Leflunomide in Combination With Decitabine for Treatment of Relapsed or Refractory Myelodysplastic Syndromes
NCT ID: NCT06923488
Last Updated: 2025-07-20
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1/PHASE2
26 participants
INTERVENTIONAL
2025-08-31
2028-10-31
Brief Summary
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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.
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Detailed Description
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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
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Leflunomide + Decitabine Treatment
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 10mg
Leflunomide 10mg tablet
Leflunomide 20mg
Leflunomide 20mg tablet
Decitabine
Decitabine dose of 20 mg/m2
Interventions
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Leflunomide 10mg
Leflunomide 10mg tablet
Leflunomide 20mg
Leflunomide 20mg tablet
Decitabine
Decitabine dose of 20 mg/m2
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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
18 Years
ALL
No
Sponsors
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West Virginia University
OTHER
Responsible Party
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Konstantinos Sdrimas
Assistant Professor
Principal Investigators
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Konstantinos Sdrimas, MD
Role: PRINCIPAL_INVESTIGATOR
West Virginia University
Locations
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West Virginia University Cancer Institute
Morgantown, West Virginia, United States
Countries
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Central Contacts
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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2502109808
Identifier Type: -
Identifier Source: org_study_id
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