Study of Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Phase 4, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes.

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-Arm<br>Azacitidine 75 mg/m^2/day Subcutaneous for 7 days Day every 28 days for up to 6 cycles | Drug: Azacitidine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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: 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 | 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: Erythroid response (HI-E): Major >20g/L increase or transfusion independent. Minor- 10-20g/L increase or ≥50% decrease in transfusion requirements. Platelet response (HI-P): Major absolute increase of ≥30x10^9/L or platelet transfusion independence. Minor-≥50% increase. 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 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. | Response assessed at end of cycle 6; through week 24; End of study | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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): 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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