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

Study Overview
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Brief Summary
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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
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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.)

Official Title
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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)

Conditions
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Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: ASTX727
* Drug: Dacogen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or European Medicines Agency (EMA) approved indications: 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. 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. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Adequate organ function defined as follows: 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. 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. No major surgery within 30 days of first study treatment. Life expectancy of at least 3 months. 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. 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: 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. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection in the 30 days before screening. 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. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment. 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.) 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. 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Multicenter, randomized, open-label, 2-period, 2-sequence crossover study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASTX727<br>ASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover) | Drug: ASTX727<br>* 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).<br>* Other names: cedazuridine + decitabine;|
| Active Comparator: IV decitabine<br>Dacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover) | Drug: Dacogen<br>* Decitabine 20 mg/m^2 one-hour IV infusion Dailyx5 (in one 28-day cycle: either Cycle 1 or Cycle 2).<br>* Other names: decitabine for injection;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03. | Safety assessment | 18 months | 
| Long Interspersed Nucleotide Elements (LINE)-1 demethylation | Pharmacodynamics assessment | 18 months | 
| Maximum plasma concentration (Cmax) | Secondary pharmacokinetics parameter | 2 months | 
| Time to reach maximum concentration (Tmax) | Secondary pharmacokinetics parameter | 2 months | 
| Elimination rate constant | Secondary pharmacokinetics parameter | 2 months | 
| Apparent total systemic clearance | Secondary pharmacokinetics parameter | 2 months | 
| Apparent elimination half life | Secondary pharmacokinetics parameter | 2 months | 
| Apparent volume of distribution | Secondary pharmacokinetics parameter | 2 months | 
| 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. | Efficacy analysis - Clinical response | 18 months | 
| 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 | Efficacy analysis - Clinical response | 18 months | 
| Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. | Efficacy analysis - RBC transfusion independence | 18 months | 
| Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. | Efficacy analysis - Platelet transfusion independence | 18 months | 
| 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. | Efficacy analysis - Leukemia-free survival | 18 months | 
| Overall survival: number of days from date subject was randomized to date of death. | Efficacy analysis - Overall survival | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, CMML, decitabine, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, AML