PK/Efficacy Bridging Study of ASTX727 in Chinese Subjects With Myelodysplastic Syndromes

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• Myelodysplastic Syndromes 2,124

Study arms

• Experimental
  ASTX727 and IV Decitabine

  Cycle1：ASTX727 tablets, oral, 1 tablet/day for 5 days；Cycle2：IV Decitabine, 20 mg/m\^2, is administered for 1 hour at a time for 5 days；≥ Cycle 3：ASTX727 tablets, oral, 1 tablet/day for 5 days

  Drug: IV Decitabine · Drug: Decitabine and cedazuridine · Drug: only Decitabine and cedazuridine

• Active comparator
  IV Decitabine and ASTX727

  Cycle1：IV Decitabine, 20 mg/m\^2, is administered for 1 hour at a time for 5 days； Cycle2：ASTX727 tablets, oral, 1 tablet/day for 5 days；≥ Cycle 3：ASTX727 tablets, oral, 1 tablet/day for 5 days

  Drug: IV Decitabine · Drug: Decitabine and cedazuridine · Drug: only Decitabine and cedazuridine

• Experimental
  ASTX727

  ASTX727 tablets, oral, 1 tablet/day for 5 days；

  Drug: only Decitabine and cedazuridine

Interventions

• DrugIV Decitabine

  The subjects will receive decitabine 20 mg/m\^2 IV daily × 5 days in 28-day cycles.

• DrugDecitabine and cedazuridine

  subjects will receive treatment with ASTX727, 1 tablet/day for 5 consecutive days, in 28-day cycles.

• Drugonly Decitabine and cedazuridine

  subjects will receive treatment with ASTX727, 1 tablet/day for 5 consecutive days, in 28-day cycles, until disease progression, unacceptable toxicity, or the subject/investigator decides that the subject should discontinue treatment or withdraw from the trial.

Primary outcomes

1. Complete Response Rate

   Assess efficacy \[Complete Response Rate (CR)\] of treatment with ASTX727 in Chinese subjects with myelodysplastic syndromes (MDS);

   Time frame: An analysis is planned when the last enrolled patient have completed Follow-up 12 months.

2. 5day_AUC0-τ

   Assess pharmacokinetic (PK) parameters (Total 5-day AUC exposures of decitabine) after treatment with ASTX727 (oral) versus decitabine for IV infusion for 5 days;

   Time frame: An analysis is planned when the last enrolled patient have completed the treatment with ASTX727 (oral) versus decitabine for IV infusion for 5 day.

Secondary outcomes

1. Objective Response Rate

   Objective Response Rate (ORR): The proportion of subjects who achieve CR and partial response (PR) based on IWG 2006 criteria;

   Time frame: through study completion, an average of 1 year.

2. Clinical Response Rate

   Clinical Response Rate: The proportion of subjects who achieve CR, PR, marrow complete response (mCR), and hematologic improvement (HI) based on IWG 2006 criteria.

   Time frame: through study completion, an average of 1 year.

3. Rate of transfusion independence

   Rate of transfusion independence: The proportion of subjects who had no blood transfusion of 2 or more units of PRBCs for 56 days or more after treatment;

   Time frame: through study completion, an average of 1 year.

4. disease progression

   Time to progression to acute myeloid leukemia (AML);

   Time frame: through study completion, an average of 1 year.

5. Overall survival

   Overall survival (OS).

   Time frame: through study completion, an average of 1 year.

6. Safety assessment

   Safety as assessed by adverse events (AEs), concomitant medications, physical examination, clinical laboratory tests (hematology , serum chemistry and urinalysis), vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and electrocardiogram (ECG).

   Time frame: through study completion, an average of 1 year.

7. peak concentration (Cmax)

   Decitabine PK parameters: peak concentration (Cmax).

   Time frame: through study completion, an average of 1 year.

8. time to peak concentration (Tmax)

   Decitabine PK parameters: time to peak concentration (Tmax).

   Time frame: through study completion, an average of 1 year.

9. area under the plasma concentration-time curve over a dosing interval (AUC0-τ).

   Decitabine PK parameters: area under the plasma concentration-time curve over a dosing interval (AUC0-τ).

   Time frame: through study completion, an average of 1 year.

10. accumulation ratio based on AUC0-τ (Rac_AUC0-τ).

    Decitabine PK parameters: accumulation ratio based on AUC0-τ (Rac\_AUC0-τ).

    Time frame: through study completion, an average of 1 year.

11. accumulation ratio based on Cmax (Rac_Cmax).

    Decitabine PK parameters: accumulation ratio based on Cmax (Rac\_Cmax).

    Time frame: through study completion, an average of 1 year.

12. Cmax

    PK parameters of E7727 and E7727-epimer: Cmax.

    Time frame: through study completion, an average of 1 year.

13. Tmax

    PK parameters of E7727 and E7727-epimer: Tmax.

    Time frame: through study completion, an average of 1 year.

14. AUC0-τ

    PK parameters of E7727 and E7727-epimer: area under the plasma concentration-time curve over a dosing interval .

    Time frame: through study completion, an average of 1 year.

15. Rac_AUC0-τ

    PK parameters of E7727 and E7727-epimer: accumulation ratio based on AUC0-τ.

    Time frame: through study completion, an average of 1 year.

16. Rac_Cmax

    PK parameters of E7727 and E7727-epimer: accumulation ratio based on Cmax.

    Time frame: through study completion, an average of 1 year.