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Study of ASTX727 vs IV Decitabine in MDS and CMML

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ClinicalTrials.gov Identifier: NCT03306264
Recruitment Status : Recruiting
First Posted : October 11, 2017
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals

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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Drug: ASTX727 Drug: Dacogen Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
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
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) and Chronic Myelomonocytic Leukemia (CMML) [ASTX727-02]
Actual Study Start Date : February 15, 2018
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : June 30, 2019


Arm Intervention/treatment
Experimental: ASTX727
ASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover)
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

Active Comparator: IV decitabine
Dacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover)
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




Primary Outcome Measures :
  1. Total 5-day Area Under the Curve (AUC) exposures of decitabine [ Time Frame: 18 months ]
    Primary Endpoint


Secondary Outcome Measures :
  1. 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

  2. Long Interspersed Nucleotide Elements (LINE)-1 demethylation [ Time Frame: 18 months ]
    Pharmacodynamics assessment

  3. Maximum plasma concentration (Cmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  4. Time to reach maximum concentration (Tmax) [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  5. Elimination rate constant [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  6. Apparent total systemic clearance [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  7. Apparent elimination half life [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  8. Apparent volume of distribution [ Time Frame: 2 months ]
    Secondary pharmacokinetics parameter

  9. 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

  10. Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. [ Time Frame: 18 months ]
    Efficacy analysis - RBC transfusion independence

  11. Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. [ Time Frame: 18 months ]
    Efficacy analysis - Platelet transfusion independence

  12. 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

  13. Overall survival: number of days from date subject was randomized to date of death. [ Time Frame: 18 months ]
    Efficacy analysis - Overall survival



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:

  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, ie, subjects 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.
  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.
  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.

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): NCT03306264


Contacts
Contact: James N Lowder, MD 925-719-6856 james.lowder@astx.com
Contact: Harold Keer, MD, PhD 925-719-0741 harold.keer@astx.com

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Sponsors and Collaborators
Astex Pharmaceuticals
Investigators
Study Director: James N Lowder, MD Astex Pharmaceuticals

Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03306264     History of Changes
Other Study ID Numbers: ASTX727-02
First Posted: October 11, 2017    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astex Pharmaceuticals:
MDS
CMML
decitabine
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia

Additional relevant MeSH terms:
Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Decitabine
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors