Clinical trial NCT04727827: Pharmacogenomic-Guided Supportive Care in Hematopoietic Cell Transplantation
Official title: A Prospective Interventional Trial of Pharmacogenomic-Guided Supportive Care in Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hematopoietic Cell Transplantation
Oncology
Keywords: pharmacogenomic
precision medicine
pharmacy practice
bone marrow transplantation
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2021-01-27
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This will be a prospective, pre/post interventional, single arm study
Primary purpose: SUPPORTIVE_CARE

Brief summary: Hematopoietic cell transplantation (HCT) is the only curative treatment modality for many hematologic malignancies. Morbidity and mortality rates have declined drastically over the years, secondary to improvements in both transplant techniques and pharmacotherapies, including immunosuppressants, anti-infectives, analgesics and other supportive care medications. Despite advances in patient care, toxicities associated with HCT (e.g., graft-versus-host disease (GVHD), infection, pain, anxiety, depression, mucositis, nausea/vomiting) continue to pose challenges in patient care and have a significant impact on quality of life. (QOL). A recent study demonstrated subjects randomized to intensive supportive care had a clinically significant improvement in their QOL during hospitalization and up to 3 months post-transplant compared to those receiving standard care.

Further follow up evaluations have evaluated the impact of focused palliative care/symptom management on QOL metrics - inclusive of Edmonton Symptom Assessment surveys (ESAS). In other malignant settings, i.e. solid tumor, ESAS has been noted as an effective measure of symptoms control and the utilization of this assessment is linked to positive outcomes. The American Society of Clinical Oncology (ASCO) has designated QOL as the second most relevant metric for post-transplant patient care behind survival, making the optimization of supportive care pharmacotherapy a clinically relevant subject to investigate. Pharmacogenetics (PGx) uses an individual's genetic factors, such as single nucleotide polymorphisms (SNPs), to personalize therapy or dose selection. SNPs encode drug-metabolizing enzymes, transporters, and targets that can significantly impact drug efficacy and toxicity. With the growing complexity of both antineoplastics and supportive care, oncologists have less time to manage each subject's myriad of supportive care concerns by trial and error. Suboptimal management of symptoms compromises potential benefits from cancer therapy, disrupts clinic workflow, increases emergency room visits, and affects both patient satisfaction and reimbursement. Genetic variation is well documented across the human genome and affects a subject's response to medications regarding efficacy and toxicity. The genome is quickly becoming a pragmatic tool that can assist oncologists and other providers in optimizing supportive care for subjects with cancer.

Detailed description: The investigators hypothesize that the implementation of a pharmacist-driven precision medicine service guided by HCT clinical pharmacists and Specialty Pharmacy pharmacists using preemptive pharmacogenomic (PGx) testing will identify drug-gene interactions relevant to the supportive care of HCT subjects. This approach to care may improve symptom management and QOL as interpreted via ESAS in adult HCT subjects treated at our institution. With the experience of past studies and a customized genetic panel, the investigators will genotype subjects prior to transplant and identify actionable drug-gene pairs and utilize these to direct supportive therapies. To date no studies have highlighted the significance of incorporating preemptive PGx testing to personalize therapy selection and dosing into the management of adult HCT subjects as a means of improving QOL and symptom management. The primary aim is to estimate the frequency of subjects undergoing PGx testing who receive at least one drug/dose selection or modification based on their test results during the study period (from admission for HCT to HCT D100). Secondarily the investigators will measure improvement in aggregate and individual scores on the ESAS survey and will further use the ESAS in its totality to assess the impact of PGx-guided care as compared to pre-implementation/non-PGx driven strategies through aggregate ESAS scores, individual ESAS scores, and differences between HCT admission (or baseline) and HCT Day 30 scores before and after the intervening program. In the outpatient setting the investigators will utilize planned medication reconciliation (with PGx guidance) by Specialty Pharmacy Service pharmacists to adhere to PGx-recommendations and capture insight into the implementation of this program to share with other practitioners. The implementation of this study will personalize pharmacotherapy, improve symptom management and QOL in adult HCT subjects treated at our institution, and offer guidance globally in supporting the role of the pharmacist in pharmacogenomics (PGx) and management of HCT subjects.

Eligibility criteria: Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information
* Age ≥ 18 years at the time of consent
* Scheduled HCT (allogeneic and autologous, any conditioning regimen) treatment for any malignant or non-malignant indications (i.e. aplastic anemia)
* Ability to read and understand English or Spanish
* Able to provide a buccal sample for DNA extraction and genotyping

Exclusion Criteria:

* Psychiatric illness/social situations, or active/recent (within 30 days) history of elicit substance abuse that would limit compliance with study requirements as determined by the investigator

Primary outcomes:
measure: Frequency of subjects undergoing PGx testing who receive at least one drug/dose selection or modification.
timeFrame: from admission for HCT to HCT Day +100
Secondary outcomes:
measure: Improvements in symptoms from PGx-guided supportive care
timeFrame: HCT admission
measure: Improvements in symptoms from PGx-guided supportive care
timeFrame: HCT Day +30
measure: Longitudinal symptoms measurements with PGx-guided supportive care
timeFrame: From baseline to Day +30, Day +60 and Day +100 in those who enroll to the study
measure: Determine the type and frequency of actionable genetic polymorphisms observed in the evaluable population and in the subset that received a drug and/or dose selection/modification
timeFrame: From baseline to Day +30 in those who enroll to the study
measure: Determine the type and frequency of actionable genetic polymorphisms observed in the evaluable population and in the subset that received a drug and/or dose selection/modification
timeFrame: From baseline to Day +60 in those who enroll to the study
measure: Determine the type and frequency of actionable genetic polymorphisms observed in the evaluable population and in the subset that received a drug and/or dose selection/modification
timeFrame: From baseline to Day +100 in those who enroll to the study
Other outcomes:
Locations:
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Justin R Arnall, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, Falkenburg JH, Farge-Bancel D, Gennery A, Kroger N, Lanza F, Marsh JC, Nagler A, Peters C, Velardi A, Mohty M, Madrigal A. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015 Aug;50(8):1037-56. doi: 10.1038/bmt.2015.6. Epub 2015 Mar 23.
citation: El-Jawahri A, LeBlanc T, VanDusen H, Traeger L, Greer JA, Pirl WF, Jackson VA, Telles J, Rhodes A, Spitzer TR, McAfee S, Chen YA, Lee SS, Temel JS. Effect of Inpatient Palliative Care on Quality of Life 2 Weeks After Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial. JAMA. 2016 Nov 22;316(20):2094-2103. doi: 10.1001/jama.2016.16786.
citation: McCabe MS, Bhatia S, Oeffinger KC, Reaman GH, Tyne C, Wollins DS, Hudson MM. American Society of Clinical Oncology statement: achieving high-quality cancer survivorship care. J Clin Oncol. 2013 Feb 10;31(5):631-40. doi: 10.1200/JCO.2012.46.6854. Epub 2013 Jan 7. No abstract available.
citation: Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med. 2003 Feb 6;348(6):538-49. doi: 10.1056/NEJMra020526. No abstract available.
citation: Patel JN, Wiebe LA, Dunnenberger HM, McLeod HL. Value of Supportive Care Pharmacogenomics in Oncology Practice. Oncologist. 2018 Aug;23(8):956-964. doi: 10.1634/theoncologist.2017-0599. Epub 2018 Apr 5.
citation: Owusu Obeng A, Hamadeh I, Smith M. Review of Opioid Pharmacogenetics and Considerations for Pain Management. Pharmacotherapy. 2017 Sep;37(9):1105-1121. doi: 10.1002/phar.1986. Epub 2017 Sep 6.
citation: Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009 Aug 20;361(8):827-8. doi: 10.1056/NEJMc0904266. No abstract available.
citation: Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar CE, Shen DD, Callaghan JT, Sadhasivam S, Prows CA, Kharasch ED, Skaar TC; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014 Apr;95(4):376-82. doi: 10.1038/clpt.2013.254. Epub 2014 Jan 23.
citation: Hicks JK, Bishop JR, Sangkuhl K, Muller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug;98(2):127-34. doi: 10.1002/cpt.147. Epub 2015 Jun 29.
citation: Altar CA, Carhart J, Allen JD, Hall-Flavin D, Winner J, Dechairo B. Clinical Utility of Combinatorial Pharmacogenomics-Guided Antidepressant Therapy: Evidence from Three Clinical Studies. Mol Neuropsychiatry. 2015 Oct;1(3):145-55. doi: 10.1159/000430915. Epub 2015 Jul 31.
citation: Perez V, Salavert A, Espadaler J, Tuson M, Saiz-Ruiz J, Saez-Navarro C, Bobes J, Baca-Garcia E, Vieta E, Olivares JM, Rodriguez-Jimenez R, Villagran JM, Gascon J, Canete-Crespillo J, Sole M, Saiz PA, Ibanez A, de Diego-Adelino J; AB-GEN Collaborative Group; Menchon JM. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry. 2017 Jul 14;17(1):250. doi: 10.1186/s12888-017-1412-1.
citation: Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013 Nov;16(89):219-27.
citation: Nassan M, Nicholson WT, Elliott MA, Rohrer Vitek CR, Black JL, Frye MA. Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine. Mayo Clin Proc. 2016 Jul;91(7):897-907. doi: 10.1016/j.mayocp.2016.02.023. Epub 2016 Jun 21.
citation: Bousman CA, Forbes M, Jayaram M, Eyre H, Reynolds CF, Berk M, Hopwood M, Ng C. Antidepressant prescribing in the precision medicine era: a prescriber's primer on pharmacogenetic tools. BMC Psychiatry. 2017 Feb 8;17(1):60. doi: 10.1186/s12888-017-1230-5.
citation: Trammel M, Roederer M, Patel J, McLeod H. Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists? Curr Oncol Rep. 2013 Jun;15(3):276-85. doi: 10.1007/s11912-013-0312-x.
citation: Chen JS, Li LS, Cheng DR, Ji SM, Sun QQ, Cheng Z, Wen JQ, Sha GZ, Liu ZH. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc. 2009 Jun;41(5):1557-61. doi: 10.1016/j.transproceed.2009.01.097.
citation: Quteineh L, Verstuyft C, Furlan V, Durrbach A, Letierce A, Ferlicot S, Taburet AM, Charpentier B, Becquemont L. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):546-52. doi: 10.1111/j.1742-7843.2008.00327.x.
citation: Tang HL, Xie HG, Yao Y, Hu YF. Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genomics. 2011 Nov;21(11):713-20. doi: 10.1097/FPC.0b013e32834a48ca.
citation: Abidi MZ, D'Souza A, Kuppalli K, Ledeboer N, Hari P. CYP2C19*17 genetic polymorphism--an uncommon cause of voriconazole treatment failure. Diagn Microbiol Infect Dis. 2015 Sep;83(1):46-8. doi: 10.1016/j.diagmicrobio.2015.05.002. Epub 2015 May 7.
citation: Bennis Y, Bodeau S, Bouquie R, Deslandes G, Verstuyft C, Gruson B, Andrejak M, Lemaire-Hurtel AS, Chouaki T. High metabolic N-oxidation of voriconazole in a patient with refractory aspergillosis and CYP2C19*17/*17 genotype. Br J Clin Pharmacol. 2015 Oct;80(4):782-4. doi: 10.1111/bcp.12713. Epub 2015 Aug 24. No abstract available.
citation: Cendejas-Bueno E, Borobia AM, Gomez-Lopez A, Escosa-Garcia L, Rio-Garcia M, Plaza D, Garcia-Rodriguez J, Carcas-Sansuan A. Invasive aspergillosis in a paediatric allogeneic stem cell transplantation recipient owing to a susceptible Aspergillus fumigatus: Treatment failure with high doses of voriconazole and influence of CYP2C19 polymorphisms. Int J Antimicrob Agents. 2016 May;47(5):410-1. doi: 10.1016/j.ijantimicag.2016.02.002. Epub 2016 Feb 27. No abstract available.
citation: Moriyama B, Jarosinski PF, Figg WD, Henning SA, Danner RL, Penzak SR, Wayne AS, Walsh TJ. Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype. Pharmacotherapy. 2013 Mar;33(3):e19-22. doi: 10.1002/phar.1192. Epub 2013 Feb 11.
citation: Moriyama B, Falade-Nwulia O, Leung J, Penzak SR, JJingo C, Huang X, Henning SA, Wilson WH, Walsh TJ. Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction. Mycoses. 2011 Nov;54(6):e877-9. doi: 10.1111/j.1439-0507.2011.02016.x. Epub 2011 May 25.
citation: Andersen RL, Johnson DJ, Patel JN. Personalizing supportive care in oncology patients using pharmacogenetic-driven treatment pathways. Pharmacogenomics. 2016 Mar;17(4):417-34. doi: 10.2217/pgs.15.178. Epub 2016 Feb 12.
citation: Patel JN, Robinson MM, Hamadeh I, et al: CYP2C19 Genotype-Guided Dosing and Voriconazole Concentrations in Hematopoietic Stem Cell Transplant Patients (HSCT) Receiving Antifungal Prophylaxis. Blood 128, 2016; abstr 3416
citation: Crews KR, Cross SJ, McCormick JN, Baker DK, Molinelli AR, Mullins R, Relling MV, Hoffman JM. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm. 2011 Jan 15;68(2):143-50. doi: 10.2146/ajhp100113.
citation: Dunnenberger HM, Crews KR, Hoffman JM, Caudle KE, Broeckel U, Howard SC, Hunkler RJ, Klein TE, Evans WE, Relling MV. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu Rev Pharmacol Toxicol. 2015;55:89-106. doi: 10.1146/annurev-pharmtox-010814-124835. Epub 2014 Oct 2.