Clinical Trials /

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

NCT03502668

Description:

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. 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.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT03502668

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ASTX727-03
  • NCT ID: NCT03502668

Conditions

  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
ASTX727 LDoral decitabine (LD) + cedazuridine (E7727)Phase 1 Stage A
ASTX727 SDoral decitabine (SD) + cedazuridine (E7727)Phase 2

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. 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 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Stage AExperimental3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
  • ASTX727 LD
Phase 1 Stage BExperimental3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
  • ASTX727 LD
Phase 2Experimental80 additional subjects randomized in a 1:1 ratio studying two different doses
  • ASTX727 LD
  • ASTX727 SD

Eligibility Criteria

        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 RBCs or Hb of
                  <8.5 g/dL in at least 2 blood counts prior to randomization.

               2. ANC of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.

               3. 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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule
Time Frame:18-24 months
Safety Issue:
Description:Phase 1: Safety

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astex Pharmaceuticals, Inc.

Trial Keywords

  • low risk myelodysplastic syndromes, MDS, ASTX727

Last Updated

August 6, 2021