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

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: NCT03306264
Recruitment Status : Active, not recruiting
First Posted : October 11, 2017
Last Update Posted : April 27, 2020
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE October 2, 2017
First Posted Date  ICMJE October 11, 2017
Last Update Posted Date April 27, 2020
Actual Study Start Date  ICMJE February 15, 2018
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 4, 2017)
Total 5-day Area Under the Curve (AUC) exposures of decitabine [ Time Frame: 18 months ]
Primary Endpoint
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
  • 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 assessment
  • Long Interspersed Nucleotide Elements (LINE)-1 demethylation [ Time Frame: 18 months ]
    Pharmacodynamics assessment
  • Maximum plasma concentration (Cmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Time to reach maximum concentration (Tmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Elimination rate constant [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent total systemic clearance [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent elimination half life [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent volume of distribution [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • 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 ]
    Efficacy analysis - Clinical response
  • 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 ]
    Efficacy analysis - Clinical response
  • Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. [ Time Frame: 18 months ]
    Efficacy analysis - RBC transfusion independence
  • Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. [ Time Frame: 18 months ]
    Efficacy analysis - Platelet transfusion independence
  • 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 ]
    Efficacy analysis - Leukemia-free survival
  • Overall survival: number of days from date subject was randomized to date of death. [ Time Frame: 18 months ]
    Efficacy analysis - Overall survival
Original Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2017)
  • Numbers of subjects with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03. [ Time Frame: 18 months ]
    Safety assessment
  • Long Interspersed Nucleotide Elements (LINE)-1 demethylation [ Time Frame: 18 months ]
    Pharmacodynamics assessment
  • Maximum plasma concentration (Cmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Time to reach maximum concentration (Tmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Elimination rate constant [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent total systemic clearance [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent elimination half life [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Apparent volume of distribution [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter
  • Complete response (CR), marrow CR, partial response; hematologic improvement based on International Working Group 2006 MDS response criteria. [ Time Frame: 18 months ]
    Efficacy analysis - Clinical response
  • Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. [ Time Frame: 18 months ]
    Efficacy analysis - RBC transfusion independence
  • Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. [ Time Frame: 18 months ]
    Efficacy analysis - Platelet transfusion independence
  • Leukemia-free survival: number of days from date of randomization to date when bone marrow or peripheral blood blasts reach ≥20%, or death. [ Time Frame: 18 months ]
    Efficacy analysis - Leukemia-free survival
  • Overall survival: number of days from date subject was randomized to date of death. [ Time Frame: 18 months ]
    Efficacy analysis - Overall survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML
Official Title  ICMJE 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)
Brief Summary 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.)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Multicenter, randomized, open-label, 2-period, 2-sequence crossover study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: ASTX727
    ASTX727 is a tablet for oral administration, containing the fixed-dose combination of 100 mg cedazuridine (a cytidine deaminase inhibitor) and 35 mg decitabine, given by mouth Dailyx5 in 28-day cycles (in Cycle 1 or Cycle 2, then in Cycle 3 and beyond).
    Other Name: cedazuridine + decitabine
  • Drug: Dacogen
    Decitabine 20 mg/m^2 one-hour IV infusion Dailyx5 (in one 28-day cycle: either Cycle 1 or Cycle 2).
    Other Name: decitabine for injection
Study Arms  ICMJE
  • Experimental: ASTX727
    ASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover)
    Intervention: Drug: ASTX727
  • Active Comparator: IV decitabine
    Dacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover)
    Intervention: Drug: Dacogen
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 5, 2019)
200
Original Estimated Enrollment  ICMJE
 (submitted: October 4, 2017)
132
Estimated Study Completion Date  ICMJE May 31, 2022
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03306264
Other Study ID Numbers  ICMJE ASTX727-02
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Astex Pharmaceuticals, Inc.
Study Sponsor  ICMJE Astex Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Harold Keer, MD, PhD Astex Pharmaceuticals, Inc.
PRS Account Astex Pharmaceuticals, Inc.
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP