Study of ASTX727 vs IV Decitabine in MDS and CMML

Official Title

A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) Versus IV Decitabine in Subjects With Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) [ASTX727-02]


Multicentre, randomized, open-label, crossover PK study of ASTX727 versus IV decitabine. Adult subjects who are candidates to receive IV decitabine will be randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, subjects will continue to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the subject discontinues treatment or withdraws from the study.

Trial Description

Primary Outcome:

  • Total 5-day Area Under the Curve (AUC) exposures of decitabine
Secondary Outcome:
  • Numbers of subjects with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03.
  • Long Interspersed Nucleotide Elements (LINE)-1 demethylation
  • Maximum plasma concentration (Cmax)
  • Time to reach maximum concentration (Tmax)
  • Elimination rate constant
  • Apparent total systemic clearance
  • Apparent elimination half life
  • Apparent volume of distribution
  • Complete response (CR), marrow CR, partial response; hematologic improvement based on International Working Group 2006 MDS response criteria.
  • Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days.
  • Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks.
  • Leukemia-free survival: number of days from date of randomization to date when bone marrow or peripheral blood blasts reach ≥20%, or death.
  • Overall survival: number of days from date subject was randomized to date of death.
This Phase 3 study will establish PK equivalence of ASTX727 to IV decitabine in approximately 118 evaluable subjects. Eligible subjects will receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: subjects will be randomly assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other therapy in Cycle 2. In the ASTX727 cycle, subjects will receive the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) will be done on Days 1, 2, and 5, along with pre-dose PK assessments on Days 1-5 and an assessment at 3 hours post dose on Day 3. Subjects will be required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours before and 2 hours after dosing. In the IV decitabine cycle, subjects will receive a 1-hour infusion of IV decitabine 20 mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3. In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments will be done from Cycle 3 onward.)

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