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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 : July 3, 2019
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc. ( Astex Pharmaceuticals )

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. 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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: ASTX727 LD 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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 122 participants
Allocation: Randomized
Intervention Model: Parallel 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 10-day schedule in 28-day cycles of ASTX727 LD
Drug: ASTX727 LD
oral decitabine + cedazuridine (E7727)
Other Name: oral decitabine + cedazuridine (E7727)

Experimental: Phase 1 Stage B
4 cohorts of 6 subjects each in a 14-day schedule in 28-day cycles of ASTX727 LD
Drug: ASTX727 LD
oral decitabine + cedazuridine (E7727)
Other Name: oral decitabine + cedazuridine (E7727)

Experimental: Phase 2
40 additional subjects randomized in a 1:1 ratio into 1 of 2 doses/schedules of ASTX727 LD selected from Phase 1
Drug: ASTX727 LD
oral decitabine + cedazuridine (E7727)
Other Name: oral decitabine + 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 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.

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: Kartik Krishnan, MD, PhD 925-560-2894 kartik.krishan@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: Frances Thorne    205-996-1384    fthorne@uabmc.edu   
Principal Investigator: Ravi Bhatia, MD         
United States, Colorado
University of Colorado, Anschutz Cancer Pavilion Recruiting
Aurora, Colorado, United States, 80045
Contact: Daniel Pollyea, MD         
Contact: Derek Schatz, BS, CCRP    720-848-0628    derek.schatz@ucdenver.edu   
United States, Florida
BRCR Medical Center Inc. Recruiting
Plantation, Florida, United States, 33324
Contact: Harshad Amin, MD         
Contact: Mariaclaudia Reyes    561-447-0614    mreyes@brcrglobal.com   
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, Kansas
University of Kansas Clinical Research Center Recruiting
Westwood, Kansas, United States, 66205
Contact: Abdulraheem Yacoub, MD    913-945-7552    khepler@kumc.edu   
Contact: Kerry Hepler, RN, BSN    913-945-7552    khepler@kumc.edu   
United States, Michigan
Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Jay Yang, MD    313-576-8952    yangj@karmanos.org   
Contact: Christiane Houde, BS    313-576-9381    houdec@karmanos.org   
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 Nurse    844-482-4812    asksarah@sarahcannon.com   
Principal Investigator: William Donnellan, MD         
United States, Texas
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   
Contact: Guillermo Garcia-Manero, MD    713-745-3428    ggarciam@mdanderson.org   
Principal Investigator: Guillermo Garcia-Manero, MD         
Sponsors and Collaborators
Astex Pharmaceuticals
Investigators
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Study Director: Kartik Krishnan, MD, PhD Astex Pharmaceuticals

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Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03502668     History of Changes
Other Study ID Numbers: ASTX727-03
First Posted: April 19, 2018    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 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. ( Astex Pharmaceuticals ):
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