Leflunomide plus decitabine for relapsed or refractory myelodysplastic syndromes

Phase I/II Study of Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory (R/R) Myelodysplastic Syndromes (MDS)

This study will test whether adding the oral drug leflunomide to IV decitabine is safe and tolerable for adults with relapsed or refractory MDS who have already received a hypomethylating agent.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 26 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: West Virginia University (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 1 site (Morgantown, West Virginia)
• Trial ID: NCT06923488 on ClinicalTrials.gov

What this trial studies

This is a phase 1/2, dose-escalation trial testing oral leflunomide given alongside standard decitabine in 28-day cycles for adults with relapsed or refractory MDS. Decitabine is given at 20 mg/m2 IV once daily for 5 days each cycle, while leflunomide is given orally at 10–20 mg daily for 14–21 days per cycle without a loading dose. The study uses a traditional dose-escalation scheme to estimate maximum tolerated and biologically active doses and defines a 30-day window after first combination dose for determining dose-limiting toxicities. Participants will undergo bone marrow biopsies and blood monitoring at baseline and after Cycles 3, 6, and 12, and responders may continue on assigned doses beyond 12 cycles.

Who should consider this trial

Good fit: Adults with pathologically confirmed relapsed or refractory MDS who have measurable disease (bone marrow blasts >5% plus cytopenias), prior treatment with a hypomethylating agent, ECOG ≤2, and acceptable liver and kidney function are ideal candidates.

Not a fit: Patients with poor performance status (ECOG >2), significant hepatic or renal dysfunction (bilirubin >2×ULN or eGFR <45 mL/min/1.73 m2), or those without prior DNMTi/HMA exposure are unlikely to be eligible or benefit.

Why it matters

Potential benefit: If successful, the combination could provide a new tolerated treatment option that controls disease or prolongs responses in patients with relapsed/refractory MDS.

How similar studies have performed: Decitabine and other hypomethylating agents have established activity in MDS and some combination regimens have shown benefit, but combining decitabine with leflunomide is largely experimental with limited prior clinical data.

Eligibility criteria

Inclusion Criteria:

* Patient has pathologically confirmed diagnosis of MDS
* Patient has currently measurable disease meeting the following criteria:

  * Bone marrow biopsy with more than 5% blasts, AND
  * Absolute neutrophil count (ANC) less than 1,000/mcL, and/or platelet count less than 100,000/mcL and/or hemoglobin levels less than 10g/dL
* Patient has received one prior treatment with a DNA methyltransferase inhibitor (DNMTi), also commonly called hypomethylating agent (HMA). Patients whose MDS has IDH1/IDH2 mutations should have received at least one available IDH1/IDH2 inhibitor
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patient has the following required baseline laboratory data (eligibility can be based on local lab results):

  * Total serum bilirubin level less than or equal to 2 times ULN
  * Estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m2
* Patients who have undergone alloHSCT are eligible if they are more than 28 days post stem cell infusion, have no evidence of GVHD \> Grade 1, and are more than a week off all immunosuppressive therapy
* If a female of childbearing potential, the patient has a negative serum or urine pregnancy test result within 7 days prior to the first dose of treatment. Women of non-childbearing potential are those who are postmenopausal greater than one year or who have had a bilateral tubal ligation or hysterectomy
* 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

Exclusion Criteria:

* Patients receiving any other investigational agents, or concurrent chemotherapy or immunotherapy
* Patients with progression to acute myeloid leukemia
* Patients with other malignancies requiring systemic chemotherapy, immunotherapy or targeted therapy in the last four weeks
* Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms)
* Patients with active or latent tuberculosis
* Uncontrolled intercurrent illness including, but not limited to, 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
* Females who are pregnant or breast feeding
* Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study

Where this trial is running

Morgantown, West Virginia

• West Virginia University Cancer Institute — Morgantown, West Virginia, United States (Recruiting)

Study contacts

• Principal investigator: Konstantinos Sdrimas, MD — West Virginia University
• Study coordinator: Konstantinos Sdrimas, MD

Conditions Myelodysplastic Syndromes; relapsed or refractory