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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

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 + cedazuridine (E7727)Phase 1 Stage A

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Stage AExperimental3 cohorts of 6 subjects each in a 10-day schedule in 28-day cycles of ASTX727 LD
  • ASTX727 LD
Phase 1 Stage BExperimental4 cohorts of 6 subjects each in a 14-day schedule in 28-day cycles of ASTX727 LD
  • ASTX727 LD
Phase 2Experimental40 additional subjects randomized in a 1:1 ratio into 1 of 2 doses/schedules of ASTX727 LD selected from Phase 1
  • ASTX727 LD

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 defined as follows:

               1. 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.

               2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or
                  glomerular filtration rate ≥50 mL/min.

          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. 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.
      
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

Trial Keywords

  • low risk myelodysplastic syndromes, MDS, ASTX727

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