Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS

Study Overview
=================
Brief Summary
-----------------
Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with International Prognostic Scoring System (IPSS) risk category of low-risk or Intermediate-1 MDS. This study will be conducted in two phases. In phase 1 subjects will be randomized into 3 cohorts in a 28-day cycles. Phase 2, 80 new subjects will be randomized in a 1:1 ratio into 2 doses/schedules.

Detailed Description
-----------------
A Phase 1-2, multicenter, open-label study of various ASTX727 LD doses and schedules to assess the safety, pharmacodynamics (PD), pharmacokinetics (PK), and hematologic response in subjects with IPSS risk category of low-risk or Intermediate-1 MDS. The study will be conducted in 2 phases. Phase 1: In Stage A, subjects will be randomized into 3 cohorts of 6 subjects each testing different doses of oral decitabine with cedazuridine in 28-day cycles. When safety has been established in Phase 1 Stage A, Phase 1 Stage B will open, wherein additional 30 subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 10 subjects. Phase 2: Using 2 doses/schedules one of which will be selected from Phase 1, 40 additional subjects per dose/schedule will be randomized in a 1:1 ratio. The selected doses/schedules will be evaluated for safety (drug-related AEs), efficacy (including hematologic response), PD (long interspersed nucleotide element-1 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Official Title
-----------------
A Randomized, Open-Label, Phase 1-2 Study of ASTX727 Low Dose (ASTX727 LD) Extended Schedule in Subjects With Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS)

Conditions
-----------------
Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: ASTX727 LD
* Drug: ASTX727 SD


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure. Men or women ≥18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization: Red blood cell (RBC) transfusion dependence of 2 or more units of RBC transfusions (RBC transfusion administered for hemoglobin (Hb) levels ≤9.0 g/dL are counted). Hb of <9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received. Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization. Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Adequate organ function. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential must agree to use contraceptive measures of birth control for 6 months after completing treatment; men must use contraceptive measures and agree not to father a child for at least 3 months after completing treatment. Exclusion Criteria: Treatment with any investigational drug or therapy within 2 weeks before study treatment. Treatments for MDS must be concluded 1 month prior to study treatment. Prior treatment with azacitidine, decitabine, or guadecitabine. Diagnosis of chronic myelomonocytic leukemia (CMML). Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year. Known active infection with human immunodeficiency virus or hepatitis viruses.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Multicenter, open label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Stage A<br>3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD | Drug: ASTX727 LD<br>* oral decitabine (LD) + cedazuridine (E7727)<br>* Other names: oral decitabine (LD) + cedazuridine (E7727);|
| Experimental: Phase 1 Stage B<br>3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD | Drug: ASTX727 LD<br>* oral decitabine (LD) + cedazuridine (E7727)<br>* Other names: oral decitabine (LD) + cedazuridine (E7727);|
| Experimental: Phase 2<br>80 additional subjects randomized in a 1:1 ratio studying two different doses | Drug: ASTX727 LD<br>* oral decitabine (LD) + cedazuridine (E7727)<br>* Other names: oral decitabine (LD) + cedazuridine (E7727);Drug: ASTX727 SD<br>* oral decitabine (SD) + cedazuridine (E7727)<br>* Other names: oral decitabine (SD) + cedazuridine (E7727);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule | Phase 1: Safety | 18-24 months | 
| Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) | Phase 2: Efficacy | 18-24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| %LINE-1 methylation change from baseline | pharmacodynamics | 18-24 months | 
| Area under the curve (AUC) | pharmacokinetics parameter | 18-24 months | 
| Maximum plasma concentration (Cmax) | pharmacokinetics parameter | 18-24 months | 
| Time to reach maximum concentration (Tmax) | pharmacokinetics parameter | 18-24 months | 
| Half life (t1/2) | pharmacokinetics parameter | 18-24 months | 
| Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) | Phase 1: Efficacy | 18-24 months | 
| Time to bone marrow blasts >5% | Number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by ≥50%. | 18-24 months | 
| Leukemia-free survival | Number of days from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause | 18-24 months | 
| Overall survival | Number of days from the date of randomization to the date of death from any cause | 18-24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
low risk myelodysplastic syndromes, MDS, ASTX727