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.
Patient has pathologically confirmed diagnosis of MDS
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
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)
Single group
Leflunomide 10mg
DrugLeflunomide 10mg tablet
Leflunomide 20mg
DrugLeflunomide 20mg tablet
Decitabine
DrugDecitabine dose of 20 mg/m2
Percentage of incidences of regimen limiting toxicities (RLTs)
Percentages of incidences of RLTs defined as: * A need to reduce the dose of one or both of the treatments * Discontinue the treatment due to dose limiting toxicities, AE/SAE * Be withheld at the discretion of the treating physician and on the basis of the expected adverse event
Percentage of Complete Remission (CR) Rate (3rd cycle)
Percentage of patients achieving complete remission (CR) rate defined as bone marrow (BM): \<5% myeloblasts (dysplasia may persist), and peripheral blood (PB): hemoglobin (Hb) ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%. Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response)
Percentage of Complete Remission (CR) Rate (6th cycle)
Percentage of patients achieving complete remission (CR) rate defined as bone marrow (BM): \<5% myeloblasts (dysplasia may persist), and peripheral blood (PB): hemoglobin (Hb) ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%. Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response)
Percentage of Complete Remission (CR) Rate (12th cycle)
Percentage of patients achieving complete remission (CR) rate defined as bone marrow (BM): \<5% myeloblasts (dysplasia may persist), and peripheral blood (PB): hemoglobin (Hb) ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%. Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response)
CR + complete remission with partial hematologic recovery (CRh) (3rd cycle)
Percentage of participants that achieve CR + complete remission with partial hematologic recovery (CRh) - defined as BM: \<5% myeloblasts (dysplasia may persist) and PB: Not meeting criteria for CR or CRL, no Hb threshold required, platelets ≥50 × 109/L; neutrophils ≥0.5 × 109/L; blasts 0%
Percentage Clonal Evolution
Percentage of participants with clonal evolution. Defined as mutations in founding clone, expansion of subclone(s), and convergent clonal evolution of signaling gene mutations; assessed by chromosomal analysis, fluorescence in situ hybridization (FISH) and mutational analysis by next generation sequencing in bone marrow evaluation.
Percentage of platelet transfusion independence
The percentage of participants that achieve the conversion from platelet transfusion dependence to transfusion independence (persons who transition from needing regular platelet transfusions to no longer requiring them).
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