Leflunomide to Prevent Cytomegalovirus Reactivation in Stem Cell Transplant Patients

Official title

Use of Leflunomide as Primary Prophylaxis Against Cytomegalovirus (CMV) Reactivation in Haploidentical Haematopoietic Stem Cell Transplant (HIT) - Single, Arm, Phase 2 Clinical Trial

Overview

Patients undergoing half-matched hematopoietic stem cell transplantation (HSCT) are at high risk of viral reactivation after bone marrow transplantation (BMT). The purpose of this study is to evaluate whether leflunomide can prevent cytomegalovirus (CMV) reactivation in these patients and to assess its safety. The main questions it aims to answer are - 1. Does leflunomide prevent cytomegalovirus (CMV) related organ damage? 2. Does leflunomide prevent a rise in cytomegalovirus (CMV) copy number to more than 2000 copies/ml? 3. Does leflunomide prevent the need to start pre-emptive therapy for cytomegalovirus (CMV)? 4. Is it safe to use in bone marrow transplant ( BMT) patients? 5. Does leflunomide prevent other viral reactivations - like Adeno virus and BK virus? 6. Does leflunomide affect the risk of acute graft-versus-host disease ( acute GVHD) after bone marrow transplant (BMT)? What medicine will the patients receive? Patients in study shall receive loading dose of Tab. Leflunomide 100 mg daily for 3 days followed by 20 mg daily orally. Leflunomide will be given till day +180 post transplant or till patient is on immunosuppressant medicines.

Detailed description

Introduction :While pre-emptive medications have lowered the frequency of cytomegalovirus (CMV) illness after HSCT, CMV reactivation remains associated with higher mortality. Haploidentical transplant (haplo-HSCT) are high risk transplants, which have increased risk of viral reactivations. Current antiviral treatments, such as ganciclovir, have serious adverse effects and are limited in their use, whereas letermovir is expensive and unavailable in India.

Leflunomide, a medicine, which is used in Rheumatoid arthritis, is a possible alternative due to its antiviral effects and low cost. It may be beneficial at preventing cytomegalovirus (CMV) reactivation, particularly in patients with low viral levels. Furthermore, leflunomide has demonstrated efficacy against BK virus and other DNA viruses, making it a possible multifaceted preventive treatment for high-risk haplo-identical hematopoietic stem cell transplantation (HSCT) recipients.

Hypothesis Leflunomide is effective in decreasing clinically significant CMV(cytomegalovirus) infection after haplo-hematopoietic stem cell transplantation (HSCT)

Target population Patients ≥18 years of age who are undergoing haplo-hematopoietic stem cell transplantation (HSCT) for any malignancy at Tata Memorial centre ACTREC, Mumbai

Aims:

To evaluate efficacy of leflunomide as a prophylactic agent against cytomegalovirus (CMV)reactivation in Haplo-hematopoietic stem cell transplantation (HSCT).

Objectives -

Primary objective To determine the rate of clinically significant CMV infection on prophylactic leflunomide in haplo-HSCT patients till day+180 post HSCT

Secondary objective

1. To evaluate the safety of post-transplant leflunomide using CTCAE 5.0 grading. 2. To evaluate the incidence of clinically significant BK virus reactivation in peripheral blood and urine till day+180. Clinically significant BK virus reactivation will be defined as per ECIL-6 guidelines as more than 10\^7 copies (7 log10 gEq/mL) in urine and 10\^3 copies (1000 gEq/mL) in blood will be considered significant thresholds to define BK virus re- activation 3. To evaluate the incidence of grade III - IV acute GVHD.

Study schema - Single-arm, Phase 2, prospective, interventional study

Administration of study treatment Once neutrophil engraftment has occurred i.e., ANC≥500/mm (on or before day-28), all patients in study shall receive loading dose of Tab. Leflunomide 100 mg daily for 3 days followed by 20 mg daily orally. Leflunomide will be given till day +180 post haplo-HSCT or till patient is on systemic immunosuppression

Timing of dose administration Study therapy should be administered/taken at the same time each day. Tablets are to be swallowed whole (i.e., no crushing or chewing the tablet is allowed). Study therapy may be administered with or without food. If a subject misses a dose, the missed dose should be given as soon as possible during the same day. If more than 18 hours have gone by after the regular dosing time, then the missed dose should be skipped and the normal dosing schedule should be resumed. The next dose should not be doubled in order to "make up" what has been missed.

Investigations During Treatment Monitoring: Weekly cytomegalovirus (CMV) PCR in blood, bi-weekly BK virus PCR in blood and urine, and additional tests as clinically indicated.

Overall study duration - 5 years

Interventions

• Drug Leflunomide 20 mg
  Patients in study shall receive loading dose of Tab Leflunomide 100 mg daily for 3 days followed by 20 mg daily orally. Leflunomide will be given till day 180 + post haploidentical transplant or till patient is on systemic immunosuppression.

Primary outcome measures

• Number of participants with clinically significant cytomegalovirus (CMV) infection [Time frame: Through Day +180 post hematopoietic stem cell transplantation (HSCT).]

Secondary outcome measures (3)

• Number of participants with treatment-emergent adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [Time frame: Day+180 post transplant]
• Number of participants with clinically significant BK virus reactivation [Time frame: Day+180 post transplant]
• Number of participants with Grade III-IV acute graft-versus-host disease [Time frame: Day+180 post transplant]

Eligibility criteria

Inclusion criteria

• Males or females undergoing Haplo-identical haematopoetic stem cell transplant.
• Age ≥18yrs on the day of signing informed consent
• Undetectable CMV from plasma sample in preceding 7 days
• Patient who has WBC engraftment (ANC>=500/cumm for 3 or more consecutive days).
• Within 7 days of WBC engraftment
• Adequate liver functions (ALT / AST less than 5 times upper limit of normal and Bilirubin <=3 times upper limit of normal) at time of starting leflunomide
• Understands the study procedures, alternative treatment available, and risks involved with the study, and voluntarily agree to participate by giving written informed consent.

Exclusion criteria

• Known hypersensitivity to Leflunomide
• History of clinically significant CMV reactivation in past 1 year
• Patient is receiving/has received drug known to have anti CMV activity within in last 7 days \[Ganciclovir, valganciclovir, foscarnet, letermovir, acyclovir (at doses >=3200 mg PO per day or >=25 mg/kg IV per day), valacyclovir (at doses \&>=3000 mg PO per day)\]
• Inadequate renal function (creatinine clearance <=30 ml/min)
• Chronic active hepatitis B (HBsAg+ or any HBV DNA+), hepatitis C, or/and HIV
• Any psychiatric condition that might limit the ability of the patient to comply with the protocol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

India · 3 centers

• Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) Tata Memorial Cen — Navi Mumbai
• Advanced Centre for Treatment, Research and Education in Cancer — Navi Mumbai
• Advanced Centre for Treatment, Research and Education in Cancer — Navi Mumbai

Publications

• PREVYMIS™ (letermovir) Whitehouse Station, NJ: Merck &amp; Co., Inc.; 2017
• Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28. PMID 27682069
• Fox R, Helfgott S (2021). Leflunomide. In St Clair EW (Ed.), UpToDate. https://www.uptodate.com/drug-interactions. Accessed June 01, 2023
• Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, Fox R, Moreland L, Olsen N, Furst D, Caldwell J, Kaine J, Sharp J, Hurley F, Loew-Friedrich I. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med. 1999 Nov 22;159(21):2542-50. doi: 10.1001/archinte.159.21.2542. PMID 10573044
• US Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2017) Common Terminology Criteria for Adverse Events (CTCAE) Version Study protocol Version -1.1 dated 22/02/2024 17 of 16 5.0 2017. https://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 01 May 2020
• Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, Ljungman P; Fourth European Conference on Infections in Leukemia. European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011). Transpl Infect Dis. 2012 Dec;14(6):555-63. doi: 10.1111/tid.12022. Epub 2012 Nov 12. PMID 23146063
• Lindemans CA, Leen AM, Boelens JJ. How I treat adenovirus in hematopoietic stem cell transplant recipients. Blood. 2010 Dec 16;116(25):5476-85. doi: 10.1182/blood-2010-04-259291. Epub 2010 Sep 13. PMID 20837781
• Anderson EJ, Guzman-Cottrill JA, Kletzel M, Thormann K, Sullivan C, Zheng X, Katz BZ. High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant. 2008 Mar;12(2):219-27. doi: 10.1111/j.1399-3046.2007.00851.x. PMID 18307672

Identifiers

NCT: NCT07709013 · 901006

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗