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

NCT02103478

Description:

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.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral CDAi in Patients With MDS
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: ASTX727-01
  • NCT ID: NCT02103478

Conditions

  • Myelodysplastic Syndrome
  • MDS

Interventions

DrugSynonymsArms
ASTX727 Dose EscalationE7727, oral decitabine, IV decitabinePhase 1 ASTX727 Dose Escalation
ASTX727 Dose ConfirmationASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabinePhase 2 ASTX727 Dose Confirmation

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.

Detailed Description

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

Trial Arms

NameTypeDescriptionInterventions
Phase 1 ASTX727 Dose EscalationExperimentalASTX727 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.
  • ASTX727 Dose Escalation
Phase 2 ASTX727 Dose ConfirmationActive ComparatorSubjects 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.
  • ASTX727 Dose Confirmation

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:Plasma Pharmacokinetics. Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC).

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Measure: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)
Safety Issue:
Description:Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Maximum Plasma Concentration (Cmax) during dose escalation and dose confirmation-randomization.
Measure: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)
Safety Issue:
Description:Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters of Minimum Plasma Concentration (Cmin) during dose escalation and dose confirmation-randomization.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Astex Pharmaceuticals

Trial Keywords

  • Myelodysplastic Syndrome
  • MDS

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