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

Trial Summary

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.

What data supports the effectiveness of the drug Leflunomide in combination with Decitabine for treating Myelodysplastic Syndrome?

Leflunomide has been shown to be effective in treating rheumatoid arthritis by inhibiting cell growth and reducing inflammation, which may suggest potential benefits in other conditions involving abnormal cell proliferation, like Myelodysplastic Syndrome. ^{1 2 3 4 5}

Is the combination of Leflunomide and Decitabine safe for humans?

Leflunomide has been studied for rheumatoid arthritis and is generally considered safe, with common side effects like diarrhea, elevated liver enzymes, and rash. There is no specific safety data available for the combination of Leflunomide and Decitabine, but Leflunomide alone has a manageable safety profile. ^{6 7 8 9 10}

What makes the combination of Leflunomide and Decitabine unique for treating Myelodysplastic Syndrome?

The combination of Leflunomide and Decitabine for treating Myelodysplastic Syndrome (MDS) is unique because it pairs a drug known for its use in autoimmune conditions (Leflunomide) with a hypomethylating agent (Decitabine) that reactivates important genes to fight cancer. This novel combination could offer a new approach by potentially enhancing the effects of Decitabine, which is already used in MDS treatment, but further studies are needed to confirm its effectiveness. ^{11 12 13 14 15}

What is the purpose of this trial?

The goal of this interventional clinical trial is to evaluate the safety and tolerability of leflunomide in combination with decitabine as treatment for patients with relapsed or refractory myelodysplastic syndromes (R/R MDS). The main question this study aims to answer are to evaluate and estimate the maximum tolerated doses and/or biologically active doses of the combination of leflunomide-decitabine in participants. Decitabine will be administered at a dose of 20 mg/m2 by continuous intravenous infusion over one hour repeated daily for 5 days with repeating cycle every 4 weeks. Leflunomide is administered orally at 10 to 20 mg once daily (without a loading dose) for 14 to 21 days, as part of a 28-day treatment cycle in adult subjects with R/R MDS. After 12 cycles (study duration) responding patients can continue progression with the assigned doses.

Research Team

Konstantinos Sdrimas, MD

Principal Investigator

West Virginia University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. [2018]

4. Spain pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Leflunomide interferes with pyrimidine nucleotide biosynthesis. [2019]

6. Canada pubmed.ncbi.nlm.nih.gov

Leflunomide: a manageable safety profile. [2018]

7. Canada pubmed.ncbi.nlm.nih.gov

Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. [2018]

8. Spain pubmed.ncbi.nlm.nih.gov

Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Leflunomide - A human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[Leflunomide: clinical effectiveness and mechanism of action]. [2006]

11. Canada pubmed.ncbi.nlm.nih.gov

Lenalidomide Plus Decitabine Treatment in a Myelodysplastic Syndrome Patient With Deletion 5q and Excess Blasts. [2020]

12. England pubmed.ncbi.nlm.nih.gov

The role of decitabine in the treatment of myelodysplastic syndromes. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Decitabine plus thalidomide yields more sustained survival rates than decitabine monotherapy for risk-tailored elderly patients with myelodysplastic syndrome. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Clinical results with the DNA hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in patients with myelodysplastic syndromes: an update. [2022]

15. United States 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. [2023]