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

NCT06923488 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2502109808
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Myelodysplastic Syndromes

Keywords

relapsed or refractory

Outcome Measures

Primary Outcomes (1)

• 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

  Date of first treatment up to 13 months

Secondary Outcomes (15)

• Percentage of Complete Remission (CR) Rate (3rd cycle)

  Within 30 days following the end of the 3rd cycle (cycle = 28 days)

• Percentage of Complete Remission (CR) Rate (6th cycle)

  Within 30 days following the end of the 6th cycle (cycle = 28 days)

• Percentage of Complete Remission (CR) Rate (12th cycle)

  Within 30 days of the end of the 12th cycle (cycle = 28 days)

• CR + complete remission with partial hematologic recovery (CRh) (3rd cycle)

  Within 30 days following the end of the 3rd cycle (cycle = 28 days)

• CR + complete remission with partial hematologic recovery (CRh) (6th cycle)

  Within 30 days following the end of the 6th cycle (cycle = 28 days)

Other Outcomes (2)

• Percentage Clonal Evolution

  Enrollment up to 3 years

• Percentage of platelet transfusion independence

  Date of first treatment up to 3 years

Study Arms (1)

Leflunomide + Decitabine Treatment

EXPERIMENTAL

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

Drug: Leflunomide 10mg; Drug: Leflunomide 20mg; Drug: Decitabine

Interventions

Leflunomide 10mg DRUG

Leflunomide 10mg tablet

Also known as: Arava

Leflunomide + Decitabine Treatment

Leflunomide 20mg DRUG

Leflunomide 20mg tablet

Also known as: Arava

Leflunomide + Decitabine Treatment

Decitabine DRUG

Decitabine dose of 20 mg/m2

Also known as: Dacogen

Leflunomide + Decitabine Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• West Virginia University: lead

Study Sites (1)

West Virginia University Cancer Institute

Morgantown, West Virginia, 26506, United States

RECRUITING

Related Publications (12)

• Chilakala S, Feng Y, Li L, Mahfouz R, Quteba E, Saunthararajah Y, Xu Y. Tracking Decitabine Incorporation into Malignant Myeloid Cell DNA in vitro and in vivo by LC-MS/MS with Enzymatic Digestion. Sci Rep. 2019 Mar 14;9(1):4558. doi: 10.1038/s41598-019-41070-y.

  PMID: 30872721 BACKGROUND

• Qin F, Wu J, Chen F, Wei Y, Zhao Y, Jiang Z, Bai J, Yu H. Optimal, minimax and admissible two-stage design for phase II oncology clinical trials. BMC Med Res Methodol. 2020 May 20;20(1):126. doi: 10.1186/s12874-020-01017-8.

  PMID: 32434577 BACKGROUND

• Zeidan AM, Platzbecker U, Bewersdorf JP, Stahl M, Ades L, Borate U, Bowen D, Buckstein R, Brunner A, Carraway HE, Daver N, Diez-Campelo M, de Witte T, DeZern AE, Efficace F, Garcia-Manero G, Garcia JS, Germing U, Giagounidis A, Griffiths EA, Hasserjian RP, Hellstrom-Lindberg E, Iastrebner M, Komrokji R, Kulasekararaj AG, Malcovati L, Miyazaki Y, Odenike O, Santini V, Sanz G, Scheinberg P, Stauder R, van de Loosdrecht AA, Wei AH, Sekeres MA, Fenaux P. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023 Apr 27;141(17):2047-2061. doi: 10.1182/blood.2022018604.

  PMID: 36724453 BACKGROUND

• Kayamori K, Nagai Y, Zhong C, Kaito S, Shinoda D, Koide S, Kuribayashi W, Oshima M, Nakajima-Takagi Y, Yamashita M, Mimura N, Becker HJ, Izawa K, Yamazaki S, Iwano S, Miyawaki A, Ito R, Tohyama K, Lennox W, Sheedy J, Weetall M, Sakaida E, Yokote K, Iwama A. DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes. Blood Adv. 2021 Jan 26;5(2):438-450. doi: 10.1182/bloodadvances.2020001461.

  PMID: 33496740 BACKGROUND

• Santini V. How I treat MDS after hypomethylating agent failure. Blood. 2019 Feb 7;133(6):521-529. doi: 10.1182/blood-2018-03-785915. Epub 2018 Dec 13.

  PMID: 30545832 BACKGROUND

• Stomper J, Rotondo JC, Greve G, Lubbert M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia. 2021 Jul;35(7):1873-1889. doi: 10.1038/s41375-021-01218-0. Epub 2021 May 6.

  PMID: 33958699 BACKGROUND

• Jabbour E, Garcia-Manero G, Batty N, Shan J, O'Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug 15;116(16):3830-4. doi: 10.1002/cncr.25247.

  PMID: 20564137 BACKGROUND

• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.

  PMID: 19230772 BACKGROUND

• Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, Dreyfus F, Rauzy OB, Recher C, Ades L, Quesnel B, Beach CL, Fenaux P, Vey N. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011 Aug 20;29(24):3322-7. doi: 10.1200/JCO.2011.35.8135. Epub 2011 Jul 25.

  PMID: 21788559 BACKGROUND

• Zeidan AM, Stahl M, Hu X, Wang R, Huntington SF, Podoltsev NA, Gore SD, Ma X, Davidoff AJ. Long-term survival of older patients with MDS treated with HMA therapy without subsequent stem cell transplantation. Blood. 2018 Feb 15;131(7):818-821. doi: 10.1182/blood-2017-10-811729. Epub 2017 Dec 19. No abstract available.

  PMID: 29259002 BACKGROUND

• Bartenstein M, Deeg HJ. Hematopoietic stem cell transplantation for MDS. Hematol Oncol Clin North Am. 2010 Apr;24(2):407-22. doi: 10.1016/j.hoc.2010.02.003.

  PMID: 20359634 BACKGROUND

• Sekeres MA, Schoonen WM, Kantarjian H, List A, Fryzek J, Paquette R, Maciejewski JP. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008 Nov 5;100(21):1542-51. doi: 10.1093/jnci/djn349. Epub 2008 Oct 28.

  PMID: 18957672 BACKGROUND

MeSH Terms

Conditions

Myelodysplastic Syndromes; Recurrence

Interventions

Leflunomide; Decitabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Konstantinos Sdrimas, MD

  West Virginia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Konstantinos Sdrimas, MD

CONTACT

304-598-4520; Konstantinos.sdrimas1@hsc.wvu.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 25, 2025
• First Posted: April 11, 2025
• Study Start: July 15, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028
• Last Updated: April 23, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)