Leflunomide + Decitabine for Myelodysplastic Syndrome

Overseen By Konstantinos Sdrimas, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: West Virginia University

Must be taking: Hypomethylating agents

Must not be taking: Investigational agents

Disqualifiers: Acute myeloid leukemia, other malignancies, others

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

Compensation: Varies

Number of Visits: 3

Duration: 12 months

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments: leflunomide, an immunomodulatory drug, and decitabine, a chemotherapy drug. The goal is to determine their safety and tolerability for people with relapsed or refractory myelodysplastic syndromes (R/R MDS), a type of blood disorder. Researchers aim to find the right doses for this combination to benefit these patients. The trial is open to individuals with a confirmed diagnosis of MDS who have tried at least one similar treatment and meet specific blood cell count criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are receiving other investigational agents, chemotherapy, or immunotherapy.

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

Research continues to assess the safety of combining leflunomide and decitabine for individuals with relapsed or refractory myelodysplastic syndromes (R/R MDS). Specific safety information for this combination is not yet available. However, leflunomide alone has a generally manageable safety profile, meaning it can cause side effects that are usually predictable and controllable.

Decitabine, when used for other conditions, often leads to low blood cell counts, known as cytopenias, which doctors monitor closely. As this trial is in its early stages, one goal is to determine the doses that patients can best tolerate. This ensures the medications are used in safe and effective amounts. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Leflunomide and Decitabine for treating Myelodysplastic Syndrome because it offers a novel approach by incorporating an existing cancer treatment with a drug typically used for autoimmune conditions. Unlike standard treatments, which often focus solely on altering blood cell production, this combination leverages Decitabine's ability to modify DNA and Leflunomide's potential to inhibit abnormal cell growth, potentially enhancing effectiveness. This dual mechanism could offer a new avenue for tackling the disease's complex nature, which sets it apart from current therapies like hypomethylating agents.

What evidence suggests that this treatment might be an effective treatment for myelodysplastic syndrome?

Research has shown that decitabine can help treat myelodysplastic syndromes (MDS) by encouraging the bone marrow to produce normal blood cells. Studies have found that it can improve blood counts and reduce the need for transfusions in patients. Leflunomide reduces immune responses, which might be beneficial when used with decitabine. In this trial, participants will receive a combination of leflunomide and decitabine. Although limited information exists on using these two drugs together, early signs suggest this combination could benefit patients whose MDS has returned or isn't responding to other treatments. The treatment aims to be effective while keeping side effects manageable. ^{1 2 3 4 6}

Who Is on the Research Team?

Konstantinos Sdrimas, MD

Principal Investigator

West Virginia University

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory myelodysplastic syndromes (R/R MDS) who can tolerate daily treatments over several weeks. Specific eligibility criteria are not provided, but typically include factors like age, disease stage, and overall health.

Inclusion Criteria

If female of childbearing potential or a male patient, patient agrees to use an effective contraceptive method from the time of informed consent, during the course of the study, and for 3 months following the last dose of treatment

Patient understands and voluntarily signs the written informed consent prior to any study-specific procedures. A copy of the signed informed consent form will be retained by the treating institution

My bilirubin levels are normal and my kidneys function well.

Exclusion Criteria

Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that per Principal Investigator's judgment would limit compliance with study requirements

Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study

I have tuberculosis, whether active or not.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leflunomide in combination with decitabine for 12 cycles, each cycle lasting 28 days

12 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

Every 3 months

Open-label extension (optional)

Responding patients can continue progression with the assigned doses after 12 cycles

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Leflunomide

Trial Overview The study tests the combination of two drugs: Leflunomide (oral pill at 10mg or 20mg daily for up to three weeks) and Decitabine (intravenous infusion at a dose of 20 mg/m2 daily for five days every four weeks). The goal is to find the safest and most effective doses.

How Is the Trial Designed?

Group I: Leflunomide + Decitabine Treatment Experimental Treatment 3 Interventions

Participants will receive combination treatment for 12 cycles consisting of 28 days. Utilizing a conventional 3+3 design, Decitabine will be at a dose of 20 mg/m2 and will be administered by intravenous infusion over 1 hour daily for 5 days each 28-day cycle. Leflunomide will have a dose escalation schedule starting at (Level +1) as follows: Dose Escalation (Level -2): Leflunomide 10mg once daily by mouth x 14 days/cycle (Level -1): Leflunomide 10mg once daily by mouth x 21 days/cycle (Level +1): Leflunomide 20mg once daily by mouth x 14 days/cycle (Level +2): Leflunomide 20mg once daily by mouth x 21 days/cycle

Who Is Running the Clinical Trial?

West Virginia University

Lead Sponsor

Trials

192

Recruited

64,700+

Published Research Related to This Trial

Decitabine, a hypomethylating agent, has been shown to improve outcomes in patients with myelodysplastic syndromes (MDS), achieving a 17% overall response rate and 9% complete remissions in a Phase III trial compared to best supportive care.

In high-risk MDS patients, decitabine significantly prolonged the time to transformation to acute myelogenous leukemia or death, indicating its potential to alter the disease's natural history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of decitabine in the treatment of myelodysplastic syndromes. Atallah, E., Kantarjian, H., Garcia-Manero, G.[2019]

In a study of 99 patients with myelodysplastic syndromes (MDS), decitabine administered at a higher dose of 20 mg/m² daily for 5 days every 4 weeks resulted in a 32% overall response rate, indicating significant efficacy in treating MDS.

The outpatient regimen of decitabine not only provided comparable efficacy to the FDA-approved inpatient schedule but also allowed for more than half of the patients to show clinical improvement, suggesting a safe and effective alternative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. Steensma, DP., Baer, MR., Slack, JL., et al.[2023]

In a study of 65 pregnancies exposed to leflunomide (LEF), only one major malformation was observed among 39 live-born children, suggesting that LEF is not a major human teratogen.

However, the study noted an increased rate of spontaneous abortions and elective terminations, indicating a potential embryotoxic effect, which raises questions about the recommended waiting period and plasma level guidelines for LEF exposure before conception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide - A human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database. Weber-Schoendorfer, C., Beck, E., Tissen-Diabaté, T., et al.[2022]

This case study reports the successful use of decitabine and lenalidomide in treating a patient with myelodysplastic syndrome (MDS) characterized by a 5q deletion and elevated blast counts, leading to significant improvements in hemoglobin levels and cessation of transfusion dependency after just two cycles.

The treatment combination was well-tolerated with no notable side effects, suggesting it could be a promising option for MDS patients with similar profiles, although further validation in larger studies is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide Plus Decitabine Treatment in a Myelodysplastic Syndrome Patient With Deletion 5q and Excess Blasts. Serin, I., Eren, R., Dogu, MH.[2020]

In a study of 40,594 rheumatoid arthritis patients, leflunomide (LEF) monotherapy showed a significantly lower incidence of serious adverse events (94 events/1000 person-years) compared to methotrexate (MTX) and other DMARDs, indicating a safer profile for LEF.

Combination therapy with LEF and MTX also resulted in lower adverse event rates than those seen with MTX alone, suggesting that LEF can be a safer option when used in conjunction with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. Cannon, GW., Holden, WL., Juhaeri, J., et al.[2018]

In a study of 107 elderly patients with myelodysplastic syndromes (MDS), the combination of decitabine (DAC) and thalidomide improved overall survival (OS) for high-risk patients compared to DAC alone, with a significant difference of 50.6% versus 40.2%.

While DAC plus thalidomide did not show a significant improvement in progression-free survival (PFS) or acute myeloid leukemia-free survival (AML-FS) compared to DAC monotherapy, thalidomide was well tolerated with no severe non-hematological toxicity, making it a safe alternative treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine plus thalidomide yields more sustained survival rates than decitabine monotherapy for risk-tailored elderly patients with myelodysplastic syndrome. Zhao, WH., Zeng, QC., Huang, BT., et al.[2018]

Leflunomide has a well-documented safety profile for treating rheumatoid arthritis, showing no increased risk of adverse events compared to other similar medications, based on clinical trials and postmarketing studies.

Common side effects include diarrhea, elevated liver enzymes, alopecia, and rash, but 95% of experts believe these are manageable, and the incidence of side effects tends to decrease with continued treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide: a manageable safety profile. van Riel, PL., Smolen, JS., Emery, P., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06923488

Leflunomide in Combination With Decitabine for Treatment ... This is a phase I/II dose-escalation trial to estimate the activity of leflunomide in combination with decitabine for treatment of relapsed or refractory MDS.

2. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/594175

Leflunomide in Combination With Decitabine for Treatment of ... The goal of this interventional clinical trial is to evaluate the safety and tolerability of leflunomide in combination with decitabine as treatment for ...

3. ctv.veeva.com ctv.veeva.com/study/leflunomide-in-combination-with-decitabine-for-treatment-of-relapsed-or-refractory-myelodysplastic-s

Leflunomide in Combination With Decitabine for Treatment of ... Leflunomide will be administered orally daily with decitabine IV for 5 days as part of a 28-day treatment cycle in adult subjects with R/R MDS.

4. withpower.com withpower.com/trial/phase-2-syndrome-4-2025-0d2bb

Leflunomide + Decitabine for Myelodysplastic Syndrome This Phase 1 & 2 medical study run by West Virginia University is evaluating whether Decitabine and Leflunomide will have tolerable side effects & efficacy ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9137053/

The effect of decitabine-combined minimally ... Improved outcomes of allogeneic hematopoietic stem cell transplantation including haploidentical transplantation for childhood myelodysplastic syndrome.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2895778/

An update on the safety and efficacy of decitabine ... Data collected from this study demonstrated a median survival of 19.4 months by the closure of the study. The most common reported side effect was cytopenias.