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Trial record 1 of 1 for:    ASTX727
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Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by Astex Pharmaceuticals
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02103478
First received: March 20, 2014
Last updated: February 13, 2017
Last verified: February 2017
  Purpose
This 2-stage, open-label study will evaluate safety and pharmacokinetics of ASTX727, as well as determine the dose for the study's second stage. In the second stage the selected dose will be confirmed and evaluated for clinical activity, including response rate.

Condition Intervention Phase
Myelodysplastic Syndrome
MDS
Drug: ASTX727 Dose Escalation
Drug: ASTX727 Dose Confirmation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)

Resource links provided by NLM:


Further study details as provided by Astex Pharmaceuticals:

Primary Outcome Measures:
  • Pharmacokinetics: plasma decitabine after oral decitabine and E7727 area under the plasma concentration versus time curve (AUC) by cohort. [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Plasma Pharmacokinetics. Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC).

  • Incidence of Dose limiting toxicities by cohort [ Time Frame: Phase 1 in Cycle 1 (28 days) ]
    Protocol specified grade 3 and 4 adverse events

  • Pharmacodynamics: Maximum %LINE-1 demethylation of ASTX727 compared to 20mg/m2 IV decitabine [ Time Frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above. ]
    Long interspread nuclear element-1 (LINE-1 or L1) sequences are highly repeated human retrotransposon sequences and constitute about 17% of the human genome. They are usually heavily methylated and their demethylation is a reliable surrogate for global genomic demethylation. Peripheral blood will be tested for DNA methylation.

  • Overall Response Rate [ Time Frame: Phase 1 and 2 through study completion ]
    Complete response rate and mCR


Secondary Outcome Measures:
  • Pharmacokinetics: area under the plasma concentration versus time curve (AUC) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of area under the plasma concentration versus time curve (AUC)during dose escalation and dose confirmation-randomization.

  • Pharmacodynamics: Mean maximum % demethylation of the LINE-1 elements in peripheral blood will be reported by cohort [ Time Frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above. ]
    Long interspread nuclear element-1 (LINE-1 or L1) sequences are highly repeated human retrotransposon sequences and constitute about 17% of the human genome. They are usually heavily methylated and their demethylation is a reliable surrogate for global genomic demethylation. Peripheral blood will be tested for DNA methylation.

  • Number and proportion of subjects with adverse events by type and grade [ Time Frame: Phase 1 and 2 , through study completion, an average of one year ]
    Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  • Pharmacokinetics: Maximum Plasma Concentration (Cmax) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Maximum Plasma Concentration (Cmax) during dose escalation and dose confirmation-randomization.

  • Pharmacokinetics: Minimum Plasma Concentration (Cmin) of oral decitabine, E7727 and E7727-epimer [ Time Frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Minimum Plasma Concentration (Cmin) during dose escalation and dose confirmation-randomization.


Estimated Enrollment: 120
Study Start Date: May 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1 ASTX727 Dose Escalation
ASTX727 is given by mouth daily X 5 consecutive days. Dosing details will vary in the first 3 courses of therapy for pharmacokinetic measurements. Based on safety and pharmacokinetic results the dose will be modified for subsequent cohorts. Dose escalation will continue until target pharmacokinetics are achieved or until a safe dose is exceeded. This dose will be carried forward into Phase 2.
Drug: ASTX727 Dose Escalation
Oral investigational product and approved IV decitabine
Other Names:
  • E7727
  • oral decitabine
  • IV decitabine
Active Comparator: Phase 2 ASTX727 Dose Confirmation
Subjects will compare one cycle of daily x 5 IV decitabine vs. one cycle of daily x 5 oral decitabine and E7727 for PK and PD. They will be randomized 1:1 as to the order the cycles are administered. In cycle 3 or greater the oral combination will be administered.
Drug: ASTX727 Dose Confirmation
Randomization cross over design for courses 1 and 2
Other Names:
  • ASTX727 oral (combination of oral E7727 and oral decitabine)
  • IV decitabine

Detailed Description:
Dose levels for the study's second stage will be based on safety and pharmacokinetics.
  Eligibility

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

Inclusion Criteria:

  • IPSS low, intermediate -1, intermediate-2, or high risk MDS (including CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
  • ECOG 0 to 2
  • No major surgery within 2 weeks of starting study treatment
  • No cytotoxic chemotherapy within 2 weeks of starting study treatment
  • Able to swallow pills

Exclusion Criteria:

  • Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
  • Treatment with investigational therapy within 2 weeks of study treatment
  • Uncontrolled medical disease(s) or active, uncontrolled infection
  • Diagnosed with AML
  • Active uncontrolled gastric or duodenal ulcer
  • Known history of HIV or hepatitis C or B
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02103478

Contacts
Contact: Jacqueline Ames +1-925-560-2929 jacqueline.ames@astx.com
Contact: Jessica Nario +1-925-560-2931 jessica.nario@astx.com

Locations
United States, Arizona
Mayo Clinic Active, not recruiting
Phoenix, Arizona, United States, 85054
United States, California
University of Southern California Completed
Los Angeles, California, United States, 90024
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Howard Weiner    773-702-2084    hweiner@medicine.bsd.uchicago.edu   
Contact: Nancy Glavin    1-773-702-2084    nglavin@medicine.bsd.uchicago.edu   
Principal Investigator: Olatoyosi Odenike, MD         
United States, Indiana
Horizon Oncology Completed
Lafayette, Indiana, United States, 47905
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Ibitayo Owoeye       iowoeye1@jhmi.edu   
Contact: Julia Canipe    410-502-9282    JCanipe1@jhmi.edu   
Principal Investigator: Amy DeZern, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Christine Connolly    617-726-5131    cconnolly1@partners.org   
Contact: Aura Ramos    1-617-643-2914    AYVASQUEZ@PARTNERS.ORG   
Sub-Investigator: Phillip Amrein, MD         
Principal Investigator: David Steensma, MD         
Dana Faber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Katelyn Brinegar    617-632-6363    Katelyn.Brinegar@dfci.harvard.edu   
Principal Investigator: David Steensma, MD         
United States, New Jersey
John Theurer Cancer Center/ Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Kevin Barga    551-996-8017    Kevin.Barga@hackensackmeridian.org   
Contact: Gillian Velardi       Gillian.Velardi@hackensackmeridian.org   
Principal Investigator: Stefan Faderl, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Heather Bashaw    716-845-4971    Heather.Bashaw@RoswellPark.org   
Principal Investigator: Elizabeth Griffiths, MD         
Weill Cornell Medical College - New York Presbyterian Hospital Recruiting
New York, New York, United States, 10021
Contact: Katherine Hassfutter    212-746-4882    kah9068@med.cornell.edu   
Contact: Tatyana Jean, MPH    646-962-9440    taj7005@med.cornell.edu   
Principal Investigator: Gail Roboz, MD         
United States, Tennessee
Vanderbilt Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Valerie Spence    615-343-3782    valerie.spence@vanderbilt.edu   
Contact: Channing Dudley    1-615-936-6725    Channing.V.Dudley@vanderbilt.edu   
Principal Investigator: Michael Savona, MD         
United States, Texas
M. D. Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Jane Waukau    713-745-3010    JBWaukau@mdanderson.org   
Contact: Monica Kwari    1-713-794-1557    mkwari@mdanderson.org   
Principal Investigator: Guilermo Garcia-Manero, MD         
United States, Wisconsin
Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Katy Schroeder, RN, BSN, OCN    414-805-8843    kbschroeder@mcw.edu   
Contact: Mike Jacklin    414-805-8839    mjacklin@mcw.edu   
Principal Investigator: Laura Michaelis, MD         
Canada, Alberta
University of Alberta Hospital Active, not recruiting
Edmonton, Alberta, Canada, T6G 2G3
Canada, Ontario
Sunnybrook Health Sciences Centre, Odette Cancer Centre Active, not recruiting
Toronto, Ontario, Canada, M4N 3M5
Princess Margaret Cancer Center Active, not recruiting
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Hôpital Maisonneuve-Rosemont Active, not recruiting
Montréal, Quebec, Canada, H1T 2M4
Sponsors and Collaborators
Astex Pharmaceuticals
Investigators
Study Director: Mohammad Azab, MD Astex Pharmaceuticals, Inc.
Study Chair: James Lowder, MD Astex Pharmaceuticals, Inc.
  More Information

Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02103478     History of Changes
Other Study ID Numbers: ASTX727-01 
Study First Received: March 20, 2014
Last Updated: February 13, 2017
Individual Participant Data  
Plan to Share IPD: Undecided

Keywords provided by Astex Pharmaceuticals:
Myelodysplastic Syndrome
MDS

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 24, 2017