Leflunomide for Chronic Graft Versus Host Disease

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Steroids

Must not be taking: New immunosuppressives

Disqualifiers: Active infection, Uncontrolled illness, Active malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether leflunomide, a medication, can help people with chronic graft versus host disease (cGVHD). This condition occurs after a bone marrow transplant when the donor's immune cells attack the recipient's body. Researchers aim to determine if leflunomide can reduce the need for steroids, which may cause side effects with long-term use. The trial seeks participants with cGVHD that hasn't fully responded to steroid treatment after two months. Those with cGVHD and ongoing symptoms despite steroid use might find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially beneficial treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have started any new immunosuppressive medications in the 4 weeks before joining. You should discuss your current medications with the study team to ensure they are compatible with the trial requirements.

Is there any evidence suggesting that leflunomide is likely to be safe for humans?

Research has shown that leflunomide is safe for patients with chronic graft versus host disease (cGVHD). In one study, patients with cGVHD who took leflunomide tolerated it well, with no major safety issues reported. This finding suggests that leflunomide could be a promising option for managing this challenging condition. However, as this was an early trial, further research is necessary to fully understand the safety of leflunomide for this specific use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for chronic graft versus host disease, which often involve steroids and immunosuppressive drugs, leflunomide offers a different approach by targeting the immune pathway more specifically. Researchers are excited about leflunomide because it inhibits pyrimidine synthesis, which is crucial for the proliferation of activated lymphocytes, the cells involved in graft versus host disease. This targeted action could potentially reduce side effects and improve outcomes compared to broader immunosuppressive therapies.

What evidence suggests that leflunomide might be an effective treatment for chronic graft versus host disease?

Research shows that leflunomide, which participants in this trial will receive, is being explored as a possible treatment for chronic graft versus host disease (cGVHD). Although direct evidence for its use in human cGVHD cases is not yet available, leflunomide has effectively treated rheumatoid arthritis by reducing immune response and inflammation. This gives researchers hope that it might also help with cGVHD, a condition where the immune system mistakenly attacks the body after a bone marrow transplant. The aim is to reduce the need for steroids, which can have many side effects, and improve patients' quality of life. Early signs suggest that leflunomide's mechanism could help control the immune response linked to cGVHD. ^{1 5 6 7 8}

Who Is on the Research Team?

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with chronic graft versus host disease (cGVHD) after a bone marrow transplant, who are dependent on steroids without full relief of symptoms. Participants must have stable organ function and blood counts, be able to swallow pills, and not be pregnant or breastfeeding. They should agree to use birth control and have no active infections or other serious health issues that could interfere with the study.

Inclusion Criteria

I can swallow pills.

Assent, when appropriate, will be obtained per institutional guidelines

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I received a donor lymphocyte infusion within the last 100 days.

I haven't taken new immunosuppressive drugs in the last 4 weeks.

I need a machine to help me breathe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide orally once daily for days 1-28, repeated every 28 days for 6 cycles

24 weeks

Optional Extension

Participants may optionally continue leflunomide for an additional 6 cycles if response or stable disease is maintained

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Leflunomide

Trial Overview The trial is testing Leflunomide's effectiveness in treating cGVHD symptoms when steroids alone aren't enough. It aims to see if this drug can reduce the immune response causing inflammation without the complications linked to prolonged steroid use.

How Is the Trial Designed?

Group I: Treatment (leflunomide) Experimental Treatment 1 Intervention

Patients receive leflunomide PO QD for days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue leflunomide for an additional 6 cycles as long as response or stable disease is maintained.

Leflunomide is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United States as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Approved in United Kingdom as Arava for:

• Rheumatoid arthritis
• Psoriatic arthritis

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Leflunomide treatment in a hamster-to-mouse heart transplantation model effectively prevents the formation of xenoantibodies (XAb) and chronic rejection in the first transplanted hearts, indicating its potential as an immunosuppressive agent for xenotransplantation.

The study suggests that leflunomide induces T-independent B-lymphocyte xenotolerance, as it prevents rejection of the first grafts while allowing for chronic lesions in second grafts after treatment withdrawal, highlighting its role in modulating immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection. Yan, Y., Verbeken, E., Yu, L., et al.[2019]

Leflunomide shows significant immunosuppressive effects in liver and kidney transplant recipients, allowing for reductions in conventional immunosuppressive drugs like cyclosporine and prednisone without evidence of acute rejection.

The drug was well tolerated in patients with lower serum creatinine levels, but those with higher levels experienced more side effects, highlighting the importance of monitoring serum drug levels for safe and effective dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experiences with leflunomide in solid organ transplantation. Williams, JW., Mital, D., Chong, A., et al.[2022]

In a study of 32 sarcoidosis patients, leflunomide was found to be effective, with a complete or partial response in 12 out of 17 patients treated with leflunomide alone and 13 out of 15 patients receiving it alongside methotrexate.

Leflunomide was well tolerated, with only three patients experiencing nausea, and no serious adverse reactions reported, suggesting it may be a safer alternative to methotrexate for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for chronic sarcoidosis. Baughman, RP., Lower, EE.[2019]

The combination of leflunomide with biological agents has been evaluated for its efficacy in treating rheumatoid arthritis, suggesting potential benefits in managing the disease.

Safety profiles of this combination therapy were also assessed, indicating that it may be a viable option for patients with rheumatoid arthritis, although specific safety outcomes were not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of the combination of leflunomide (Arava) and biological agents in treatment of rheumatoid arthritis]. Novak, S.[2018]

Leflunomide effectively prevents and treats acute graft-versus-host disease (GVHD) in a rat model, demonstrating its potential as a powerful immunomodulating drug.

Given its safety and efficacy in treating chronic rheumatoid arthritis in humans, leflunomide may be a promising candidate for clinical trials aimed at preventing GVHD in bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide. Mrowka, C., Thoenes, GH., Langer, KH., et al.[2019]

Leflunomide is an effective treatment for active rheumatoid arthritis (RA), showing comparable efficacy and safety to methotrexate and sulfasalazine in phase III clinical trials.

While leflunomide is generally safe, it can cause side effects like diarrhea and liver enzyme elevations, and it has a much longer half-life than other RA medications, raising concerns about potential hepatotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of leflunomide]. Hirohata, S.[2018]

A 64-year-old woman developed a lichenoid drug reaction after two months of treatment with leflunomide for rheumatoid arthritis, indicating a potential adverse effect of this immunomodulator.

The reaction improved significantly after stopping the medication and using colestyramine and topical corticosteroids, suggesting that leflunomide can cause serious skin reactions, although such side effects are generally rare and benign.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lichenoid drug reaction to leflunomide]. Canonne-Courivaud, D., Carpentier, O., Dejobert, Y., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6081307/

Leflunomide: Is It the Game Changer in Musculoskeletal ... To date there is no data of Leflunomide use in human beings in GVHD. Leflunomide with its anti-rheumatoid and proposed anti-GVHD effect was thus beneficial in ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04212416?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(Leflunomide)))&rank=5

Study Details | Leflunomide in Treating Patients With Steroid ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11917373/

Updates in Chronic Graft-Versus-Host Disease The results of this study support ruxolitinib as a steroid-sparing agent, as corticosteroid dose was decreased by ≥50% in half of patients, and 21% of patients ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S266663672501156X

Changes in Chronic Graft-versus-Host Disease Treatment ... Changes in Chronic Graft-versus-Host Disease Treatment Over Time: A 15-Years Survey Within Allogeneic Hematopoietic Stem Cell Transplant Centers in Germany, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04932564

Leflunomide for Musculoskeletal GVHD After Allogeneic ... The purpose of the current study is to study the efficacy and safety of leflunomide in patients with musculoskeletal GVHD in a prospective way. Detailed ...

6. astctjournal.org astctjournal.org/article/S2666-6367(23)02116-4/fulltext

Phase 1 Trial Investigating the Safety and Tolerability of ... Leflunomide is safe in patients with cGVHD, and is associated with a promising ORR in patients with multisystem cGVHD involvement.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124019074

Review Article Chronic graft-versus-host disease At 3 years, overall survival, relapse, and nonrelapse mortality (NRM) were 77%, 23%, and 8%, respectively, resulting in a cGVHD-free, relapse- ...

8. researchgate.net researchgate.net/publication/378059903_Phase_1_Trial_Investigating_the_Safety_and_Tolerability_of_Leflunomide_in_Patients_with_Steroid-Dependent_Chronic_Graft-Versus-Host_Disease_cGVHD_after_Allogeneic_Hematopoietic_Cell_Transplant_alloHCT?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbH19

Phase 1 Trial Investigating the Safety and Tolerability of ... Phase 1 Trial Investigating the Safety and Tolerability of Leflunomide ... Chronic graft-versus-host disease remains a frequent and morbid outcome ...