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Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02103478
Recruitment Status : Completed
First Posted : April 4, 2014
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Brief Summary:
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 or disease Intervention/treatment Phase
Myelodysplastic Syndrome MDS Drug: ASTX727 Dose Escalation Drug: ASTX727 Dose Confirmation Phase 1 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 113 participants
Allocation: Randomized
Intervention Model: Sequential 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)
Study Start Date : May 2014
Actual Primary Completion Date : June 5, 2018
Actual Study Completion Date : December 4, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Decitabine

Arm Intervention/treatment
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




Primary Outcome Measures :
  1. 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).

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

  3. 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.

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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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]

  4. 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.

  5. 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.



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:

  • 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

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
Show Show 17 study locations
Sponsors and Collaborators
Astex Pharmaceuticals, Inc.
Investigators
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Study Director: Mohammad Azab, MD Astex Pharmaceuticals, Inc.
Study Chair: James Lowder, MD Astex Pharmaceuticals, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02103478    
Other Study ID Numbers: ASTX727-01
First Posted: April 4, 2014    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Astex Pharmaceuticals, Inc.:
Myelodysplastic Syndrome
MDS
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