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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
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.

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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: ASTX727 LD Drug: ASTX727 SD Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Multicenter, open label
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : July 27, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Decitabine

Arm Intervention/treatment
Experimental: Phase 1 Stage A
3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Name: oral decitabine (LD) + cedazuridine (E7727)

Experimental: Phase 1 Stage B
3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Name: oral decitabine (LD) + cedazuridine (E7727)

Experimental: Phase 2
80 additional subjects randomized in a 1:1 ratio studying two different doses
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)




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. %LINE-1 methylation change from baseline [ Time Frame: 18-24 months ]
    pharmacodynamics

  2. Area under the curve (AUC) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter

  3. Maximum plasma concentration (Cmax) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter

  4. Time to reach maximum concentration (Tmax) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter

  5. Half life (t1/2) [ Time Frame: 18-24 months ]
    pharmacokinetics parameter

  6. 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

  7. 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%.

  8. 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

  9. Overall survival [ Time Frame: 18-24 months ]
    Number of days from the date of randomization to the date of death from any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03502668


Contacts
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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

Locations
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United States, Alabama
The University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
Contact: Nandika S Nagodawithana, MBBS, MSc, MD, MSHI    205-934-6624    nandika@uab.edu   
Principal Investigator: Kimo Bachiashvili, MD         
United States, Colorado
University of Colorado, Anschutz Cancer Pavilion Recruiting
Aurora, Colorado, United States, 80045
Contact: Derek Schatz, BS, CCRP    720-848-0628    derek.schatz@ucdenver.edu   
Principal Investigator: Daniel Pollyea, MD         
United States, Florida
BRCR Medical Center Inc. Recruiting
Plantation, Florida, United States, 33324
Contact: Ana Losada    561-447-0614 ext 106    alosada@brcrglobal.com   
Principal Investigator: Harshad Amin, MD         
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: William Prada, MD    813-745-2071    william.cisnerosprada@moffitt.org   
Principal Investigator: David A Sallman, MD         
United States, Indiana
Indiana University Health Hospital - Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Jill Weisenbach, RN    317-278-0597    jweisenb@iupui.edu   
Principal Investigator: Larry Cripe, MD         
United States, Kansas
University of Kansas Clinical Research Center Recruiting
Westwood, Kansas, United States, 66205
Contact: Jeanette Firth-Braun, RN, BSN       jfirthbraun@kumc.edu   
Principal Investigator: Abdulraheem Yacoub, MD         
United States, Maryland
The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division) Recruiting
Bethesda, Maryland, United States, 20817
Contact: Natalie Bongiorno, RN, MSHS    301-571-2016    nbongiorno@regionalcancercare.org   
Principal Investigator: Victor Priego, MD         
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Amberley Proctor, RN, BSN    402-836-9171    amberley.proctor@unmc.edu   
Principal Investigator: Lori Maness, MD         
United States, New York
Roswell Park Comprehensive Cancer Center Recruiting
Buffalo, New York, United States, 14263
Contact: Krista Belko, PhD    716-845-3373    krista.belko@roswellpark.org   
Principal Investigator: Elizabeth Griffiths, MD         
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Nurse    844-482-4812    asksarah@sarahcannon.com   
Principal Investigator: William Donnellan, MD         
United States, Texas
Texas Oncology - Ft. Worth Recruiting
Fort Worth, Texas, United States, 76104
Contact: Cindi Schoenfeldt, RN    817-413-1645    cindi.schoenfeldt@usoncology.com   
Principal Investigator: Stephen Richey, MD         
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jennifer Frazer, RN, BSN    713-745-5468    jafraser@mdanderson.org   
Principal Investigator: Guillermo Garcia-Manero, MD         
Texas Oncology - San Antonio Recruiting
San Antonio, Texas, United States, 78240
Contact: Debbie Ponce, RN    210-595-5692    Debbie.Ponce@usoncology.com   
Principal Investigator: Roger Lyons, MD         
Texas Oncology - Tyler Recruiting
Tyler, Texas, United States, 75702
Contact: Karen Poe    903-579-9800    karen.poe@usoncology.com   
Principal Investigator: Habte Yimer, MD         
United States, Virginia
Virginia Oncology Associates Recruiting
Norfolk, Virginia, United States, 23502
Contact: Karen McClain, RN, BSN, OCN    757-213-5658    karen.mcclain@usoncology.com   
Principal Investigator: Paul Conkling, MD         
Sponsors and Collaborators
Astex Pharmaceuticals, Inc.
Investigators
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Study Director: Yuri Sano, MD, PhD Astex Pharmaceuticals, Inc.

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Responsible Party: Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03502668    
Other Study ID Numbers: ASTX727-03
First Posted: April 19, 2018    Key Record Dates
Last Update Posted: December 3, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astex Pharmaceuticals, Inc.:
low risk myelodysplastic syndromes, MDS, ASTX727
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors