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

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ClinicalTrials.gov Identifier: NCT03502668
Recruitment Status : Recruiting
First Posted : April 19, 2018
Last Update Posted : December 3, 2019
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE April 11, 2018
First Posted Date  ICMJE April 19, 2018
Last Update Posted Date December 3, 2019
Actual Study Start Date  ICMJE July 27, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • 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 ]
    Phase 1: Safety
  • Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) [ Time Frame: 18-24 months ]
    Phase 2: Efficacy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • %LINE-1 methylation change from baseline [ Time Frame: 18-24 months ]
    pharmacodynamics
  • Area under the curve (AUC) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter
  • Maximum plasma concentration (Cmax) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter
  • Time to reach maximum concentration (Tmax) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter
  • Half life (t1/2) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter
  • 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 ]
    Phase 1: Efficacy
  • Time to bone marrow blasts >5% [ Time Frame: 18-24 months ]
    Number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by ≥50%.
  • Leukemia-free survival [ Time Frame: 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 [ Time Frame: 18-24 months ]
    Number of days from the date of randomization to the date of death from any cause
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS
Official Title  ICMJE 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)
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Multicenter, open label
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myelodysplastic Syndromes
Intervention  ICMJE
  • Drug: ASTX727 LD
    oral decitabine (LD) + cedazuridine (E7727)
    Other Name: oral decitabine (LD) + cedazuridine (E7727)
  • Drug: ASTX727 SD
    oral decitabine (SD) + cedazuridine (E7727)
    Other Name: oral decitabine (SD) + cedazuridine (E7727)
Study Arms  ICMJE
  • Experimental: Phase 1 Stage A
    3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
    Intervention: Drug: ASTX727 LD
  • Experimental: Phase 1 Stage B
    3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
    Intervention: Drug: ASTX727 LD
  • Experimental: Phase 2
    80 additional subjects randomized in a 1:1 ratio studying two different doses
    Interventions:
    • Drug: ASTX727 LD
    • Drug: ASTX727 SD
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 15, 2019)
160
Original Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
122
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. Diagnosis of chronic myelomonocytic leukemia (CMML).
  4. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
  5. 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.
  6. Known active infection with human immunodeficiency virus or hepatitis viruses.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yuri Sano, MD, PhD 925-560-2844 yuri.sano@astx.com
Contact: Harold N Keer, MD, PhD 925-719-0741 harold.keer@astx.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03502668
Other Study ID Numbers  ICMJE ASTX727-03
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Astex Pharmaceuticals, Inc.
Study Sponsor  ICMJE Astex Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Yuri Sano, MD, PhD Astex Pharmaceuticals, Inc.
PRS Account Astex Pharmaceuticals, Inc.
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP