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

September 29, 2023 updated by: Astex Pharmaceuticals, Inc.

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)

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.

Study Overview

Status

Active, not recruiting

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

160

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Antwerp, Belgium
        • Zna - Campus Middelheim
      • Brugge, Belgium
        • Az St-Jan Brugge-Oostende A.V.
      • Edmonton, Canada, T6G 2B7
        • University of Alberta Hospital - Hematology Research
    • Ontario
      • London, Ontario, Canada, N6A 5W9
        • London Regional Cancer Center
      • Freiburg, Germany, 79106
        • Universitaetsklinikum Freiburg Site#703
      • Halle, Germany, 06120
        • Universitätsklinikum Halle
      • Firenze, Italy
        • Università degli studi di Firenze
      • Barcelona, Spain
        • Hospital Universitario Vall D Hebron
      • Barcelona, Spain
        • Institut Català d'Oncologia Badalona Hospital Universitari Germans Trias i Pujol
      • Madrid, Spain
        • Hospital General Universitario Gregorio Marañon
      • Valencia, Spain, 46026
        • Hospital Univeristario y Politecnico La Fe Servicio de Hematologia
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • The University of Alabama at Birmingham
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado, Anschutz Cancer Pavilion
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Yale Cancer Center
    • Florida
      • Jacksonville, Florida, United States, 32224
        • Mayo Clinic Florida
      • Plantation, Florida, United States, 33324
        • BRCR Medical Center Inc.
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center Site#507
    • Illinois
      • Chicago, Illinois, United States, 60637
        • The University Of Chicago
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University Health Hospital - Simon Cancer Center
    • Kansas
      • Westwood, Kansas, United States, 66205
        • University of Kansas Clinical Research Center
    • Maryland
      • Bethesda, Maryland, United States, 20817
        • The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division)
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska Medical Center
    • New York
      • Buffalo, New York, United States, 14263
        • Roswell Park Comprehensive Cancer Center
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health and Science University Knight Cancer Institute
    • Tennessee
      • Nashville, Tennessee, United States, 37203
        • Sarah Cannon Research Institute
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center - Hematology-Oncology
    • Texas
      • Houston, Texas, United States, 77030
        • The University of Texas MD Anderson Cancer Center
      • Tyler, Texas, United States, 75702
        • Texas Oncology - Tyler

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 1 Stage A
3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
  • oral decitabine (LD) + cedazuridine (E7727)
Experimental: Phase 1 Stage B
3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
  • oral decitabine (LD) + cedazuridine (E7727)
Experimental: Phase 2
80 additional subjects randomized in a 1:1 ratio studying two different doses
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
  • oral decitabine (LD) + cedazuridine (E7727)
oral decitabine (SD) + cedazuridine (E7727)
Other Names:
  • oral decitabine (SD) + cedazuridine (E7727)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
18-24 months
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
18-24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
%LINE-1 methylation change from baseline
Time Frame: 18-24 months
pharmacodynamics
18-24 months
Area under the curve (AUC)
Time Frame: 18-24 months
pharmacokinetics parameter
18-24 months
Maximum plasma concentration (Cmax)
Time Frame: 18-24 months
pharmacokinetics parameter
18-24 months
Time to reach maximum concentration (Tmax)
Time Frame: 18-24 months
pharmacokinetics parameter
18-24 months
Half life (t1/2)
Time Frame: 18-24 months
pharmacokinetics parameter
18-24 months
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
18-24 months
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%.
18-24 months
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
18-24 months
Overall survival
Time Frame: 18-24 months
Number of days from the date of randomization to the date of death from any cause
18-24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 27, 2018

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

April 11, 2018

First Submitted That Met QC Criteria

April 11, 2018

First Posted (Actual)

April 19, 2018

Study Record Updates

Last Update Posted (Actual)

October 2, 2023

Last Update Submitted That Met QC Criteria

September 29, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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