Clinical trial NCT04645667: Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant (HCT)
Official title: Development of a Population Pharmacokinetic Model to Optimize Tacrolimus Dosing in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplant.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Acute GVHD
Keywords: tacrolimus
aGVHD
pharmacokinetics
pharmacodynamics
pharmacogenomics
CYP3A5 genetic polymorphisms
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: University of North Carolina, Chapel Hill
First posted: 2020-11-27
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility 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)

Primary outcomes:
measure: Tacrolimus clearance
timeFrame: Day +1 of tacrolimus administration to Day +4 of tacrolimus administration
Secondary outcomes:
measure: Incidence and severity of aGVHD
timeFrame: Day +21 to Day +100 from HCT
measure: Incidence of tacrolimus-induced toxicities
timeFrame: Day -3 to Day +100 from HCT
measure: Time to aGVHD
timeFrame: Day +21 to Day +100 from HCT
measure: Time to tacrolimus-induced toxicities (AKI, hypertension, metabolic panel abnormalities)
timeFrame: Day -3 to Day +100 from HCT
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Daniel J Crona, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mahmoud HK, Elhaddad AM, Fahmy OA, Samra MA, Abdelfattah RM, El-Nahass YH, Fathy GM, Abdelhady MS. Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders. J Adv Res. 2015 May;6(3):449-58. doi: 10.1016/j.jare.2014.11.001. Epub 2014 Nov 7.
citation: Broder MS, Quock TP, Chang E, Reddy SR, Agarwal-Hashmi R, Arai S, Villa KF. The Cost of Hematopoietic Stem-Cell Transplantation in the United States. Am Health Drug Benefits. 2017 Oct;10(7):366-374.
citation: Yalniz FF, Murad MH, Lee SJ, Pavletic SZ, Khera N, Shah ND, Hashmi SK. Steroid Refractory Chronic Graft-Versus-Host Disease: Cost-Effectiveness Analysis. Biol Blood Marrow Transplant. 2018 Sep;24(9):1920-1927. doi: 10.1016/j.bbmt.2018.03.008. Epub 2018 Mar 14.
citation: Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91. doi: 10.1097/00007691-199512000-00007.
citation: Ganetsky A, Shah A, Miano TA, Hwang WT, He J, Loren AW, Hexner EO, Frey NV, Porter DL, Reshef R. Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant. 2016 Apr;51(4):568-72. doi: 10.1038/bmt.2015.323. Epub 2015 Dec 21.
citation: Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004 May;75(5):434-47. doi: 10.1016/j.clpt.2003.12.009.
citation: Przepiorka D, Devine S, Fay J, Uberti J, Wingard J. Practical considerations in the use of tacrolimus for allogeneic marrow transplantation. Bone Marrow Transplant. 1999 Nov;24(10):1053-6. doi: 10.1038/sj.bmt.1702032.
citation: Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53. doi: 10.2165/00003088-200443100-00001.
citation: Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. doi: 10.1002/cpt.113. Epub 2015 Jun 3.
citation: Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014 Feb;53(2):123-39. doi: 10.1007/s40262-013-0120-3.
citation: Provenzani A, Santeusanio A, Mathis E, Notarbartolo M, Labbozzetta M, Poma P, Provenzani A, Polidori C, Vizzini G, Polidori P, D'Alessandro N. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol. 2013 Dec 28;19(48):9156-73. doi: 10.3748/wjg.v19.i48.9156.
citation: 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.
citation: Bremer S, Vethe NT, Skauby M, Kasbo M, Johansson ED, Midtvedt K, Bergan S. NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. Br J Clin Pharmacol. 2017 Nov;83(11):2494-2502. doi: 10.1111/bcp.13367. Epub 2017 Aug 16.
citation: Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, McMichael J, Lever J, Burckart G, Starzl T. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995 Dec;29(6):404-30. doi: 10.2165/00003088-199529060-00003.
citation: Undre NA. Pharmacokinetics of tacrolimus-based combination therapies. Nephrol Dial Transplant. 2003 May;18 Suppl 1:i12-5. doi: 10.1093/ndt/gfg1029.
citation: Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet. 2001;40(4):283-95. doi: 10.2165/00003088-200140040-00004.
citation: Moller A, Iwasaki K, Kawamura A, Teramura Y, Shiraga T, Hata T, Schafer A, Undre NA. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos. 1999 Jun;27(6):633-6.
citation: Dai Y, Hebert MF, Isoherranen N, Davis CL, Marsh C, Shen DD, Thummel KE. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos. 2006 May;34(5):836-47. doi: 10.1124/dmd.105.008680. Epub 2006 Feb 24.
citation: Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev. 1997 Sep 15;27(2-3):201-214. doi: 10.1016/s0169-409x(97)00043-4.
citation: Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, Beaune P, Legendre C, Thervet E. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol. 2003 Jul;14(7):1889-96. doi: 10.1097/01.asn.0000073901.94759.36.
citation: Furlong T, Storb R, Anasetti C, Appelbaum FR, Deeg HJ, Doney K, Martin P, Sullivan K, Witherspoon R, Nash RA. Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities. Bone Marrow Transplant. 2000 Nov;26(9):985-91. doi: 10.1038/sj.bmt.1702639.
citation: 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
citation: Center for International Blood and Marrow Transplant Research Transplant Activity Report Covering 2010-2014.
citation: Zhu J, Campagne O, Torrice CD, Flynn G, Miller JA, Patel T, Suzuki O, Ptachcinski JR, Armistead PM, Wiltshire T, Mager DE, Weiner DL, Crona DJ. Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients. Clin Transl Sci. 2021 May;14(3):908-918. doi: 10.1111/cts.12956. Epub 2021 Jan 27.