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

Phase 1

Active, not recruiting

• Conditions: Myelodysplastic Syndromes
• Interventions: Drug: ASTX727 LD; Drug: ASTX727 SD

• Registration Number: NCT03502668
• Lead Sponsor: Taiho Oncology, Inc.

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.

Study Timeline

• Study First Submitted: 2018-04-11
• Study First Submitted QC: 2018-04-11
• Study First Posted: 2018-04-19
• Study Start: 2018-07-27
• Status Verified: 2025-10
• Last Update Submitted: 2025-10-30
• Primary Completion: 2025-10-31
• Last Update Posted: 2025-10-31
• Study Completion: 2025-12-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

1. 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.

2. 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:

   1. 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).
   2. 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.
   3. Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.
   4. Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

4. Adequate organ function.

5. 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.

6. 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

1. Treatment with any investigational drug or therapy within 2 weeks before study treatment.
2. Treatments for MDS must be concluded 1 month prior to study treatment.
3. Prior treatment with azacitidine, decitabine, or guadecitabine.
4. Diagnosis of chronic myelomonocytic leukemia (CMML).
5. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
6. 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.
7. Known active infection with human immunodeficiency virus or hepatitis viruses.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2	ASTX727 SD	80 additional subjects randomized in a 1:1 ratio studying two different doses
Phase 1 Stage A	ASTX727 LD	3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
Phase 1 Stage B	ASTX727 LD	3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
Phase 2	ASTX727 LD	80 additional subjects randomized in a 1:1 ratio studying two different doses

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (29)

The University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of Colorado, Anschutz Cancer Pavilion; 🇺🇸 Aurora, Colorado, United States

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States

Mayo Clinic Florida; 🇺🇸 Jacksonville, Florida, United States

BRCR Medical Center Inc.; 🇺🇸 Plantation, Florida, United States

Moffitt Cancer Center Site#507; 🇺🇸 Tampa, Florida, United States

The University of Chicago; 🇺🇸 Chicago, Illinois, United States

Indiana University Health Hospital - Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

University of Kansas Clinical Research Center; 🇺🇸 Westwood, Kansas, United States

The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division); 🇺🇸 Bethesda, Maryland, United States

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