Myelodysplastic Syndromes
Conditions
Keywords
Myelodysplastic Syndromes, Taiwan, Azacitidine, Vidaza, Celgene, Pathologic Processes, Neoplasms, Bone Marrow Diseases, Hematologic Diseases, Antineoplastic Agents, Antimetabolites, Antineoplastic, Antimetabolites, Molecular Mechanisms of Pharmacological Action, Pharmacologic Actions, Therapeutic Uses, Enzyme inhibitors
Brief summary
The primary purpose of this study is to determine the effectiveness and safety of azacitidine in the treatment of Taiwanese subjects with higher-risk Myelodysplastic Syndrome (MDS).
Detailed description
The study has 3 phases which include the Screening Phase, the Treatment Phase, and the Post-Treatment Phase and outlined as follows: Screening Phase: Subjects will provide informed consent prior to undergoing any study-related procedures. Screening procedures are to take place within 28 days prior to the initiation of azacitidine treatment (Day 1, Cycle 1). Subject eligibility will be based on central pathology review. Bone marrow aspirate and bone marrow biopsy will be collected at screening and sent for morphological assessment by a central pathology reviewer prior to the subject receiving IP. The central pathology reviewer will document the MDS classification according to the FAB and WHO criteria (Appendix A and B, respectively). A standard cytogenetic metaphase preparation will be prepared from the bone marrow aspirate and sent to the local or central laboratory (for sites without local analysis capability) for the cytogenetic analysis prior to receiving IP. The IPSS score will be calculated using the central reviewer's pathology report for bone marrow blast percentage, local cytogenetic assessment for karyotype, and central laboratory report for number of cytopenias (Appendix D). Treatment Phase: The first dose of azacitidine for each subject begins on Day 1 of Cycle 1. All subjects will receive azacitidine 75 mg/m2/day SC for 7 days every 28 days for up to 6 cycles, unless they are discontinued from treatment. Visits during the treatment phase are to be scheduled weekly for the first 2 cycles, then every other week for all subsequent cycles throughout the rest of the study. Safety and efficacy measures are to be performed weekly, every other week, every 4 weeks, or at 24 weeks, depending on the procedure. Post-Treatment Phase: All discontinued subjects, regardless of reason for discontinuation, should undergo end-of-study procedures at the time of study discontinuation. Subjects will have a follow-up visit for the collection of adverse events up to 28 days after last IP dose.
Interventions
DRUGAzacitidine
Subjects will receive azacitidine 75 mg/m2/day SC for 7 days every 28 days for up to 6 cycles, unless they are discontinued from the treatment. In addition, subjects may receive best supportive care as needed, including antibiotics and transfusions, per Investigator discretion.
Sponsors
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of RAEB or RAEB-T according to FAB classification for MDS and with an IPSS score of intermediate-2 or high risk or a diagnosis of myelodysplastic CMML per modified FAB criteria. * Taiwanese males and females ≥ 18 years of age * ECOG 0, 1, or 2; * Adequate hepatic and renal organ function
Exclusion criteria
* Previous treatment with azacitidine or decitabine * Malignant disease diagnosed within prior 12 months * Uncorrected red cell folate deficiency or vitamin B12 deficiency * Diagnosis of metastatic disease * Malignant hepatic tumors * Known or suspected hypersensitivity to azacitidine or mannitol * Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS * Treatment with erythropoietin or myeloid growth factors during the 21 days prior to Day 1 of Cycle 1 or androgenic hormones during the 14 days prior to Day 1 of Cycle 1; * Active HIV or viral hepatitis type B or C * Treatment with other investigational drugs within the previous 30 days prior to Day 1 of Cycle 1, or ongoing adverse events from previous treatment with investigational drugs, regardless of the time period; * Pregnant or lactating females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Response assessed at end of cycle 6; through week 24; End of study | Hematologic Response according to the 2000 International Working Group (IWG) response criteria for MDS was based on the Investigators determination and defined as: * Complete Response (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 * Partial Response (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 AML |
| Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Response assessed at end of cycle 6; through week 24; End of study | 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 Overall 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following multiple doses of Azacitidine on Day 7; if possible, the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ was not reported. |
| Time to Maximum Plasma Concentration (Tmax) of Azacitidine | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. |
| Terminal Phase of Half-life (T1/2) of Azacitidine | Timeframe: Day 7 pre-dose at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz. |
| Apparent Total Plasma Clearance (CL/F) of Azacitidine | Timeframe: Days 5 and 6 at predose and Day 7 (pre-dose) at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞ |
| Apparent Volume of Distribution (Vd/F) of Azacitidine | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz |
| Number of Red Blood Cell (RBC) Transfusions by Cycle | Up to week 24;The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | The number of transfusions received 56 days prior to treatment and during study were standardized per 28 days and summarized by cycle for RBCs. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of RBC transfusions per cycle. |
| Number of Platelet Transfusions by Cycle | Up to week 24; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | The number of transfusions received 56 days prior to treatment and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of platelet transfusions per cycle. |
| Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Up to week 24; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | The on-treatment adverse event of infection requiring IV antibiotics, antifungals, or antivirals per 28 days/cycle. The overall post-baseline average is the average of number of infections requiring IV antibiotics or IV antiviral per 28 days/cycle. For each participant the overall post-baseline average was calculated as the average of # of infections requiring IV antibiotics or IV antiviral per 28 days per cycle. |
| Number of Participants With Adverse Events (AE) | From the first dose of study drug through 28 days after completion of/discontinuation from the study (maximum time on study drug 244 days) | An AE that resulted in any of the following outcomes was defined as a serious adverse event (SAE): * Death; * Life-threatening event; * Any inpatient hospitalization or prolongation of existing hospitalization; * Persistent or significant disability or incapacity; * Congenital anomaly or birth defect; * Any other important medical event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Treatment Emergent AEs (TEAE) were defined as AEs with an onset date on or after the first dose of study drug and within 28 days after the date of the last dose. In addition, any AE that occurred beyond this timeframe and that was assessed by the investigator as possibly related to study drug was considered a TEAE. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. |
| Maximum Observed Plasma Concentration (Cmax) of Azacitidine | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose | The observed maximum plasma concentration obtained directly from the observed concentration versus time data. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | A participant was considered platelet transfusion independent at baseline if the participant had no platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26) |
| Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | A participant was considered RBC transfusion-independent at baseline if the participant had no RBC transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no RBC transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12) |
| Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit | A participant was considered transfusion dependent at baseline if the participant had one or more Red Blood Cell transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no transfusions during any 56 consecutive days or more (e.g., Day 1 through 56, Day 2 through 57, etc). Otherwise, they were considered transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12) |
| Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit. | A participant was considered platelet transfusion dependent at baseline if the participant had one or more platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26) |
Countries
Taiwan
Participant flow
Recruitment details
The study was conducted at nine investigational sites within Taiwan. The purpose of the current study was to evaluate the efficacy, safety, and steady-state Pharmacokinetic (PK) profile of subcutaneous (SC) azacitidine given at a dose of 75 mg/m\^2/day for 7 days in Taiwanese participants with higher-risk Myelodysplastic Syndrome (MDS).
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine Azacitidine 75 mg/m\^2/day subcutaneously (SC) for 7 days every 28 days for up to 6 cycles | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 4 |
| Overall Study | Disease progression | 3 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Treatment Failure | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Azacitidine |
|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 11.76 |
| International Prognostic Scoring System (IPSS) High Risk (≥ 2.5) | 26 Participants |
| International Prognostic Scoring System (IPSS) Intermediate-1 (0.5 - 1.0) | 2 Participants |
| International Prognostic Scoring System (IPSS) Intermediate-2 (1.5 - 2.0) | 16 Participants |
| International Prognostic Scoring System (IPSS) Low risk (0) | 0 Participants |
| Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification Acute myelogenous leukemia (AML) | 0 Participants |
| Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification Chronic myelomonocytic leukemia (Modified CMML) | 2 Participants |
| Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification RAEB in transformation | 7 Participants |
| Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification Refractory anemia with excess blasts (RAEB) | 35 Participants |
| Race/Ethnicity, Customized Asian | 44 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 27 Participants |
| World Health Organization (WHO) Classification Acute myelogenous leukemia (AML) | 5 Participants |
| World Health Organization (WHO) Classification Chronic myelomonocytic leukemia (CMML -1) | 1 Participants |
| World Health Organization (WHO) Classification Chronic myelomonocytic leukemia (CMML-2) | 0 Participants |
| World Health Organization (WHO) Classification Myelodysplastic Syndrome - Unclassified (MDS-U) | 0 Participants |
| World Health Organization (WHO) Classification RA with ringed sideroblasts (RARS) | 0 Participants |
| World Health Organization (WHO) Classification Refractory anemia (RA) | 0 Participants |
| World Health Organization (WHO) Classification Refractory anemia with excess blasts (RAEB-1) | 15 Participants |
| World Health Organization (WHO) Classification Refractory anemia with excess blasts (RAEB-2) | 23 Participants |
| World Health Organization (WHO) Classification Refractory Cytopenia Multilineage Dysplasia (RCMD) | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 28 / 44 |
Outcome results
Primary
Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor
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 Overall 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.
Time frame: Response assessed at end of cycle 6; through week 24; End of study
Population: The intention-to-treat (ITT) population was defined as all enrolled participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Any improvement | 50.0 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-E (major) | 31.8 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-E (minor) | 9.1 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-P (major) | 37.8 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-P (minor) | 0 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-N (major) | 7.1 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Hematologic Improvement-N (minor) | 0 percentage of participants |
| Azacitidine | Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor | Progression/relapse after HI | 27.3 percentage of participants |
Primary
Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator
Hematologic Response according to the 2000 International Working Group (IWG) response criteria for MDS was based on the Investigators determination and defined as: * Complete Response (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 * Partial Response (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 AML
Time frame: Response assessed at end of cycle 6; through week 24; End of study
Population: The intention-to-treat (ITT) population was defined as all enrolled participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Overall (CR+PR) | 0 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Overall (CR+PR+SD) | 63.6 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Complete Remission (CR) | 0.0 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Partial Remission (PR) | 0.0 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Stable Disease (SD) | 63.6 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Disease Progression (DP) | 2.3 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Transformation to AML | 4.5 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | Failure | 4.5 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator | No Response Assessed | 25.0 percentage of participants |
Secondary
Apparent Total Plasma Clearance (CL/F) of Azacitidine
Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞
Time frame: Timeframe: Days 5 and 6 at predose and Day 7 (pre-dose) at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Apparent Total Plasma Clearance (CL/F) of Azacitidine | 149.6 L/hr | Geometric Coefficient of Variation 29.6 |
Secondary
Apparent Volume of Distribution (Vd/F) of Azacitidine
Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Time frame: Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Apparent Volume of Distribution (Vd/F) of Azacitidine | 205.3 Liters | Geometric Coefficient of Variation 32.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine
Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following multiple doses of Azacitidine on Day 7; if possible, the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ was not reported.
Time frame: Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine | 859.1 ng*h/mL | Geometric Coefficient of Variation 23.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine
Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Time frame: Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine | 852.8 ng*h/mL | Geometric Coefficient of Variation 23.3 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Azacitidine
The observed maximum plasma concentration obtained directly from the observed concentration versus time data.
Time frame: Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Maximum Observed Plasma Concentration (Cmax) of Azacitidine | 972.3 ng/mL | Geometric Coefficient of Variation 44 |
Secondary
Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days
The on-treatment adverse event of infection requiring IV antibiotics, antifungals, or antivirals per 28 days/cycle. The overall post-baseline average is the average of number of infections requiring IV antibiotics or IV antiviral per 28 days/cycle. For each participant the overall post-baseline average was calculated as the average of # of infections requiring IV antibiotics or IV antiviral per 28 days per cycle.
Time frame: Up to week 24; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: The intent-to-treat (ITT) population was defined as all enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Baseline | 0.1 Infections per cycle | Standard Deviation 0.51 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Overall Post Baseline | 0.5 Infections per cycle | Standard Deviation 0.79 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Overall Change from Baseline | 0.4 Infections per cycle | Standard Deviation 0.98 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 1 | 0.5 Infections per cycle | Standard Deviation 0.85 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 2 | 0.4 Infections per cycle | Standard Deviation 0.61 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 3 | 0.4 Infections per cycle | Standard Deviation 0.82 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 4 | 0.1 Infections per cycle | Standard Deviation 0.39 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 5 | 0.1 Infections per cycle | Standard Deviation 0.38 |
| Azacitidine | Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days | Cycle 6 | 0.2 Infections per cycle | Standard Deviation 0.66 |
Secondary
Number of Participants With Adverse Events (AE)
An AE that resulted in any of the following outcomes was defined as a serious adverse event (SAE): * Death; * Life-threatening event; * Any inpatient hospitalization or prolongation of existing hospitalization; * Persistent or significant disability or incapacity; * Congenital anomaly or birth defect; * Any other important medical event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Treatment Emergent AEs (TEAE) were defined as AEs with an onset date on or after the first dose of study drug and within 28 days after the date of the last dose. In addition, any AE that occurred beyond this timeframe and that was assessed by the investigator as possibly related to study drug was considered a TEAE.
Time frame: From the first dose of study drug through 28 days after completion of/discontinuation from the study (maximum time on study drug 244 days)
Population: Safety Population included enrolled participants who received at least one dose of investigational product and had at least one postdose assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 TEAE | 44 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 NCI Grade 3 or 4 TEAE | 37 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ TEAE related to study drug | 34 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 NCI Grade 3 or 4 TEAE related to study drug | 22 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 serious TEAE | 28 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 NCI CTC Grade 3 or 4 serious TEAE | 24 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | ≥ 1 serious TEAE related to study drug | 14 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | TEAE leading to discontinuation of study drug | 8 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | TEAE leading to study drug dose reduction | 7 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | TEAE leading to study drug dose interruption | 16 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | TEAE leading to dose reduction or interruption | 20 participants |
| Azacitidine | Number of Participants With Adverse Events (AE) | TEAE leading to death | 7 participants |
Secondary
Number of Platelet Transfusions by Cycle
The number of transfusions received 56 days prior to treatment and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of platelet transfusions per cycle.
Time frame: Up to week 24; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: The intent-to-treat (ITT) population was defined as all enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | Number of Platelet Transfusions by Cycle | Baseline ( N = 44) | 0.9 Transfusions | Standard Deviation 2.4 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Overall Post-Baseline Average ( N= 44) | 2.7 Transfusions | Standard Deviation 3.56 |
| Azacitidine | Number of Platelet Transfusions by Cycle | OverallChange from Baseline ( N = 44) | 1.8 Transfusions | Standard Deviation 3.53 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 1 ( N = 44) | 2.6 Transfusions | Standard Deviation 3.38 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 2 | 2.3 Transfusions | Standard Deviation 3.28 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 3 | 3.0 Transfusions | Standard Deviation 4.85 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 4 | 1.6 Transfusions | Standard Deviation 2.89 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 5 | 1.9 Transfusions | Standard Deviation 3.61 |
| Azacitidine | Number of Platelet Transfusions by Cycle | Cycle 6 | 2.7 Transfusions | Standard Deviation 6.01 |
Secondary
Number of Red Blood Cell (RBC) Transfusions by Cycle
The number of transfusions received 56 days prior to treatment and during study were standardized per 28 days and summarized by cycle for RBCs. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of RBC transfusions per cycle.
Time frame: Up to week 24;The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: ITT Population- The intent-to-treat (ITT) population was defined as all enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Baseline (N = 44) | 1.3 Transfusions | Standard Deviation 1.97 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Overall Post-Baseline Average (N = 44) | 2.4 Transfusions | Standard Deviation 2.47 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | overall Change from Baseline ( N = 44) | 1.0 Transfusions | Standard Deviation 2.59 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 1 ( N = 44) | 2.5 Transfusions | Standard Deviation 2.27 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 2 | 2.3 Transfusions | Standard Deviation 2.03 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 3 | 2.2 Transfusions | Standard Deviation 2.9 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 4 | 1.5 Transfusions | Standard Deviation 2.11 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 5 | 1.4 Transfusions | Standard Deviation 2.59 |
| Azacitidine | Number of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 6 | 1.9 Transfusions | Standard Deviation 3.96 |
Secondary
Terminal Phase of Half-life (T1/2) of Azacitidine
The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz.
Time frame: Timeframe: Day 7 pre-dose at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Terminal Phase of Half-life (T1/2) of Azacitidine | 1.0 hours | Geometric Coefficient of Variation 38.7 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Azacitidine
Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.
Time frame: Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose
Population: The PK population includes all participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Time to Maximum Plasma Concentration (Tmax) of Azacitidine | 0.29 hours | Geometric Coefficient of Variation 27.65 |
Other Pre-specified
Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline
A participant was considered platelet transfusion dependent at baseline if the participant had one or more platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26)
Time frame: Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: The intent-to-treat (ITT) population who were transfusion dependent
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline Dependent; On-Treatment Independent | 38.9 percentage of participants |
| Azacitidine | Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline Dependent; On-Treatment Dependent | 61.1 percentage of participants |
Other Pre-specified
Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline
A participant was considered platelet transfusion independent at baseline if the participant had no platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26)
Time frame: Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: The intent-to-treat (ITT) participants who were transfusion independent
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline Independent: On-Treatment Independent | 76.9 percentage of particpants |
| Azacitidine | Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline Independent; On-Treatment Dependent | 23.1 percentage of particpants |
Other Pre-specified
Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline
A participant was considered transfusion dependent at baseline if the participant had one or more Red Blood Cell transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no transfusions during any 56 consecutive days or more (e.g., Day 1 through 56, Day 2 through 57, etc). Otherwise, they were considered transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12)
Time frame: Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit
Population: The intent-to-treat (ITT) participants who were transfusion dependent
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Azacitidine | Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline Dependent: On-Treatment Independent | 37.5 percentage of participants | 95% Confidence Interval 1.97 |
| Azacitidine | Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline | Baseline Dependent; On-Treatment Dependent | 62.5 percentage of participants | 95% Confidence Interval 2.47 |
Other Pre-specified
Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline
A participant was considered RBC transfusion-independent at baseline if the participant had no RBC transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no RBC transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered transfusion dependent. The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12)
Time frame: Baseline to Cycle 6; The on-treatment period was considered the period from the date of the first dose to the last treatment study visit.
Population: The Intent to Treat (ITT) participants who were transfusion independent
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline Independent; On-Treatment Independent | 75.0 percentage of participants |
| Azacitidine | Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline | Baseline Independent; On-Treatment Dependent | 25.0 percentage of participants |