A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers

Study Overview
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Brief Summary
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Extension study to provide ongoing long-term treatment with ASTX727 for participants who were benefitting from ASTX727 treatment in a previous Astex-sponsored clinical study of ASTX727 (including, but not limited to ASTX727-01 [NCT02103478], ASTX727-02 [NCT03306264], ASTX727-04 [NCT03813186]), and Food Effect Substudy to obtain survival information and long-term safety information. The purpose of the Food Effect Substudy is to evaluate the pharmacokinetics (PK) and safety of decitabine and cedazuridine when ASTX727 is given under fed (high-calorie/high-fat meal or low-calorie/low-fat meal) versus fasted conditions.

Detailed Description
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Main Extension Study: Participants will attend clinic visits on Day 1 of each 28-day cycle to undergo study procedures and to be given ASTX727 tablets for Days 1-5 of that dose cycle. Participants should continue to receive the same ASTX727 dose and regimen they were receiving in the last cycle of the parent study in which they were originally enrolled. Subsequent treatment delays and/or dose reductions are at the discretion of the investigator as guided by the dose adjustment guidelines of the parent study protocol. Food Effect Substudy: Participants will receive ASTX727 once daily on Days 1 through 5 followed by a 23-day treatment-free period in a 28-day cycle (Cycle 1). Participants will receive either a high-calorie, high-fat breakfast meal (Arm A) or a low-calorie/low-fat breakfast meal (Arm B) predose on Day 4. Participants in Arms A and B will receive ASTX727 on Days 1, 2, 3, and 5 in the fasted condition. Participants may continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727. This substudy consists of a 21-day Screening Period, a 1-cycle (28 days) Treatment Period, and a 30-day (+7 days) Safety Follow-up Period (only if the participant discontinues from the ASTX727-06 food effect substudy and does not continue to receive ASTX727 in the ASTX727-06 study).

Official Title
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An Open-Label, Multicenter, Extension Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers

Conditions
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Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: ASTX727


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for the Main Extension Study: Participants must fulfill all of the following inclusion criteria: Previous participation in an Astex-sponsored ASTX727 clinical trial (including, but not limited to studies ASTX727-01, ASTX727-02, and ASTX727-04) in which the participant was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex. Participant is considered to be benefitting from ASTX727 treatment in the opinion of the treating investigator at the time of parent study completion (Participants must not be withdrawn from the parent study until eligibility for this study is confirmed). Participant is able to understand and comply with the study procedures and understands the risks involved in the study. Participant provides legally effective informed consent before undergoing any study-specific procedure. Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive methods of birth control and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment. Inclusion Criteria for the Food Effect Substudy: Participants must have a confirmed diagnosis of- i. 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, CMML), and participants with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MD. ii. AML, as diagnosed according to the 2016 World Health Organization (WHO) guidelines on acute leukemia, of any subtype except M3 (acute promyelocytic leukemia), who are not candidates for intensive chemotherapy, including participants receiving hypomethylating agent (HMA) treatment, who have a confirmed diagnosis and a prior confirmatory bone marrow report. Participants who are currently receiving HMA treatment must complete the ongoing (at the time of Screening) treatment cycle before enrolling in this study; timing of start of treatment cycle with ASTX727 is at the principal investigator's discretion. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Adequate organ function defined as follows: Hepatic: Total bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤5 × ULN. Renal: Calculated creatinine clearance ≥60 mL/min. Exclusion Criterion for the Main Extension Study: 1. Any participant who, in the opinion of the investigator, may have other conditions, organ dysfunction, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits. Exclusion Criteria for the Food Effect Substudy: Participants with known or suspected hypersensitivity to decitabine, cedazuridine, or any of the excipients in the ASTX727 tablets. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections. Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of decitabine + cedazuridine or compromise the integrity of the study outcomes. Prior gastric surgery for ulcer disease, weight loss, etc, that would impair normal motility or absorption. Second malignancy currently requiring active chemotherapy. To clarify, participants with breast or prostate cancer stable on or responding to endocrine therapy, are eligible. Known history of human immunodeficiency virus or known seropositive for hepatitis C virus or hepatitis B virus. Active uncontrolled gastric or duodenal ulcer. Participants with acute promyelocytic leukemia. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts. Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant AEs from previous treatment with investigational drug or therapy.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main Extension Study: ASTX727<br>The recommended starting dose is the fixed-dose combination (FDC) tablet, containing 100 mg cedazuridine and 35 mg decitabine, once daily, Days 1 through 5 in 28-day cycles. Participants should receive ASTX727 at the same dose they received in the last cycle of their parent study; if an adjustment from that dose is required, a different total cycle dose may be employed, as guided by the dose adjustment guidelines in the parent study protocol. | Drug: ASTX727<br>* ASTX727 film-coated, immediate-release FDC tablets<br>* Other names: DEC-C;|
| Experimental: Substudy Arm A: ASTX727 With High-Calorie/High-Fat Breakfast Meal on Day 4<br>Participants will receive ASTX727 once daily on Days 1 through 5 in a 28-day cycle (Cycle 1). Participants will fast for at least 2 hours before and 2 hours after dosing on Days 1, 3, 5 and for at least 10 hours before and 4 hours after dosing on Day 2. Participants will receive a high-calorie/high-fat breakfast meal after an overnight fast of at least 10 hours before dosing on Day 4 and will continue to fast for at least 4 hours post-dose. Participants will continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727 unless there is occurrence of disease progression requiring alternative therapy, unacceptable toxicity, noncompliance, a decision to discontinue treatment, or if the participant withdraws from the study. | Drug: ASTX727<br>* ASTX727 film-coated, immediate-release FDC tablets<br>* Other names: DEC-C;|
| Experimental: Substudy Arm B: ASTX727 With Low-Calorie/Low-Fat Breakfast Meal on Day 4<br>Participants will receive ASTX727 once daily on Days 1 through 5 in a 28-day cycle (Cycle 1). Participants will fast for at least 2 hours before and 2 hours after dosing on Days 1, 3, 5 and for at least 10 hours before and 4 hours after dosing on Day 2. Participants will receive low-calorie/low-fat breakfast meal after an overnight fast of at least 10 hours before dosing on Day 4 and will continue to fast for at least 4 hours post-dose. Participants will continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727 unless there is occurrence of disease progression requiring alternative therapy, unacceptable toxicity, noncompliance, a decision to discontinue treatment, or if the participant withdraws from the study. | Drug: ASTX727<br>* ASTX727 film-coated, immediate-release FDC tablets<br>* Other names: DEC-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Extension Study: Safety: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. TEAEs are defined as events that first occur or worsen on or after the date of the first study treatment until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever first. | From date of transition into this extension study until 30 days following the last dose, up to approximately 2 years | 
| Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 ( up to 28 days) | 
| Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: T1/2: Terminal Half Life of Decitabine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: T1/2: Terminal Half Life of Cedazuridine in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 
| Food Effect Substudy: T1/2: Terminal Half Life of Cedazuridine-epimer in the Fasted and Fed State |  | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Extension Study: Overall Survival: Time to Death from Any Cause |  | Up to approximately 2 years | 
| Main Extension Study: Percentage of Participants with Haematological Malignancies Undergoing Conversion to AML | Assessments of conversion to AML in participants with hematological malignancies will be performed following local standards at the discretion of the Investigator. | Up to approximately 2 years | 
| Main Extension Study: Number of Participants with Solid Tumors with Disease Status: Complete Response (CR), Partial Response (PR), Stable Disease (SD) |  | Up to approximately 2 years | 
| Food Effect Substudy: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs), by Severity | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. TEAEs are defined as events that first occur or worsen on or after the date of the first study treatment (Cycle 1 Day 1) until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever first. Severity of TEAEs will be graded using Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03). | From first dose of study drug up to 30 days after the last dose (Up to approximately 65 days) | 
| Food Effect Substudy: Percentage of Participants with Clinically Significant Abnormal Laboratory Values | The laboratory parameters of hematology, serum chemistry, and urinalysis will be assessed. | From Day 1 up to Day 28 in Cycle 1 (Up to 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cedazuridine, decitabine, MDS, CMML, AML, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia, ASTX727, INQOVI