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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
44
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.
Changhua Christian Hospital
Changhua, Taiwan
Chiayi Chang Gung Memorial Hospital
Chiayi City, Taiwan
Buddhist Tzu Chi General Hospital-Hualien Tzu Chi Medical Center
Hualien City, Taiwan
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
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
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Kaohsiung Medical Hospital University
Kaohsiung City, Taiwan
Kaohsiung Chang Gung Memorial Hospital
Kaohsiung City, Taiwan
Shuang-ho Hospital
New Taipei City, Taiwan
China Medical University Hospital
Taichung, Taiwan
National Cheng Kung University Hospital
Tainan, Taiwan
National Taiwan University Hospital
Taipei, Taiwan
Taipei Veterans General Hospital
Taipei, Taiwan
...and 1 more locations
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.
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.
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.
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)
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
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
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
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
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
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
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