Purpose

Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with IPSS risk category of low-risk or Intermediate-1 MDS. In Phase 1 Stage A, subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 6 subjects each in a 10-day schedule in 28-day cycles; when safety is established in Stage A, 24 evaluable subjects will be randomized in a 1:1:1:1 ratio in Phase 1 Stage B into 4 cohorts of 6 subjects each in a 14-day schedule in 28-day cycles. In Phase 2, 40 new subjects will be randomized in a 1:1 ratio into 2 doses/schedules selected from Phase 1.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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:
  3. Red blood cell (RBC) transfusion dependence of 2 or more units of RBCs or Hb of <8.5 g/dL in at least 2 blood counts prior to randomization.
  4. ANC of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.
  5. Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  7. Adequate organ function defined as follows:
  8. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤5 × ULN.
  9. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate ≥50 mL/min.
  10. 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.
  11. Subjects and their partners with reproductive potential must agree to use 2 highly effective contraceptive measures during the study and must agree not to become pregnant or father a child for 3 months after the last dose of study treatment.

Exclusion Criteria

  1. Treatment with any investigational drug or therapy within 2 weeks before study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant AEs from previous treatment.
  2. Treatments for MDS, including erythropoietins, colony-stimulating factors (CSFs), thrombopoietins, chemotherapy, and immunosuppression including calcineurin inhibitors, glucocorticoids, etc., must be concluded 1 month prior to study treatment.
  3. Diagnosis of chronic myelomonocytic leukemia (CMML).
  4. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
  5. Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
  6. Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ASTX727 LD, or compromise the integrity of the study outcomes.
  7. 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.
  8. Known active infection with human immunodeficiency virus or hepatitis viruses.

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Multicenter, open label
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Phase 1 Stage A
3 cohorts of 6 subjects each in a 10-day schedule in 28-day cycles of ASTX727 LD
  • Drug: ASTX727 LD
    oral decitabine + cedazuridine (E7727)
    Other names:
    • oral decitabine + cedazuridine (E7727)
Experimental
Phase 1 Stage B
4 cohorts of 6 subjects each in a 14-day schedule in 28-day cycles of ASTX727 LD
  • Drug: ASTX727 LD
    oral decitabine + cedazuridine (E7727)
    Other names:
    • oral decitabine + cedazuridine (E7727)
Experimental
Phase 2
40 additional subjects randomized in a 1:1 ratio into 1 of 2 doses/schedules of ASTX727 LD selected from Phase 1
  • Drug: ASTX727 LD
    oral decitabine + cedazuridine (E7727)
    Other names:
    • oral decitabine + cedazuridine (E7727)

Recruiting Locations

The University of Alabama at Birmingham
Birmingham, Alabama 35233
Contact:
Frances Thorne
205-996-1384
fthorne@uabmc.edu

More Details

NCT ID
NCT03502668
Status
Recruiting
Sponsor
Astex Pharmaceuticals

Study Contact

Kartik Krishnan, MD, PhD
925-560-2894
kartik.krishan@astx.com

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 Stages A and B, and Phase 2. Randomization will be stratified by diagnostic category (low-risk vs Intermediate-1 based on IPSS), baseline absolute neutrophil count (ANC) (≤10^9/L vs >10^9/L), and ECOG Performance Score (0-1 vs 2).

Phase 1: In Stage A, subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 6 subjects each in a 10-day schedule in 28-day cycles. When safety has been established in Phase 1 Stage A, Phase 1 Stage B will open, wherein additional subjects (n=24 evaluable) will be randomized in a 1:1:1:1 ratio into 4 cohorts of 6 subjects each in a 14-day schedule in 28-day cycles.

Dose Levels by Cohort (Dailyx5, Offx2, Dailyx5):

- 1: 5 mg decitabine, 100 mg cedazuridine

- 2: 10 mg decitabine, 100 mg cedazuridine

- 3: 15 mg decitabine, 100 mg cedazuridine

Phase 2: Using 2 doses/schedules 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 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.