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

Study Overview
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Brief Summary
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This is an Open-Label, Crossover, Pharmacokinetic and Efficacy Bridging Study of Oral ASTX727 versus IV Decitabine in Chinese Subjects with Myelodysplastic Syndromes

Official Title
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An Open-label, Crossover, Pharmacokinetic and Efficacy Bridging Study of Oral ASTX727 Versus IV Decitabine in Chinese Subjects With Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: IV Decitabine
* Drug: Decitabine and cedazuridine
* Drug: only Decitabine and cedazuridine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Agree to participate in this trial and voluntarily sign the informed consent form. Men or women ≥ 18 years at the time of signing the informed consent form. Subjects with MDS previously treated or untreated with de novo or secondary MDS. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening. Exclusion Criteria: Prior treatment with more than 1 cycle of azacitidine or decitabine. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment. Conditions as judged by the investigator to be inappropriate for participation in the clinical trial. Previous diagnosis of malignant tumor. History of immune deficiency. Acute myeloid leukemia (AML) with bone marrow or peripheral blast count ≥ 20% or other malignant hematological diseases.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASTX727 and IV Decitabine<br>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<br>* The subjects will receive decitabine 20 mg/m^2 IV daily × 5 days in 28-day cycles.<br>Drug: Decitabine and cedazuridine<br>* subjects will receive treatment with ASTX727, 1 tablet/day for 5 consecutive days, in 28-day cycles.<br>Drug: only Decitabine and cedazuridine<br>* 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.<br>|
| Active Comparator: IV Decitabine and ASTX727<br>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<br>* The subjects will receive decitabine 20 mg/m^2 IV daily × 5 days in 28-day cycles.<br>Drug: Decitabine and cedazuridine<br>* subjects will receive treatment with ASTX727, 1 tablet/day for 5 consecutive days, in 28-day cycles.<br>Drug: only Decitabine and cedazuridine<br>* 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.<br>|
| Experimental: ASTX727<br>ASTX727 tablets, oral, 1 tablet/day for 5 days； | Drug: only Decitabine and cedazuridine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Assess efficacy [Complete Response Rate (CR)] of treatment with ASTX727 in Chinese subjects with myelodysplastic syndromes (MDS); | An analysis is planned when the last enrolled patient have completed Follow-up 12 months. | 
| 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; | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective Response Rate (ORR): The proportion of subjects who achieve CR and partial response (PR) based on IWG 2006 criteria; | through study completion, an average of 1 year. | 
| 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. | through study completion, an average of 1 year. | 
| 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; | through study completion, an average of 1 year. | 
| disease progression | Time to progression to acute myeloid leukemia (AML); | through study completion, an average of 1 year. | 
| Overall survival | Overall survival (OS). | through study completion, an average of 1 year. | 
| 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). | through study completion, an average of 1 year. | 
| peak concentration (Cmax) | Decitabine PK parameters: peak concentration (Cmax). | through study completion, an average of 1 year. | 
| time to peak concentration (Tmax) | Decitabine PK parameters: time to peak concentration (Tmax). | through study completion, an average of 1 year. | 
| 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). | through study completion, an average of 1 year. | 
| accumulation ratio based on AUC0-τ (Rac_AUC0-τ). | Decitabine PK parameters: accumulation ratio based on AUC0-τ (Rac_AUC0-τ). | through study completion, an average of 1 year. | 
| accumulation ratio based on Cmax (Rac_Cmax). | Decitabine PK parameters: accumulation ratio based on Cmax (Rac_Cmax). | through study completion, an average of 1 year. | 
| Cmax | PK parameters of E7727 and E7727-epimer: Cmax. | through study completion, an average of 1 year. | 
| Tmax | PK parameters of E7727 and E7727-epimer: Tmax. | through study completion, an average of 1 year. | 
| AUC0-τ | PK parameters of E7727 and E7727-epimer: area under the plasma concentration-time curve over a dosing interval . | through study completion, an average of 1 year. | 
| Rac_AUC0-τ | PK parameters of E7727 and E7727-epimer: accumulation ratio based on AUC0-τ. | through study completion, an average of 1 year. | 
| Rac_Cmax | PK parameters of E7727 and E7727-epimer: accumulation ratio based on Cmax. | through study completion, an average of 1 year. |