Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory Myelodysplastic Syndromes

Phase 1

Not yet recruiting

• Conditions: Myelodysplastic Syndromes
• Interventions: Drug: Leflunomide 10mg; Drug: Leflunomide 20mg; Drug: Decitabine

• Registration Number: NCT06923488
• Lead Sponsor: West Virginia University

Brief Summary

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.

Detailed Description

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

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-25
• Study First Submitted QC: 2025-04-03
• Last Update Submitted: 2025-04-03
• Study First Posted: 2025-04-11
• Last Update Posted: 2025-04-11
• Study Start: 2025-05
• Primary Completion: 2027-10
• Study Completion: 2028-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 26

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Leflunomide + Decitabine Treatment	Leflunomide 10mg	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
Leflunomide + Decitabine Treatment	Leflunomide 20mg	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
Leflunomide + Decitabine Treatment	Decitabine	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

Primary Outcome Measures

Name	Time	Method
Percentage of incidences of regimen limiting toxicities (RLTs)	Date of first treatment up to 13 months	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

Secondary Outcome Measures

Name	Time	Method
CR + complete remission with partial hematologic recovery (CRh) (6th cycle)	Within 30 days following the end of the 6th cycle (cycle = 28 days)	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 of Complete Remission (CR) Rate (3rd cycle)	Within 30 days following the end of the 3rd cycle (cycle = 28 days)	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)	Within 30 days following the end of the 6th cycle (cycle = 28 days)	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)	Within 30 days of the end of the 12th cycle (cycle = 28 days)	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)	Within 30 days following the end of the 3rd cycle (cycle = 28 days)	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%
CR + complete remission with partial hematologic recovery (CRh) (12th cycle)	Within 30 days following the end of the 12th cycle (cycle = 28 days)	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%
CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) (3rd cycle)	Within 30 days following the end of the 3rd cycle (cycle = 28 days)	Percentage of participants that achieve CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) - defined as BM: \<5% myeloblasts (dysplasia may persist), and PB: blasts 0%; CRuni: PB, not meeting CR but only 1 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; CRbi: PB, not meeting CR but only 2 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L
CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) (6th cycle)	Within 30 days following the end of the 6th cycle (cycle = 28 days)	Percentage of participants that achieve CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) - defined as BM: \<5% myeloblasts (dysplasia may persist), and PB: blasts 0%; CRuni: PB, not meeting CR but only 1 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; CRbi: PB, not meeting CR but only 2 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L
CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) (12th cycle)	Within 30 days following the end of the 12th cycle (cycle = 28 days)	Percentage of participants that achieve CR + CRh + complete remission with limited count recovery (CRL) including CR bilineage (CRbi) and CR unilineage (CRuni) - defined as BM: \<5% myeloblasts (dysplasia may persist), and PB: blasts 0%; CRuni: PB, not meeting CR but only 1 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; CRbi: PB, not meeting CR but only 2 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L
Allogeneic hematopoietic stem cell transplant (alloHSCT)	Enrollment up to 3 years	The percentage of participants that proceed to allogeneic hematopoietic stem cell transplant (alloHSCT).
Overall Survival (OS)	From first treatment up to 3 years	Overall Survival (OS) defined for all patients of the trial; measured from the first day of receiving study drugs on the clinical trial to the date of death by any cause
Event-free survival (EFS)	From first treatment up to 3 years	Event-free survival (EFS) defined for all patients of the trial; measured from the first day of receiving study drugs to the date of treatment failure, or relapse from CR or CRh or CRL, or death by any cause. Treatment is defined as failure to achieve CR or CRh or CRL after at least three cycles of treatment; the date of treatment failure is defined as date of marrow evaluation after the last course of treatment.
Relapse-free survival (RFS) defined only for patients achieving CR or CRh or CRL;	From the date of achievement of a CR/CRh/CRL up to 3 years	Relapse-free survival (RFS) defined only for patients achieving CR or CRh or CRL; measured from the date of achievement of a CR/CRh/CRL until the date of relapse or death from any cause; RFS and disease-free survival (DFS) have been used with the same definition.
Progression to acute myeloid leukemia (AML)	Enrollment up to 3 years	Percentage of participant progression to acute myeloid leukemia (AML)
Percentage of Red Blood Cell transfusion independence	Date of first treatment up to 3 years	The percentage of participants that achieve the conversion from red blood cell transfusion dependence to transfusion independence. Transfusion Independence is defined as a period of time, usually 8 weeks, with no transfusion between first dose of study drug and the last dose of study drug + 30 days.

Trial Locations

Locations (1)

West Virginia University Cancer Institute; 🇺🇸 Morgantown, West Virginia, United States