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.

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. 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. Patients who have been previously treated with decitabine will be eligible. The trial will consist of dose escalation to evaluate safety and tolerability of leflunomide in combination with decitabine. There will be no intra-patient dose escalation or reduction. In the event of an RLT, one or both drugs (leflunomide or decitabine) could be withheld at the discretion of the treating physician and on the basis of the expected adverse event. The period for determination of RLT will be from the first day of treatment until 30 days after receiving the first dose of leflunomide + decitabine. After 12 cycles (study duration) responding patients can continue progression with the assigned doses.

Staging studies, including bone marrow biopsy and complete blood counts will be performed within 45 days prior to study enrollment and again within 30 days after completing Cycle 3, Cycle 6, and Cycle 12 and within 30 days of discontinuing study treatment. A repeat bone marrow biopsy will be performed at the end of the study (Cycle 12). Patients will be followed every 3 months for 2 years after completion of study.

Study assessments will also include monitoring of all toxicities and adverse events. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, will be used for grading adverse events and all toxicities

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