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Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02103478
First Posted: April 4, 2014
Last Update Posted: August 29, 2017
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. Read our disclaimer for details.
Information provided by (Responsible Party):
Astex Pharmaceuticals
  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: Crossover Assignment
Masking: None (Open Label)
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.


Enrollment: 113
Study Start Date: May 2014
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2018 (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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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
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): NCT02103478


Locations
United States, Arizona
Mayo Clinic
Phoenix, Arizona, United States, 85054
United States, California
University of Southern California
Los Angeles, California, United States, 90024
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Horizon Oncology
Lafayette, Indiana, United States, 47905
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Faber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New Jersey
John Theurer Cancer Center/ Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Weill Cornell Medical College - New York Presbyterian Hospital
New York, New York, United States, 10021
United States, Tennessee
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
M. D. Anderson
Houston, Texas, United States, 77030
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
University of Alberta Hospital
Edmonton, Alberta, Canada, T6G 2G3
Canada, Ontario
Sunnybrook Health Sciences Centre, Odette Cancer Centre
Toronto, Ontario, Canada, M4N 3M5
Princess Margaret Cancer Center
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Hôpital Maisonneuve-Rosemont
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
First Submitted: March 20, 2014
First Posted: April 4, 2014
Last Update Posted: August 29, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
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