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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Single-Arm | Experimental | Azacitidine 75 mg/m^2/day Subcutaneous for 7 days Day every 28 days for up to 6 cycles |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azacitidine | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
| Response assessed at end of cycle 6; through week 24; End of study |
| 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:
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. | Response assessed at end of cycle 6; through week 24; End of study |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| C L Beach, PharmD | Celgene | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Changhua Christian Hospital | Changhua | 500 | Taiwan | |||
| Chiayi Chang Gung Memorial Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28124500 | Background | Chou WC, Yeh SP, Hsiao LT, Lin SF, Chen YC, Chen TY, Laille E, Galettis A, Dong Q, Songer S, Beach CL. Efficacy, safety, and pharmacokinetics of subcutaneous azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Asia Pac J Clin Oncol. 2017 Oct;13(5):e430-e439. doi: 10.1111/ajco.12659. Epub 2017 Jan 25. |
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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).
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| ID | Title | Description |
|---|---|---|
| FG000 | Azacitidine | Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days for up to 6 cycles |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The intention-to-treat (ITT) population was defined as all enrolled participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Azacitidine | Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days for up to 6 cycles |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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:
| The intention-to-treat (ITT) population was defined as all enrolled participants | Posted | Number | 95% Confidence Interval | percentage of participants | Response assessed at end of cycle 6; through week 24; End of study |
From the first dose of study drug through 28 days after completion of/discontinuation from the study (maximum time on study drug 244 days)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Azacitidine | Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days for up to 6 cycles |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Anne McClain | Celgene Corporation | 1-888-260-1599 | clinicaltrialdisclosure@celgene.com |
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| ID | Term |
|---|---|
| D009190 | Myelodysplastic Syndromes |
| D010335 | Pathologic Processes |
| D009369 | Neoplasms |
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| ID | Term |
|---|---|
| D006425 | Hemic and Lymphatic Diseases |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D001374 | Azacitidine |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
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|
| 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. |
| 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. | 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. |
| 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. | 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. |
| 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):
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. | From the first dose of study drug through 28 days after completion of/discontinuation from the study (maximum time on study drug 244 days) |
| 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. | 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 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. | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
| Maximum Observed Plasma Concentration (Cmax) of Azacitidine | The observed maximum plasma concentration obtained directly from the observed concentration versus time data. | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
| Time to Maximum Plasma Concentration (Tmax) of Azacitidine | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
| 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. | Timeframe: 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 | Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞ | 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 Volume of Distribution (Vd/F) of Azacitidine | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
| 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 |
| 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) | 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. |
| 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) | 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. |
| 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) | 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. |
| Chiayi City |
| 613 |
| Taiwan |
| Buddhist Tzu Chi General Hospital-Hualien Tzu Chi Medical Center | Hualien City | 970 | Taiwan |
| Kaohsiung Medical Hospital University | Kaohsiung City | 807 | Taiwan |
| Kaohsiung Chang Gung Memorial Hospital | Kaohsiung City | 833 | Taiwan |
| Shuang-ho Hospital | New Taipei City | 23561 | Taiwan |
| China Medical University Hospital | Taichung | 404 | Taiwan |
| National Cheng Kung University Hospital | Tainan | 704 | Taiwan |
| National Taiwan University Hospital | Taipei | 10002 | Taiwan |
| Taipei Veterans General Hospital | Taipei | 11217 | Taiwan |
| Tri-Service General Hospital | Taipei | 11490 | Taiwan |
| Death |
|
| Treatment Failure |
|
| Physician Decision |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Taiwanese origin | Count of Participants | Participants |
|
| Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification | FAB is a classification system for five (5) subtypes of myelodysplastic syndrome that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts or a monocytosis. Classification was made by the Local Reviewer. | Count of Participants | Participants |
|
| World Health Organization (WHO) Classification | The World Health Organization (WHO) classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q. | Count of Participants | Participants |
|
| International Prognostic Scoring System (IPSS) | The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis. The assessment was performed by the local investigator | Count of Participants | Participants |
|
|
|
|
| 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:
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. | The intention-to-treat (ITT) population was defined as all enrolled participants | Posted | Number | 95% Confidence Interval | percentage of participants | Response assessed at end of cycle 6; through week 24; End of study |
|
|
|
| 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) | The intent-to-treat (ITT) participants who were transfusion dependent | Posted | Number | 95% Confidence Interval | percentage of participants | 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 |
|
|
|
| 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) | The Intent to Treat (ITT) participants who were transfusion independent | Posted | Number | 95% Confidence Interval | percentage of participants | 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. |
|
|
|
| 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. | ITT Population- The intent-to-treat (ITT) population was defined as all enrolled participants. | Posted | Mean | Standard Deviation | Transfusions | 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. |
|
|
|
| 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) | The intent-to-treat (ITT) population who were transfusion dependent | Posted | Number | 95% Confidence Interval | percentage of participants | 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. |
|
|
|
| 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) | The intent-to-treat (ITT) participants who were transfusion independent | Posted | Number | 95% Confidence Interval | percentage of particpants | 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. |
|
|
|
| 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. | The intent-to-treat (ITT) population was defined as all enrolled participants. | Posted | Mean | Standard Deviation | Transfusions | 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. |
|
|
|
| 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. | The intent-to-treat (ITT) population was defined as all enrolled participants. | Posted | Mean | Standard Deviation | Infections per 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. |
|
|
|
| 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):
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. | Safety Population included enrolled participants who received at least one dose of investigational product and had at least one postdose assessment | Posted | Number | participants | From the first dose of study drug through 28 days after completion of/discontinuation from the study (maximum time on study drug 244 days) |
|
|
|
| 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. | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| 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. | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Azacitidine | The observed maximum plasma concentration obtained directly from the observed concentration versus time data. | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| Secondary | Time to Maximum Plasma Concentration (Tmax) of Azacitidine | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| 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. | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Timeframe: Day 7 pre-dose at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| Secondary | Apparent Total Plasma Clearance (CL/F) of Azacitidine | Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞ | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/hr | 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 |
|
|
|
| Secondary | Apparent Volume of Distribution (Vd/F) of Azacitidine | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz | The PK population includes all participants with evaluable azacitidine plasma PK profile. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Timeframe: Day 7 pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8 hours post-dose |
|
|
|
| 28 |
| 44 |
| 44 |
| 44 |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Splenic infarction | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA 15.1 | Systematic Assessment |
|
| Cardiac failure congestive | Cardiac disorders | MedDRA 15.1 | Systematic Assessment |
|
| Caecitis | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Colitis | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Enteritis | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Ileitis | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pancreatitis acute | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Cholecystitis acute | Hepatobiliary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Abdominal infection | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Anal abscess | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Biliary tract infection | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Enterobacter infection | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Epiglottitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Liver abscess | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Postoperative wound infection | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Septic shock | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Soft tissue infection | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Subdiaphragmatic abscess | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Subdural haemorrhage | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Hyperglycaemic hyperosmolar nonketotic syndrome | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Acute monocytic leukaemia | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 15.1 | Systematic Assessment |
|
| Tumour associated fever | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 15.1 | Systematic Assessment |
|
| Cerebellar haemorrhage | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Haemorrhage intracranial | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Sciatica | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Acute pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pneumonia aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Conjunctivitis | Eye disorders | MedDRA 15.1 | Systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA 15.1 | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Gingival bleeding | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Lip ulceration | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Melaena | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Feeling cold | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Injection site pain | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Malaise | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Gingivitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Periodontitis | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Allergic transfusion reaction | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Transfusion reaction | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Haemochromatosis | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 15.1 | Systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
|
Multicenter publication must include input from all Investigators involved in the study and Sponsor before its publication; it has priority over subset (single center) publication during 1 year after study completion; Each Investigator has publication rights after multicenter publication is submitted or 1 year after study completion. Sponsor has the right to comment on the publication and ask for a 90-day delay to protect its intellectual property and/or deletion of any confidential information.
| D011743 |
| Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
|
| Hematologic Improvement-P (major) |
|
| Hematologic Improvement-P (minor) |
|
| Hematologic Improvement-N (major) |
|
| Hematologic Improvement-N (minor) |
|
| Progression/relapse after HI |
|
|
| overall Change from Baseline ( N = 44) |
|
|
| Cycle 1 ( N = 44) |
|
|
| Cycle 2 |
|
|
| Cycle 3 |
|
|
| Cycle 4 |
|
|
| Cycle 5 |
|
|
| Cycle 6 |
|
|
|
| OverallChange from Baseline ( N = 44) |
|
|
| Cycle 1 ( N = 44) |
|
|
| Cycle 2 |
|
|
| Cycle 3 |
|
|
| Cycle 4 |
|
|
| Cycle 5 |
|
|
| Cycle 6 |
|
|
| Title | Measurements |
|---|---|
|
| Cycle 1 |
|
| Cycle 2 |
|
| Cycle 3 |
|
| Cycle 4 |
|
| Cycle 5 |
|
| Cycle 6 |
|
| Title | Measurements |
|---|---|
|
| ≥ 1 NCI Grade 3 or 4 TEAE related to study drug |
|
| ≥ 1 serious TEAE |
|
| ≥ 1 NCI CTC Grade 3 or 4 serious TEAE |
|
| ≥ 1 serious TEAE related to study drug |
|
| TEAE leading to discontinuation of study drug |
|
| TEAE leading to study drug dose reduction |
|
| TEAE leading to study drug dose interruption |
|
| TEAE leading to dose reduction or interruption |
|
| TEAE leading to death |
|