Azacitidine

PFS is defined as the time from randomization into the study to the first observation of documented disease progression (local assessment using Lugano Response Criteria 2014) or death due to any cause, whichever occurs first. If a participant has not progressed or died, PFS will be censored at the time of last visit with adequate assessment. C2 censoring rules were used per US FDA guidance 2015. Progression will be determined as per Response criteria for lymphoma: Lugano classification.

RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive "rolling" 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.

Overall survival was defined as time from randomization to death from any cause; participants surviving at the end of the follow-up period, or who withdraw consent, or who were lost to follow up were censored at the date last known alive.

Overall Survival was defined as the time from randomization to death from any cause. Overall survival was calculated by the formula: date of death - date of randomization + 1. Participants surviving at the end of the follow-up period or who withdrew consent to follow-up were censored at the date of last contact. Participants who were lost to follow-up were censored at the date last known alive.

Participant counts for a variety of subsets of treatment emergent adverse events (TEAEs)during the extension study period (43-68 months). Subsets include participants counts for serious TEAEs, serious TEAEs that the investigator evaluated as releated to treatment, TEAEs leading to discontinuation of therapy, or a dose reduction, or a dose interruption.

Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact.

Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact. Subgroups that were analyzed are age, gender, French-American-British (FAB) classification, World Health Organization (WHO) classification and International Prognostic Scoring System (IPSS) classification.

Count of participants who died during the study

Phase 2

Phase 2 and 3

The time from randomization to the date of documented relapse after CR or CRi per central review, or death from any cause, whichever occurs first. Participants who are still alive without documented relapse after CR or CRi, or who were lost to follow-up without documented relapse, will be censored at the date of their last response assessment.

Overall response rate (ORR) is defined as the percentage of participants achieving a complete remission (CR), partial remission (PR), marrow complete remission (mCR), and/or hematological improvement (HI) based on International Working Group (IWG) 2006 response criteria for MDS and central review. CR: ≤ 5% myeloblasts in bone marrow (BM), and peripheral blood: hemoglobin ≥ 11 g/dL; platelets ≥ 100 × 10⁹/L; neutrophils ≥ 1.0 × 10⁹/L; blasts 0% PR: BM blasts decreased by ≥ 50% but still \> 5%; peripheral blood as for CR mCR: BM ≤ 5% myeloblasts and decrease by ≥ 50% HI: Any of the following: •Hemoglobin increase by ≥ 1.5 g/dL or reduction of units of red blood cell (RBC) transfusions of at least 4 RBC transfusions/8 weeks compared with pretreatment •Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value \> 20 × 10⁹/L or increase from \< 20 × 10⁹/L to \> 20 × 10⁹/L and by at least 100% •At least 100% increase in neutrophils and an absolute increase of \> 0.5 × 10⁹/L

Overall response rate for AML is defined as the percentage of participants achieving an overall response of morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) based on modified IWG 2003 response criteria for AML and central review. CR: The following conditions must be met: •Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L •Platelet count ≥ 100 x10⁹/L •The bone marrow should contain less than 5% blast cells; •Auer rods should not be detectable; •No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. CRi: Defined as a morphologic complete remission but the ANC count may be \< 1.0 x10⁹/L and/or the platelet count may be \< 100 x10⁹/L.

A treatment emergent adverse event is any untoward medical occurrence that begins or worsens after the first dose of study treatment, including any unfavorable sign, symptom, disease, or abnormal lab finding, whether or not related to the product, and may include worsening of pre-existing conditions. A Serious Adverse Event (SAE) is any untoward medical occurrence that results in death, is life-threatening, requires or prolongs hospitalization, causes persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is considered an important medical event requiring intervention to prevent these outcomes.

Defined as proportion of subjects with complete remission \[CR\], partial remission \[PR\] or marrow CR according to modified criteria described by Cheson 2006, adapted to pediatric reference values at 3 months (28 days cycle). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 months to end of 4th months).

Defined as proportion of subjects with sustained clinical complete remission \[cCR\] or clinical partial remission \[cPR\] according to the International JMML response criteria in Niemeyer 2014 at 3 months (28 days cycles). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 monthsto end of 4 months).

All reported adverse events during the first treatment cycle

Number of participant with DLT The rate of the following treatment-related DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEs) version 4.0, occurring during Cycle 1 only will be considered in determining the tolerability of the 100 mg/m2 dose of azacitidine: * Grade 4 nonhematologic toxicity (excluding transient transaminase elevation) * Grade 3 nonhematological toxicity lasting more than 7 days despite optimal treatment with standard supportive measures * Grade 3 or 4 hematologic toxicity requiring treatment delay greater than 21 days (disease-related Grade 3 or 4 hematologic toxicity will not be counted as a DLT)

Proportion of subjects free from clinical progression (clinical relapse and death from any cause) and from molecular progression (defined as lack of stabilization or lack of decrease in molecular aberrations concerning FLT3-ITD mutated, CBF leukemias (eg, t(8;21) and/or inv(16)), MLL-gene rearrangements or NPM1-mutations using central assessment of BM samples by the central laboratories identified for the study, obtained at time points identically prespecified in both randomization arms) at Day 84 (±4 days) post randomization.

The overall response rate (ORR) was defined as the percentage of participants who achieved an objective response including: hematologic improvement (HI), partial remission (PR), complete remission (CR), or marrow complete remission (mCR). Hematologic response was defined as: • CR: ≤ 5% myeloblasts with normal maturation of all cell lines; peripheral blood (PB) shows: hemoglobin ≥11 g/dL, neutrophils ≥1.0x10\^9/L, platelets ≥100x10\^9/dL, blasts (0%) • PR: same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still \> 5%; cellularity and morphology not relevant • mCR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB, PB: if HI responses, noted in addition to mCR • HI: HI erythroid response (HI-E); HI neutrophil response (HI-N) ; HI platelet response (HI-P)

Overall response rate was defined as the combined incidence of Complete Response (CR) or Partial Response (PR), confirmed no less than 4 weeks after the criteria for response were first met, based on independent radiology assessment according to RECIST 1.1 criteria. Complete response was defined as the disappearance of all target lesions and non-target lesions; Partial response is at least a 30% decrease from baseline in the sum of diameters of target lesions with no progression of non-target lesions and no new lesions or disappearance of target lesions with persistence of one or more non-target lesions from baseline.

PFS was defined as the time from the date of start of the study treatment to the date of disease progression or death (any cause) on or prior to the data cut-off date for the statistical analysis, whichever occurred earlier, based on an independent radiology assessment of response using RECIST v1.1 criteria. Progressive disease was defined as at least a 20% increase in the sum of diameters of target or non-target lesions from nadir or appearance of a new lesion.

Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.

Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.

Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major \>20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10\^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of \>0.5x10\^9/L. Minor: ≥100% increase and absolute increase of \<0.5x10\^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin \<100g/L or RBC transfusion-dependent, platelet count \<100x10\^9/L or platelet transfusion dependent, absolute neutrophil count \<1.5x10\^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI.

One-year survival rate was defined as all deaths within one year from the date of randomization. All others censored at the at year 1 or date of discontinuation

Overall Survival reported at the end of the study are for those participants who were alive at the end of the study

Participant counts by best hematological response; complete remission(CR) is better than a partial remission(PR) which is better than stable disease(SD). Investigator determined responses followed IWG 2000 criteria for MDS CR: repeat bone marrow show \<5% myeloblasts, and peripheral blood evaluations lasting \>=2 months of hemoglobin(\>110 g/L), neutrophils(\>=1.5x10\^9/L), platelets(\>=100x10\^9/L), blasts (0%) and no dysplasia PR is the same as CR for peripheral blood: bone marrow shows blasts decrease by \>=50% or a less advanced FAB classification from pretreatment (see Population Descrip)

IWG 2000 Criteria: Pretreatment=hemoglobin \<110g/L or RBC transfusion-dependence, platelet count \<100x10\^9/L or platelet transfusion dependence, absolute neutrophil count \<1.5x10\^9/L. Erythroid response: Major-\>20g/L increase in hemoglobin or transfusion independence. Minor- 10-20g/L increase in hemoglobin or \>=50% decrease in transfusion requirements. Platelet response: Major-absolute increase of platelet count by \>=30x10\^9/L or platelet transfusion independence. Minor-\>=50% increase in platelet count with net increase \>10x10\^9/L but \<30x10\^9/L. (continued in Population Description)

Number of participants whose best hematological outcome was either complete remission (CR), partial remission (PR) (as determined by the investigator), or any hematologic improvement (based on the IWG 2000 criteria for MDS). See previous outcomes for detailed definitions.

Hematologic response during the maintenance period are compared to the response in the initial study period. Initial response could have been a complete remission, a partial remission, stable disease or a hematologic improvement. Maintenance period best response is after randomization to a maintenance arm for those randomized, and is after the start of cycle 7 for those remaining on initial period treatment throughout the study.

Assessed by the investigator based upon criteria derived from the ECOG 5998 and BNZ-1 clinical trials.

Dose-limiting toxicities (DLTs) are defined as an event that constitute a change from baseline irrespective of outcome and determined by the investigator to be related to treatment. The DLT-evaluable participants were defined as participants who took at least 1 dose of study drug in the Phase 1b Dose-Finding Stage and either had a DLT during Cycle 1 (regardless of amount of study drug exposure), or had no DLT and completed at least 75% of AG-120 or AG-221 doses (21 out of 28 days) and a minimum of 5 doses of AZA, at least 50% of the planned combination doses for AG-120 or AG-221 and AZA administered together (in the same day for 4 out of 7 days) in the first 28 days from C1D1, and were also considered by the Clinical Study Team to have sufficient safety data available to conclude that a DLT did not occur during Cycle 1.

The number of participants experiencing different types of adverse events (AE). An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A Serious Adverse Event (SAE) is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or constitutes an important medical event. Adverse events were analyzed in terms of treatment-emergent AEs (TEAEs). Treatment-emergent adverse events (TEAE) was defined as events that began on or after the start of study drug through 28 days after the last study treatment. The severity/intensity of AEs were graded based upon the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.

The percent of participants with MLFS + CR + CRi + CRp + PR according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria as assessed by investigator. Complete response (CR) and morphologic leukemia-free state (MLFS) are defined as \<5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. Partial remission (PR) is defined as all hematologic criteria of CR with a \>50% decrease in the percentage of BM blasts to 5% to 25%. (\<5% considered if Auer rods are present).

The highest recorded dose administered to a subject if the MTD is not reached

Number of participants with adverse events

The observed maximum concentration

The observed time to first maximum concentration

Area under the concentration-time curve from time zero to the last quantifiable time point calculated by the linear trapezoidal rule

Area under the concentration time-curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity. It will be calculated as AUC∞ = \[AUCt + Ct/λz\]. Ct is the last quantifiable concentration

Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear concentration-time curve

Terminal phase half-life, calculated according to the following equation: t½ = 0.693/λz

Apparent total clearance, calculated as Dose/AUC∞

Apparent volume of distribution, calculated according to the equation: Vd/F = (CL/F) / λz

The observed maximum concentration

The observed time to first maximum concentration

Area under the concentration-time curve from time zero to the last quantifiable time point calculated by the linear trapezoidal rule.

Area under the concentration time-curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity. It will be calculated as AUC∞ = \[AUCt + Ct/λz\]. Ct is the last quantifiable concentration.

Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear concentration-time curve

Terminal phase half-life, calculated according to the following equation: t½ = 0.693/λz

Apparent total clearance, calculated as Dose/AUC∞

Apparent volume of distribution, calculated according to the equation: Vd/F = (CL/F) / λz

A DLT included events that started within 28 days of the first dose of CC-486 in a 28-day cycle, constituted a change from baseline irrespective of outcome, as decided by the investigator to be related to CC-486 including: * ≥ Grade (GR) 3 nausea, diarrhea, or vomiting despite the use of medical support * Other significant nonhematologic toxicity of ≥ GR 3 considered not related to the disease or intercurrent illness • Absolute neutrophil count (ANC) \< 0.5 x 10\^9/L for \> 1 week despite growth factor support * Platelets \< 25 x 10\^9/L for \> 1 week despite transfusion support * Failure of recovery to an ANC ≥ 1.0 x 10\^9/L and/or platelets ≥ 50 x 10\^9/L with a hypocellular marrow by 56 days after the start of a cycle of CC-486 not due to relapse or progressive disease. The maximum tolerated dose is defined as the cohort delivering the highest dose in which no more than 33% of the evaluable subjects had a DLT The safety population included subjects who received ≥ 1 dose of CC-486

A TEAE was defined as any AE with an onset date on or after the first dose of IP or any event already present that worsened in severity or increased in frequency after exposure to IP up to 28 days after the last dose. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.0, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above.

PK-Area under the plasma concentration time curve (AUC)

PK-Terminal half-life (T½)

Observed maximum concentration in plasma (Cmax)

PK-Time to maximum plasma concentration (Tmax)

To evaluate the effect of gastric acid pH modulation, through a proton pump inhibitor, on the PK of oral azacitidine.

An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity.

Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.

The maximum observed plasma concentration of azacitidine after a single dose on Day 1.

The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.

The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.

The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.

The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz)

The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule.

The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment.

The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.

The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment.

The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment.

The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.

The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf.

The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz).

A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: * Results in death; * Is life threatening; * Requires inpatient hospitalization or prolongation of existing hospitalization; * Results in persistent or significant disability/incapacity; * Is a congenital anomaly/birth defect; * Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).