Clinical Trials /

Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML

NCT03306264

Description:

Multicenter, randomized, open-label, crossover PK study of ASTX727 versus IV decitabine. Adult subjects who are candidates to receive IV decitabine will be randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, subjects will continue to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the subject discontinues treatment or withdraws from the study.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Refractory Anemia
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML
  • Official Title: A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) Versus IV Decitabine in Subjects With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: ASTX727-02
  • NCT ID: NCT03306264

Conditions

  • Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
ASTX727cedazuridine + decitabineASTX727
Dacogendecitabine for injectionIV decitabine

Purpose

Multicenter, randomized, open-label, crossover PK study of ASTX727 versus IV decitabine. Adult subjects who are candidates to receive IV decitabine will be randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, subjects will continue to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the subject discontinues treatment or withdraws from the study.

Detailed Description

      This Phase 3 study will establish PK equivalence of ASTX727 to IV decitabine in approximately
      118 evaluable subjects. Eligible subjects will receive both study treatments: oral
      investigational drug ASTX727, and IV decitabine, as follows: subjects will be randomly
      assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other
      therapy in Cycle 2.

      In the ASTX727 cycle, subjects will receive the ASTX727 tablet Daily×5. Serial PK
      measurements (blood draws) will be done on Days 1, 2, and 5, along with pre-dose PK
      assessments on Days 1-5 and an assessment at 3 hours post dose on Day 3. Subjects will be
      required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours
      before and 2 hours after dosing.

      In the IV decitabine cycle, subjects will receive a 1-hour infusion of IV decitabine 20
      mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and
      1-hour post-infusion assessments on Day 3.

      In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK
      assessments will be done from Cycle 3 onward.)
    

Trial Arms

NameTypeDescriptionInterventions
ASTX727ExperimentalASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover)
  • ASTX727
IV decitabineActive ComparatorDacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover)
  • Dacogen

Eligibility Criteria

        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; specifically able to comply with the PK assessment schedule during the
             first 2 treatment cycles.

          2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or
             European Medicines Agency (EMA) approved indications:

               1. In North America: Participants with MDS previously treated or untreated with de
                  novo or secondary MDS, including all French-American-British subtypes (refractory
                  anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess
                  blasts, refractory anemia with excess blasts in transformation, and chronic
                  myelomonocytic leukemia [CMML]), and subjects with MDS International Prognostic
                  Scoring System (IPSS) int-1, -2, or high-risk MDS.

               2. In Europe: Participants with de novo or secondary AML, as defined by the World
                  Health Organization (WHO) criteria, who are not candidates for standard induction
                  chemotherapy.

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          4. Adequate organ function defined as follows:

               1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate
                  transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine
                  transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN.

               2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or
                  glomerular filtration rate >50 mL/min/1.73 m2 for subjects with creatinine levels
                  above institutional normal.

          5. No major surgery within 30 days of first study treatment.

          6. Life expectancy of at least 3 months.

          7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a
             negative pregnancy test at screening. Women of non-childbearing potential are those
             who have had a hysterectomy or bilateral oophorectomy, or who have completed
             menopause, defined as no menses for at least 1 year AND either age ≥65 years or
             follicle-stimulating hormone levels in the menopausal range.

          8. Subjects and their partners with reproductive potential must agree to use effective
             contraceptive measures during the study and for 3 months after the last dose of study
             treatment. Effective contraception includes methods such as oral contraceptives or
             double-barrier method (eg, use of a condom AND diaphragm, with spermicide).

        Exclusion Criteria:

          1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic
             chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC)
             counts.

          2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia,
             sepsis, or systemic infection in the 30 days before screening.

          3. Treatment with any investigational drug or therapy within 2 weeks of study treatment,
             or 5 half-lives, whichever is longer, before the first dose of study treatment, or
             ongoing clinically significant adverse events (AEs) from previous treatment.

          4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose
             of study treatment.

          5. Concurrent MDS therapies, including lenalidomide, erythropoietin,
             cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF),
             granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with these
             agents is permitted, provided that completion is at least 1 week before the first dose
             of study treatment.)

          6. Poor medical risk because of other conditions such as uncontrolled systemic diseases,
             active uncontrolled infections, or comorbidities that may put the patient at risk of
             not being able to complete at least 2 cycles of treatment.

          7. Known significant mental illness or other condition, such as active alcohol or other
             substance abuse or addiction, that in the opinion of the investigator predisposes the
             subject to high risk of noncompliance with the protocol.

          8. Rapidly progressive or highly proliferative disease (total white blood cell count of
             >15 × 10^9/L) or other criteria that render the subject at high risk of requiring
             intensive cytotoxic chemotherapy within the next 3 months.

          9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled
             congestive heart failure or chronic obstructive pulmonary disease, or other reasons
             including laboratory abnormalities, which, in the investigator's opinion, could
             compromise the subject's safety, interfere with the absorption or metabolism of
             ASTX727, or compromise completion of the study or integrity of the study outcomes.

         10. 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 2 years.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Total 5-day Area Under the Curve (AUC) exposures of decitabine
Time Frame:18 months
Safety Issue:
Description:Primary Endpoint

Secondary Outcome Measures

Measure:Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03.
Time Frame:18 months
Safety Issue:
Description:Safety assessment
Measure:Long Interspersed Nucleotide Elements (LINE)-1 demethylation
Time Frame:18 months
Safety Issue:
Description:Pharmacodynamics assessment
Measure:Maximum plasma concentration (Cmax)
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:Time to reach maximum concentration (Tmax)
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:Elimination rate constant
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:Apparent total systemic clearance
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:Apparent elimination half life
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:Apparent volume of distribution
Time Frame:2 months
Safety Issue:
Description:Secondary pharmacokinetics parameter
Measure:MDS/CMML: Number of participants with complete response (CR), marrow CR, partial response; hematologic improvement based on International Working Group (IWG) 2006 MDS response criteria.
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - Clinical response
Measure:AML: Number of participants with CR, CR with incomplete platelet recovery (CRp) and CR with incomplete blood count recovery (CRi) based on IWG 2003 AML response criteria
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - Clinical response
Measure:Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days.
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - RBC transfusion independence
Measure:Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks.
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - Platelet transfusion independence
Measure:Leukemia-free survival in MDS/CMML participants: number of days from date of randomization to date when bone marrow or peripheral blood blasts reach ≥20%, or death.
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - Leukemia-free survival
Measure:Overall survival: number of days from date subject was randomized to date of death.
Time Frame:18 months
Safety Issue:
Description:Efficacy analysis - Overall survival

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astex Pharmaceuticals, Inc.

Trial Keywords

  • MDS
  • CMML
  • decitabine
  • Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • Acute Myeloid Leukemia
  • AML

Last Updated

December 12, 2019