT.

  4. Time to tacrolimus-induced toxicities (AKI, hypertension, metabolic panel abnormalities) [ Time Frame: Day -3 to Day +100 from HCT ]
    The duration from the day of transplant to the first occurrence of AKI, hypertension, and metabolic panel abnormalities, censored at 100 days post-HCT.


Biospecimen Retention:   Samples With DNA
Blood will be collected at baseline prior to the first dose of tacrolimus, and will will consist of 2 tubes of 5 mL blood (one for PK and one pharmacogenetics). Then, serial blood sampling will occur at 0.5, 1, 2, 4, 6, and 10h after the first tacrolimus dose. On Day -2 and Day -1, blood will be collected prior to the morning dose for the 24h and 48h estimates. On Day 0, blood will again be collected at 0.5, 1, 2, 4, 6, and 10. Also, 10 mL of blood on Day +1, Day +8, and Day +15 (30 mL total) for PD biomarker analysis. For haplo-transplant patients, blood sampling will be similar but will occur on Day +5, Day +6, Day +7, and Day +8 once tacrolimus is initiated, and blood for PD biomarkers will occur on Day +9, Day +16, and Day +23.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
This study is a single-center prospective observational study that seeks to characterize steady-state tacrolimus pharmacokinetics pharmacodynamics in adult recipients of their first allogeneic HCT. Adult subjects who receive prophylactic tacrolimus for aGVHD prevention, and who receive active follow-up surveillance at our institution, are eligible for enrollment. The study population will consist of subjects treated in the Inpatient Bone Marrow Transplant Unit at the University of North Carolina Medical Center. A total of 50 subjects will be enrolled.
Criteria

Inclusion Criteria:

  1. ≥18 years of age
  2. Patients who will undergo their first HCT
  3. Patients who will start tacrolimus for aGVHD prophylaxis
  4. Patients who have provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information

Exclusion Criteria:

  1. Patients who have cognitive impairments that could affect informed decision-making
  2. Patients who are incarcerated
  3. Patients started on a strong CYP3A4 inhibitor (i.e. posaconazole)

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): NCT04645667


Contacts
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Contact: Jing Zhu, PharmD 4128606417 daisy23@email.unc.edu
Contact: Veronica Q Nguyen, PharmD 7185010484 venguyen@email.unc.edu

Locations
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United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Jing Zhu, PharmD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
University of North Carolina, Chapel Hill
Investigators
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Principal Investigator: Daniel J Crona, PharmD, PhD UNC Lineberger Comprehensive Cancer Center
Publications:
Astellas Pharma US. Prograf (tacrolimus) [package insert]. U. S. Food and Drug Administra-tion website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050709s031lbl.pdf. Revised May 2018. Accessed Feburary 7, 2020.
US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). 5.0. National Institutes of Health; 2017. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf
Center for International Blood and Marrow Transplant Research Transplant Activity Report Covering 2010-2014.

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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04645667    
Other Study ID Numbers: LCCC2034
IRB 19-3328 ( Other Identifier: University of North Carolina at Chapel Hill )
First Posted: November 27, 2020    Key Record Dates
Last Update Posted: March 1, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
tacrolimus
aGVHD
pharmacokinetics
pharmacodynamics
pharmacogenomics
CYP3A5 genetic polymorphisms
Additional relevant MeSH terms:
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Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action