Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
MDS, CMML, decitabine, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, AML
Brief summary
Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were 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, participants continued to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the participants discontinued treatment or withdrew from the study.
Detailed description
This Phase 3 study established PK equivalence of ASTX727 to IV decitabine in approximately 227 evaluable participants. Eligible participants were randomized to receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: participants were 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, participants received the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) were 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. Participants were 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, participants received a 1-hour infusion of IV decitabine 20 mg/m\^2 Daily×5. Serial PK measurements were done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3. In Cycles ≥3, participants received the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments were done from Cycle 3 onward.)
Interventions
DRUGASTX727
ASTX727 oral tablet
DRUGDacogen
Decitabine 20 mg/m\^2 one-hour IV infusion
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter, randomized, open-label, 2-period, 2-sequence crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days) | Total 5-day ASTX727 AUC0-24 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-24 (first ASTX727 dose) was added to (Day 2 AUC0-24+ Day 5 AUC0-24) × 2. Decitabine 5-day AUC0-24 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-24+ Day 5 AUC0-24) / 2 was multiplied by 5. If AUC0-24 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-24 on Day 5; the converse was also true. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AML: Number of Participants With Treatment-emergent Adverse Events (AEs) | From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years) | An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. |
| MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs | From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years) | TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. |
| AML: Number of Participants With Grade 3 or Higher TEAEs | From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years) | TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using CTCAE version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. |
| Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days) | Summarized data for Cycle 1 and Cycle 2 was reported. |
| Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days) | Summarized data of Vz/F on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. |
| Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days) | Total 5-day ASTX727 AUC0-inf exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-inf (first ASTX727 dose) was added to (Day 2 AUC0-inf+ Day 5 AUC0-inf) × 2. Decitabine 5-day AUC0-inf exposures after IV decitabine were calculated as follows: (Day 1 AUC0-inf+ Day 5 AUC0-inf) / 2 was multiplied by 5. If AUC0-inf on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-inf on Day 5; the converse was also true. |
| Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days) | Total 5-day ASTX727 AUC0-last exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-last (first ASTX727 dose) was added to (Day 2 AUC0-last + Day 5 AUC0-last) × 2. Decitabine 5-day AUC0-last exposures after IV decitabine were calculated as follows: (Day 1 AUC0-last + Day 5 AUC0-last) / 2 was multiplied by 5. If AUC0-last on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-last on Day 5; the converse was also true. |
| Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days) | Total 5-day ASTX727 AUC0-8 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-8 (first ASTX727 dose) was added to (Day 2 AUC0-8 + Day 5 AUC0-8) × 2. Decitabine 5-day AUC0-8 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-8 + Day 5 AUC0-8) / 2 was multiplied by 5. If AUC0-8 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-8 on Day 5; the converse was also true. |
| Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days) | AUC0-inf was calculated using the formula AUClast + (Clast / λZ), where Clast is the last quantifiable concentration and λZ is the elimination rate constant. AUC0-inf will be calculated using the linear up-log down method. Summarized data has been reported for cycle 1 and 2. |
| Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days) | Summarized data of Cmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Cmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days) | Summarized data of Tmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Tmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine. |
| Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days) | Oral CL/F for oral decitabine was measured only on Day 1 and oral CL/F for oral cedazuridine was measured on Days 1, 2 and 5. Summarized data of Oral CL/F for oral decitabine on Day 1 for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of oral CL/F for oral cedazuridine on Day 1,2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. |
| Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days) | Summarized data of t1/2 on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of t1/2 on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine. |
| MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years) | An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. |
| AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | Up to approximately 2.4 years | CR was defined as absolute neutrophil content (ANC) ≥1000/ microliter (μL), platelets ≥100,000/μL, independence from red blood cell (RBC) and platelet transfusions over the past week, no leukemic blasts and \<5% leukemic blasts. CRp was defined as CR criteria except platelets \<100,000/μL.and platelet transfusion over the past week. CRi was defined as CR criteria except ANC \<1000/μL or platelets \<100,000/μL. Percentage of participants with CR, CRi, CRp, and CR Plus CRp based on IWG 2003 AML response criteria are reported. |
| AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria | Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days) | CRh was defined as \<5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets \>50,000/μL and ANC \>500/μL), independence from RBC and platelet transfusions within 7 days of bone marrow evaluation, and peripheral blast ≤1%. Percentage of participants with CRh based on IWG 2003 AML response criteria are reported. |
| AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria | Up to approximately 2.4 years | Time to first response was defined as time in months from the date of first treatment to the first date when any response is achieved. Time to best response was defined in months from the date of first treatment to the first date when a subject's best response, in the order of CR, CRi (or CRp or CRh), or PR, was achieved. Time to CR was defined in months from the date of first treatment to the first date when CR is achieved. CR:ANC ≥1000/ microliter (μL),platelets ≥100,000/μL,independence from RBC and platelet transfusions over the past week, no leukemic blasts, and \<5% leukemic blasts.CRp: CR criteria except ANC ≥1000/μL, platelets \< 100,000/μL.and platelet transfusion over the past week. CRi:CR criteria except ANC \<1000/μL or platelets \<100,000/μL.CRh: \<5% of blasts in the bone marrow,platelets \>50,000/μL and ANC \>500/μL, independence from RBC and platelet transfusions within 7 days and peripheral blast ≤1%. PR: CR criteria except decrease of ≥50% in leukemic blasts. |
| AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria | Up to approximately 2.4 years | Duration of CR was defined as the time interval from the first CR to time of relapse. Duration of combined CR and CRh was defined as the time interval from the first CR or CRh to time of relapse. Duration of CR and combined CR and CRh was presented using a Kaplan-Meier estimate. |
| MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Up to approximately 2.7 years | Transfusion independence was defined as no transfusion for 56 consecutive days or more (84 and 112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI). |
| AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Up to approximately 2.4 years | Transfusion independence was defined as no transfusion for 56 consecutive days or more (112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI). |
| MDS/CMML: Leukemia-free Survival (LFS) | From randomization up to approximately 2.7 years | LFS was defined as time from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. Participants who hadn't reached AML at the time of the analysis were censored at the date of the last follow-up. Leukemia-free survival was presented using a Kaplan-Meier estimate. |
| MDS/CMML: Overall Survival (OS) | From randomization up to approximately 2.7 years | OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate. |
| AML: Overall Survival (OS) | From randomization up to approximately 2.4 years | OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate. |
| AML: Survival Rates at 6 Months, 1 Year, and 2 Years | At Month 6, Year 1 and 2 | One-year survival rate was defined as the survival rate at the end of the first year from the date of randomization. The survival rates at 6 months and at 2 years were calculated similarly. |
| AML: Event-free Survival (EFS) | From randomization up to approximately 2.4 years | EFS was defined as time from the date of randomization to the date of treatment failure \[disease progression/relapse (due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse), discontinue treatment due to disease progression or treatment-related AE, or alternative anti-leukemia therapy except for HCT\] or death from any cause, whichever occurs first. Participants without documented treatment failure at the time of the analysis were censored at the date of the last follow-up. Event-free survival was presented using a Kaplan-Meier estimate. |
| AML: Progression-free Survival (PFS) | From randomization up to approximately 2.4 years | PFS was defined as time from the date of randomization to the date disease progression due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse) or death from any cause, whichever occurs first. Participants without documented disease progression/relapse or death at the time of the analysis were censored at the date of the last follow-up. Progression-free survival was presented using a Kaplan-Meier estimate. |
| MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Up to approximately 2.7 years | CR: normal peripheral, persistent granulocyte count ≥1.0x10\^9/liter(L), platelet ≥100x10\^9/L, Hemoglobin (Hgb) ≥11g/dL, normal bone marrow with persistent marrow blasts ≤5%. mCR: reduction of bone marrow blasts to≤5%, decrease by 50% or more with/without normalization of peripheral counts.PR: normal peripheral counts, granulocyte count ≥1.0x10\^9/L, platelet count ≥100x10\^9/L, Hgb ≥11 g/dL, normal bone marrow, marrow blasts \>5%, reduced by 50% or more for at least 4 weeks. HI: HI-E: Hb increase ≥1.5 g/dL in absence of RBC transfusions. HI-P: Absolute increase of platelet count from \<20 to \>20X10\^9/L by at least 100%,if more than 20x10\^9/L, by absolute increase of at least 30x10\^9/L in absence of platelet transfusions. HI-N: granulocyte increase ≥100%, by an absolute increase ≥0.5x10\^9/L for at least 8 weeks. Percentage of participants with CR, mCR, PR, and HI based on IWG 2003 MDS response criteria are reported. Response has been reported based on participants with MDS or CMML. |
Countries
Austria, Canada, Czechia, France, Germany, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 227 participants took part in the study from 15 February 2018 to 25 May 2023. 138 participants with a diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) took part from the United States and Canada. 89 participants with a diagnosis of acute myeloid leukemia (AML) took part from Austria, Canada, Czech Republic, France, Germany, Hungary, Italy, Spain, and United Kingdom.
Pre-assignment details
A total of 138 participants with a diagnosis of MDS or CMML were enrolled and randomized in a 1:1 ratio to receive ASTX727 or decitabine in a crossover manner. A total of 89 participants with a diagnosis of AML were enrolled and randomized in a 1:1 ratio to receive ASTX727 or decitabine in a crossover manner.
Participants by arm
| Arm | Count |
|---|---|
| MDS or CMML: ASTX727 or IV Decitabine Participants with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. | 133 |
| AML: ASTX727 or IV Decitabine Participants with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m\^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. | 87 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Complete Consent Withdrawal | 4 | 4 | 1 | 8 |
| Overall Study | Death | 33 | 25 | 34 | 34 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Overall Study | Rollover to ASTX727-06 | 10 | 18 | 4 | 2 |
| Overall Study | Study Centre Terminated by Sponsor | 21 | 22 | 4 | 1 |
Baseline characteristics
| Characteristic | MDS or CMML: ASTX727 or IV Decitabine | AML: ASTX727 or IV Decitabine | Total |
|---|---|---|---|
| Age, Customized 18 to 64 years | 36 Participants | 3 Participants | 39 Participants |
| Age, Customized 65 to 84 years | 93 Participants | 75 Participants | 168 Participants |
| Age, Customized ≥85 years | 4 Participants | 9 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 0 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 87 Participants | 89 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 87 Participants | 92 Participants |
| Race (NIH/OMB) White | 121 Participants | 0 Participants | 121 Participants |
| Sex: Female, Male Female | 46 Participants | 34 Participants | 80 Participants |
| Sex: Female, Male Male | 87 Participants | 53 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 132 | 56 / 130 | 0 / 5 | 5 / 78 | 61 / 80 | 2 / 2 |
| other Total, other adverse events | 127 / 132 | 130 / 130 | 0 / 5 | 70 / 78 | 76 / 80 | 0 / 2 |
| serious Total, serious adverse events | 24 / 132 | 81 / 130 | 0 / 5 | 19 / 78 | 65 / 80 | 1 / 2 |
Outcome results
Primary
Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine
Total 5-day ASTX727 AUC0-24 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-24 (first ASTX727 dose) was added to (Day 2 AUC0-24+ Day 5 AUC0-24) × 2. Decitabine 5-day AUC0-24 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-24+ Day 5 AUC0-24) / 2 was multiplied by 5. If AUC0-24 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-24 on Day 5; the converse was also true.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Primary Endpoint Pharmacokinetics (PK) Analysis Set included participants who received full dose of ASTX727 within 3 hours of the intended dosing time, and no vomiting within 6 hours of dosing, and had at least 2 days of evaluable decitabine (AUC0-24) measurements in the ASTX727 cycle, i.e, Day 1 and either Day 2 or Day 5 and received the full IV decitabine dose as a 1-hour infusion.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine | 864.34 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40 |
| MDS or CMML: ASTX727 | Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine | 855.96 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 50.6 |
| AML: IV Decitabine | Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine | 910.1 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 52.4 |
| AML: ASTX727 | Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine | 900.5 hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 52 |
Comparison: MDS or CMML: IV Decitabine Versus MDS or CMML: ASTX72790% CI: [92.66, 105.6]
Comparison: AML: IV Decitabine Versus AML: ASTX72790% CI: [91.23, 108.8]
Secondary
AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria
Duration of CR was defined as the time interval from the first CR to time of relapse. Duration of combined CR and CRh was defined as the time interval from the first CR or CRh to time of relapse. Duration of CR and combined CR and CRh was presented using a Kaplan-Meier estimate.
Time frame: Up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria | Duration of Complete Response | 6.9 months |
| MDS or CMML: IV Decitabine | AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria | Duration of Combined CR and CRh | 9.0 months |
Secondary
AML: Event-free Survival (EFS)
EFS was defined as time from the date of randomization to the date of treatment failure \[disease progression/relapse (due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse), discontinue treatment due to disease progression or treatment-related AE, or alternative anti-leukemia therapy except for HCT\] or death from any cause, whichever occurs first. Participants without documented treatment failure at the time of the analysis were censored at the date of the last follow-up. Event-free survival was presented using a Kaplan-Meier estimate.
Time frame: From randomization up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Event-free Survival (EFS) | 5.9 months |
Secondary
AML: Number of Participants With Grade 3 or Higher TEAEs
TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using CTCAE version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.
Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
Population: The Safety Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Number of Participants With Grade 3 or Higher TEAEs | 43 Participants |
| MDS or CMML: ASTX727 | AML: Number of Participants With Grade 3 or Higher TEAEs | 73 Participants |
Secondary
AML: Number of Participants With Treatment-emergent Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first.
Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
Population: The Safety Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Number of Participants With Treatment-emergent Adverse Events (AEs) | 71 Participants |
| MDS or CMML: ASTX727 | AML: Number of Participants With Treatment-emergent Adverse Events (AEs) | 80 Participants |
Secondary
AML: Overall Survival (OS)
OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate.
Time frame: From randomization up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Overall Survival (OS) | 8.9 months |
Secondary
AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria
CR was defined as absolute neutrophil content (ANC) ≥1000/ microliter (μL), platelets ≥100,000/μL, independence from red blood cell (RBC) and platelet transfusions over the past week, no leukemic blasts and \<5% leukemic blasts. CRp was defined as CR criteria except platelets \<100,000/μL.and platelet transfusion over the past week. CRi was defined as CR criteria except ANC \<1000/μL or platelets \<100,000/μL. Percentage of participants with CR, CRi, CRp, and CR Plus CRp based on IWG 2003 AML response criteria are reported.
Time frame: Up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | Complete Response (CR) | 14.0 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR with Incomplete Platelet Recovery (CRp) | 4.7 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR with Incomplete Blood Count Recovery (CRi) | 11.6 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR Plus CRp | 18.6 percentage of participants |
| MDS or CMML: ASTX727 | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR Plus CRp | 29.5 percentage of participants |
| MDS or CMML: ASTX727 | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | Complete Response (CR) | 29.5 percentage of participants |
| MDS or CMML: ASTX727 | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR with Incomplete Blood Count Recovery (CRi) | 0 percentage of participants |
| MDS or CMML: ASTX727 | AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria | CR with Incomplete Platelet Recovery (CRp) | 0 percentage of participants |
Secondary
AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria
CRh was defined as \<5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets \>50,000/μL and ANC \>500/μL), independence from RBC and platelet transfusions within 7 days of bone marrow evaluation, and peripheral blast ≤1%. Percentage of participants with CRh based on IWG 2003 AML response criteria are reported.
Time frame: Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days)
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria | 4.7 percentage of participants |
| MDS or CMML: ASTX727 | AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria | 0 percentage of participants |
Secondary
AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)
Transfusion independence was defined as no transfusion for 56 consecutive days or more (112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).
Time frame: Up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure. 'Number analyzed' signifies those subjects who were evaluable for this outcome measure at specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | RBC TI ≥56 Days | 37.8 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | RBC TI ≥112 Days | 24.3 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Platelet TI ≥56 Days | 35.7 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Platelet TI ≥112 Days | 28.6 percentage of participants |
Secondary
AML: Progression-free Survival (PFS)
PFS was defined as time from the date of randomization to the date disease progression due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse) or death from any cause, whichever occurs first. Participants without documented disease progression/relapse or death at the time of the analysis were censored at the date of the last follow-up. Progression-free survival was presented using a Kaplan-Meier estimate.
Time frame: From randomization up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDS or CMML: IV Decitabine | AML: Progression-free Survival (PFS) | 6.1 months |
Secondary
AML: Survival Rates at 6 Months, 1 Year, and 2 Years
One-year survival rate was defined as the survival rate at the end of the first year from the date of randomization. The survival rates at 6 months and at 2 years were calculated similarly.
Time frame: At Month 6, Year 1 and 2
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | AML: Survival Rates at 6 Months, 1 Year, and 2 Years | Month 6 | 61 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Survival Rates at 6 Months, 1 Year, and 2 Years | Year 1 | 44 percentage of participants |
| MDS or CMML: IV Decitabine | AML: Survival Rates at 6 Months, 1 Year, and 2 Years | Year 2 | 16 percentage of participants |
Secondary
AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria
Time to first response was defined as time in months from the date of first treatment to the first date when any response is achieved. Time to best response was defined in months from the date of first treatment to the first date when a subject's best response, in the order of CR, CRi (or CRp or CRh), or PR, was achieved. Time to CR was defined in months from the date of first treatment to the first date when CR is achieved. CR:ANC ≥1000/ microliter (μL),platelets ≥100,000/μL,independence from RBC and platelet transfusions over the past week, no leukemic blasts, and \<5% leukemic blasts.CRp: CR criteria except ANC ≥1000/μL, platelets \< 100,000/μL.and platelet transfusion over the past week. CRi:CR criteria except ANC \<1000/μL or platelets \<100,000/μL.CRh: \<5% of blasts in the bone marrow,platelets \>50,000/μL and ANC \>500/μL, independence from RBC and platelet transfusions within 7 days and peripheral blast ≤1%. PR: CR criteria except decrease of ≥50% in leukemic blasts.
Time frame: Up to approximately 2.4 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria | Time to First Response | 2.91 months |
| MDS or CMML: IV Decitabine | AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria | Time to Best Response | 3.45 months |
| MDS or CMML: IV Decitabine | AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria | Time to Complete Response | 3.02 months |
Secondary
Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer
Summarized data of t1/2 on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of t1/2 on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MDS or CMML: IV Decitabine | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.14 hours | Geometric Coefficient of Variation 44.9 |
| MDS or CMML: IV Decitabine | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 0.967 hours | Geometric Coefficient of Variation 46.8 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 5.50 hours | Geometric Coefficient of Variation 21.8 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.47 hours | Geometric Coefficient of Variation 26.9 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 5.90 hours | Geometric Coefficient of Variation 23.2 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 2.59 hours | Geometric Coefficient of Variation 5.43 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 2.58 hours | Geometric Coefficient of Variation 5.16 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 1.18 hours | Geometric Coefficient of Variation 22.8 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 1.38 hours | Geometric Coefficient of Variation 24.7 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 6.33 hours | Geometric Coefficient of Variation 18.1 |
| MDS or CMML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 6.70 hours | Geometric Coefficient of Variation 18.9 |
| AML: IV Decitabine | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.18 hours | Geometric Coefficient of Variation 49 |
| AML: IV Decitabine | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 1.16 hours | Geometric Coefficient of Variation 56.7 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 2.57 hours | — |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 1.07 hours | Geometric Coefficient of Variation 31.6 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 1.36 hours | Geometric Coefficient of Variation 35 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.45 hours | Geometric Coefficient of Variation 34 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 6.68 hours | Geometric Coefficient of Variation 18.5 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 7.05 hours | Geometric Coefficient of Variation 17.6 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 2.41 hours | — |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 6.22 hours | Geometric Coefficient of Variation 17.4 |
| AML: ASTX727 | Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 6.15 hours | Geometric Coefficient of Variation 22.8 |
Secondary
Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine
Oral CL/F for oral decitabine was measured only on Day 1 and oral CL/F for oral cedazuridine was measured on Days 1, 2 and 5. Summarized data of Oral CL/F for oral decitabine on Day 1 for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of oral CL/F for oral cedazuridine on Day 1,2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MDS or CMML: IV Decitabine | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 1 | 342 Litres per hour (L/h) | Geometric Coefficient of Variation 54.8 |
| MDS or CMML: IV Decitabine | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 1 | 30.6 Litres per hour (L/h) | Geometric Coefficient of Variation 46.4 |
| MDS or CMML: IV Decitabine | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 2 | 25.6 Litres per hour (L/h) | Geometric Coefficient of Variation 159 |
| MDS or CMML: IV Decitabine | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 5 | 16.8 Litres per hour (L/h) | Geometric Coefficient of Variation 15.9 |
| MDS or CMML: ASTX727 | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 5 | 86.8 Litres per hour (L/h) | — |
| MDS or CMML: ASTX727 | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 1 | 297 Litres per hour (L/h) | Geometric Coefficient of Variation 54.4 |
| MDS or CMML: ASTX727 | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 2 | 27.4 Litres per hour (L/h) | Geometric Coefficient of Variation 45.4 |
| MDS or CMML: ASTX727 | Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 1 | 28.6 Litres per hour (L/h) | Geometric Coefficient of Variation 55.5 |
Secondary
Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine
Summarized data of Vz/F on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.
Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 1 | 585 Litres | Geometric Coefficient of Variation 55 |
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 2 | 369 Litres | Geometric Coefficient of Variation 59 |
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 5 | 417 Litres | Geometric Coefficient of Variation 54.3 |
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 1 | 280 Litres | Geometric Coefficient of Variation 50.9 |
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 2 | 296 Litres | Geometric Coefficient of Variation 51.3 |
| MDS or CMML: IV Decitabine | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 5 | 62.8 Litres | Geometric Coefficient of Variation 10.4 |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 2 | 278 Litres | Geometric Coefficient of Variation 49.8 |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 1 | 434 Litres | Geometric Coefficient of Variation 60.4 |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 1 | 272 Litres | Geometric Coefficient of Variation 59.9 |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 2 | 337 Litres | Geometric Coefficient of Variation 67.6 |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Cedazuridine: Day 5 | 302 Litres | — |
| MDS or CMML: ASTX727 | Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | Decitabine: Day 5 | 373 Litres | Geometric Coefficient of Variation 68.9 |
Secondary
Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine
AUC0-inf was calculated using the formula AUClast + (Clast / λZ), where Clast is the last quantifiable concentration and λZ is the elimination rate constant. AUC0-inf will be calculated using the linear up-log down method. Summarized data has been reported for cycle 1 and 2.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MDS or CMML: IV Decitabine | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 5 | 170 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 41.7 |
| MDS or CMML: IV Decitabine | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 1 | 174 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 40.8 |
| MDS or CMML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 2 | 186 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 55.3 |
| MDS or CMML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 1 | 102 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 54.8 |
| MDS or CMML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 5 | 178 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 52.7 |
| AML: IV Decitabine | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 1 | 175 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 54.9 |
| AML: IV Decitabine | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 5 | 181 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 58.1 |
| AML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 5 | 187 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 57.1 |
| AML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 1 | 118 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 54.4 |
| AML: ASTX727 | Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | Day 2 | 193 nanograms*hours per millilitres(ng*h/mL) | Geometric Coefficient of Variation 59.6 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer
Summarized data of Cmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Cmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MDS or CMML: IV Decitabine | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 180 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49.2 |
| MDS or CMML: IV Decitabine | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 184 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 48.1 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 169 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 65.9 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 150 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 65.7 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 155 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 64.6 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 83.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 66.1 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 145 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 54.7 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 140 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.8 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 321 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 53.8 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 349 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49.1 |
| MDS or CMML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 371 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 51.8 |
| AML: IV Decitabine | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 187 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 64.7 |
| AML: IV Decitabine | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 192 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.4 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 139 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62.7 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 182 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 60 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 191 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58.4 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 313 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 47.7 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 85.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 56.6 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 350 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 42.7 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 204 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 59.2 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 139 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58.5 |
| AML: ASTX727 | Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 343 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 43.4 |
Secondary
Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation
Summarized data for Cycle 1 and Cycle 2 was reported.
Time frame: Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days)
Population: Pharmacodynamic (PD) LINE-1 Analysis Set included participants who received any amount of study treatment and have LINE-1 methylation data at baseline (Day 1) of Cycle 1 or 2 and on either Day 8 or Day 15 of the respective cycle. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure. 'Number analyzed' signifies those participants who were evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 1 | 14.019 percentage of demethylation |
| MDS or CMML: IV Decitabine | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 2 | 11.968 percentage of demethylation |
| MDS or CMML: ASTX727 | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 2 | 11.151 percentage of demethylation |
| MDS or CMML: ASTX727 | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 1 | 13.289 percentage of demethylation |
| AML: IV Decitabine | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 2 | 8.153 percentage of demethylation |
| AML: IV Decitabine | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 1 | 8.243 percentage of demethylation |
| AML: ASTX727 | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 1 | 9.357 percentage of demethylation |
| AML: ASTX727 | Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | Cycle 2 | 8.037 percentage of demethylation |
Secondary
MDS/CMML: Leukemia-free Survival (LFS)
LFS was defined as time from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. Participants who hadn't reached AML at the time of the analysis were censored at the date of the last follow-up. Leukemia-free survival was presented using a Kaplan-Meier estimate.
Time frame: From randomization up to approximately 2.7 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Leukemia-free Survival (LFS) | 889.0 days |
Secondary
MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs
TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.
Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
Population: The Safety Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs | 89 Participants |
| MDS or CMML: ASTX727 | MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs | 121 Participants |
Secondary
MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first.
Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
Population: The Safety Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 127 Participants |
| MDS or CMML: ASTX727 | MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 130 Participants |
Secondary
MDS/CMML: Overall Survival (OS)
OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate.
Time frame: From randomization up to approximately 2.7 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Overall Survival (OS) | 966.0 days |
Secondary
MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria
CR: normal peripheral, persistent granulocyte count ≥1.0x10\^9/liter(L), platelet ≥100x10\^9/L, Hemoglobin (Hgb) ≥11g/dL, normal bone marrow with persistent marrow blasts ≤5%. mCR: reduction of bone marrow blasts to≤5%, decrease by 50% or more with/without normalization of peripheral counts.PR: normal peripheral counts, granulocyte count ≥1.0x10\^9/L, platelet count ≥100x10\^9/L, Hgb ≥11 g/dL, normal bone marrow, marrow blasts \>5%, reduced by 50% or more for at least 4 weeks. HI: HI-E: Hb increase ≥1.5 g/dL in absence of RBC transfusions. HI-P: Absolute increase of platelet count from \<20 to \>20X10\^9/L by at least 100%,if more than 20x10\^9/L, by absolute increase of at least 30x10\^9/L in absence of platelet transfusions. HI-N: granulocyte increase ≥100%, by an absolute increase ≥0.5x10\^9/L for at least 8 weeks. Percentage of participants with CR, mCR, PR, and HI based on IWG 2003 MDS response criteria are reported. Response has been reported based on participants with MDS or CMML.
Time frame: Up to approximately 2.7 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Complete Response (CR) | 26.2 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Marrow Complete Response (mCR) | 29.5 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Partial Response (PR) | 0 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Erythroid Response (HI-E) | 0 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Platelet Response (HI-P) | 3.3 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Neutrophil Response (HI-N) | 0 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Neutrophil Response (HI-N) | 0 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Erythroid Response (HI-E) | 1.8 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Complete Response (CR) | 19.6 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Partial Response (PR) | 0 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Marrow Complete Response (mCR) | 30.4 percentage of participants |
| MDS or CMML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Platelet Response (HI-P) | 8.9 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Marrow Complete Response (mCR) | 40.0 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Partial Response (PR) | 0 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Erythroid Response (HI-E) | 20.0 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Neutrophil Response (HI-N) | 0 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Platelet Response (HI-P) | 0 percentage of participants |
| AML: IV Decitabine | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Complete Response (CR) | 0 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Platelet Response (HI-P) | 0 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Neutrophil Response (HI-N) | 9.1 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Marrow Complete Response (mCR) | 54.5 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | HI: Erythroid Response (HI-E) | 0 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Complete Response (CR) | 18.2 percentage of participants |
| AML: ASTX727 | MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria | Partial Response (PR) | 0 percentage of participants |
Secondary
MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)
Transfusion independence was defined as no transfusion for 56 consecutive days or more (84 and 112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).
Time frame: Up to approximately 2.7 years
Population: Efficacy Analysis Set included all participants who received any amount of study treatment. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure. 'Number analyzed' signifies those subjects who were evaluable for this outcome measure in specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | RBC TI: ≥56 Days | 51.9 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | RBC TI: ≥84 Days | 40.7 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | RBC TI: ≥112 Days | 33.3 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Platelet TI: ≥56 Days | 50.0 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Platelet TI: ≥84 Days | 33.3 percentage of participants |
| MDS or CMML: IV Decitabine | MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) | Platelet TI: ≥112 Days | 33.3 percentage of participants |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer
Summarized data of Tmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Tmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Overall number of participants analyzed:Number of participants evaluable for this outcome measure. Number analyzed:Number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 0.97 hours |
| MDS or CMML: IV Decitabine | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 0.98 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 1.00 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.00 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 1.00 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 3.00 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 3.01 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 3.00 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 3.08 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 3.03 hours |
| MDS or CMML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 3.08 hours |
| AML: IV Decitabine | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 0.98 hours |
| AML: IV Decitabine | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 0.98 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 5 | 4.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 1 | 4.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 2 | 1.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 5 | 1.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Decitabine: Day 1 | 1.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 1 | 3.98 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 2 | 4.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine-epimer: Day 2 | 4.00 hours |
| AML: ASTX727 | Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | Cedazuridine: Day 5 | 3.98 hours |
Secondary
Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine
Total 5-day ASTX727 AUC0-8 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-8 (first ASTX727 dose) was added to (Day 2 AUC0-8 + Day 5 AUC0-8) × 2. Decitabine 5-day AUC0-8 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-8 + Day 5 AUC0-8) / 2 was multiplied by 5. If AUC0-8 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-8 on Day 5; the converse was also true.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine | 856.63 h*ng/mL | Geometric Coefficient of Variation 40.6 |
| MDS or CMML: ASTX727 | Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine | 839.37 h*ng/mL | Geometric Coefficient of Variation 50.4 |
| AML: IV Decitabine | Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine | 910.1 h*ng/mL | Geometric Coefficient of Variation 52 |
| AML: ASTX727 | Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine | 883.8 h*ng/mL | Geometric Coefficient of Variation 52.1 |
Comparison: MDS or CMML: IV Decitabine Versus MDS or CMML: ASTX72790% CI: [91.74, 104.5]
Comparison: AML: IV Decitabine Versus AML: ASTX72790% CI: [89.32, 106.5]
Secondary
Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine
Total 5-day ASTX727 AUC0-inf exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-inf (first ASTX727 dose) was added to (Day 2 AUC0-inf+ Day 5 AUC0-inf) × 2. Decitabine 5-day AUC0-inf exposures after IV decitabine were calculated as follows: (Day 1 AUC0-inf+ Day 5 AUC0-inf) / 2 was multiplied by 5. If AUC0-inf on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-inf on Day 5; the converse was also true.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants who may not have been included in the Primary Endpoint PK Analysis Set and who received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | 866.15 h*ng/mL | Geometric Coefficient of Variation 39.9 |
| MDS or CMML: ASTX727 | Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | 849.63 h*ng/mL | Geometric Coefficient of Variation 50.4 |
| AML: IV Decitabine | Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | 912.3 h*ng/mL | Geometric Coefficient of Variation 52.3 |
| AML: ASTX727 | Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine | 902.1 h*ng/mL | Geometric Coefficient of Variation 51.8 |
Comparison: MDS or CMML: IV Decitabine Versus MDS or CMML: ASTX72790% CI: [91.8, 104.6]
Comparison: AML: IV Decitabine Versus AML: ASTX72790% CI: [91.2, 108.8]
Secondary
Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine
Total 5-day ASTX727 AUC0-last exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-last (first ASTX727 dose) was added to (Day 2 AUC0-last + Day 5 AUC0-last) × 2. Decitabine 5-day AUC0-last exposures after IV decitabine were calculated as follows: (Day 1 AUC0-last + Day 5 AUC0-last) / 2 was multiplied by 5. If AUC0-last on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-last on Day 5; the converse was also true.
Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Population: Overall PK Analysis Set included participants who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. 'Overall number of participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MDS or CMML: IV Decitabine | Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine | 853.02 h*ng/mL | Geometric Coefficient of Variation 40.7 |
| MDS or CMML: ASTX727 | Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine | 837.38 h*ng/mL | Geometric Coefficient of Variation 50.7 |
| AML: IV Decitabine | Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine | 902.7 h*ng/mL | Geometric Coefficient of Variation 53 |
| AML: ASTX727 | Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine | 881.8 h*ng/mL | Geometric Coefficient of Variation 52.5 |
Comparison: MDS or CMML: IV Decitabine Versus MDS or CMML: ASTX72790% CI: [91.88, 104.8]
Comparison: AML: IV Decitabine Versus AML: ASTX72790% CI: [89.75, 107.2]