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

Sponsor
Astex Pharmaceuticals, Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03502668
Collaborator
(none)
160
43
3
58.2
3.7
0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • 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 (long interspersed nucleotide element-1 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
160 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Multicenter, open labelMulticenter, 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 :
Jul 27, 2018
Anticipated Primary Completion Date :
Jun 1, 2023
Anticipated Study Completion Date :
Jun 1, 2023

Arms and Interventions

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 Names:
  • 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 Names:
  • 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 Names:
  • oral decitabine (LD) + cedazuridine (E7727)
  • Drug: ASTX727 SD
    oral decitabine (SD) + cedazuridine (E7727)
    Other Names:
  • oral decitabine (SD) + cedazuridine (E7727)
  • Outcome Measures

    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 [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) [18-24 months]

      Phase 2: Efficacy

    Secondary Outcome Measures

    1. %LINE-1 methylation change from baseline [18-24 months]

      pharmacodynamics

    2. Area under the curve (AUC) [18-24 months]

      pharmacokinetics parameter

    3. Maximum plasma concentration (Cmax) [18-24 months]

      pharmacokinetics parameter

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

      pharmacokinetics parameter

    5. Half life (t1/2) [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) [18-24 months]

      Phase 1: Efficacy

    7. Time to bone marrow blasts >5% [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 [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 [18-24 months]

      Number of days from the date of randomization to the date of death from any cause

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    3. 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).

    4. 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.

    5. Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.

    6. Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.

    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

    8. Adequate organ function.

    9. 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.

    10. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pinnacle Research Group, LLC Anniston Alabama United States 36207
    2 The University of Alabama at Birmingham Birmingham Alabama United States 35233
    3 City of Hope National Medical Center Duarte California United States 91010
    4 University of Colorado, Anschutz Cancer Pavilion Aurora Colorado United States 80045
    5 Yale Cancer Center New Haven Connecticut United States 06510
    6 Mayo Clinic Florida Jacksonville Florida United States 32224
    7 BRCR Medical Center Inc. Plantation Florida United States 33324
    8 Moffitt Cancer Center Tampa Florida United States 33612
    9 The University of Chicago Chicago Illinois United States 60637
    10 Indiana University Health Hospital - Simon Cancer Center Indianapolis Indiana United States 46202
    11 University of Kansas Clinical Research Center Westwood Kansas United States 66205
    12 The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division) Bethesda Maryland United States 20817
    13 University of Michigan Ann Arbor Michigan United States 48109-5271
    14 Mayo Clinic Rochester Minnesota United States 55905
    15 University of Nebraska Medical Center Omaha Nebraska United States 68198
    16 Roswell Park Comprehensive Cancer Center Buffalo New York United States 14263
    17 Oregon Health and Science University Knight Cancer Institute Portland Oregon United States 97239
    18 Charleston Oncology Charleston South Carolina United States 29414
    19 Sarah Cannon Research Institute Nashville Tennessee United States 37203
    20 Vanderbilt University Medical Center - Hematology-Oncology Nashville Tennessee United States 37232
    21 Texas Oncology - Ft. Worth Fort Worth Texas United States 76104
    22 The University of Texas MD Anderson Cancer Center Houston Texas United States 77030
    23 Texas Oncology - San Antonio San Antonio Texas United States 78240
    24 Texas Oncology - Tyler Tyler Texas United States 75702
    25 Virginia Oncology Associates Norfolk Virginia United States 23502
    26 Fred Hutchinson Cancer Research Center Seattle Washington United States 98109
    27 ZNA - Campus Middelheim Antwerp Belgium
    28 Az St-Jan Brugge-Oostende A.V. Brugge Belgium
    29 Hospital De Jolimont Haine-Saint-Paul Belgium
    30 UZ Leuven - Campus Gasthuisberg Leuven Belgium 3000
    31 London Regional Cancer Center London Ontario Canada N6A 5W9
    32 University of Alberta Hospital - Hematology Research Edmonton Canada T6G 2B7
    33 Sir Mortimer B Davis/Jewish General Hospital Québec Canada
    34 Staedtisches Klinikum Braunschweig gGmbH Braunschweig Germany
    35 Universitaetsklinikum Freiburg Freiburg Germany 79106
    36 Universitätsklinikum Halle Halle Germany 06120
    37 Universita degli Studi di Firenze Firenze Italy
    38 Hospital de La Santa Creu i Sant Pau Barcelona Spain
    39 Hospital Universitario Vall d Hebron Barcelona Spain
    40 Institut Català d'Oncologia Badalona Hospital Universitari Germans Trias i Pujol Barcelona Spain
    41 H. San Pedro de Alcántara Cáceres Spain
    42 Hospital General Universitario Gregorio Marañón Madrid Spain
    43 Hospital Univeristario y Politecnico La Fe Servicio de Hematologia Valencia Spain 46026

    Sponsors and Collaborators

    • Astex Pharmaceuticals, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Astex Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03502668
    Other Study ID Numbers:
    • ASTX727-03
    First Posted:
    Apr 19, 2018
    Last Update Posted:
    Jul 20, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Astex Pharmaceuticals, Inc.
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 20, 2022