Back to resultsStudy of Azacitidine to Evaluate Safety and Effectiveness for Chinese Patients With Higher Risk Myelodysplastic Syndrome
Primary Purpose
Myelodysplastic Syndrome (MDS)
Status
Completed
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome (MDS)
Eligibility Criteria
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
- Chinese males and females of Asian descent ≥ 18 years of age at the time of signing the informed consent document;
Must have a documented diagnosis of refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T) according to French-American-British (FAB) classification for Myelodysplastic Syndrome (MDS) and with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk or a diagnosis of myelodysplastic chronic myelomonocytic leukemia (CMML) per modified FAB criteria meeting the following:
- Monocytosis in peripheral blood > 1 x 10^9/L;
- Dysplasia in one or more myeloid cell lines;
- 10% to 29% blasts in the bone marrow; and White blood cell (WBC) count < 13 x 10^9/L
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ;
- Adequate organ function, defined as:
- Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN);
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 times the ULN;
- Serum Creatinine ≤ 1.5 times the ULN;
- Females of childbearing potential (FCBP) must:
- Agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine; and
- for 3 months following the last dose of azacitidine; and have a negative serum pregnancy test within 72 hours prior to starting Investigational Product (IP).
- Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine;
- Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted;
- Able to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
- Previous treatment with azacitidine or decitabine;
- Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, "in-situ" carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure);
- Uncorrected red cell folate deficiency or vitamin B12 deficiency;
- Diagnosis of metastatic disease;
- Malignant hepatic tumors;
- Known or suspected hypersensitivity to azacitidine or mannitol;
- Candidate to proceed to bone marrow or stem cell transplant during the study;
- Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS;
- Treatment with erythropoietin or myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) during the 21 days prior to Day 1 of Cycle 1;
- Treatment with androgenic hormones during the 14 days prior to Day 1 of Cycle 1;
- Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C;
- Treatment with other investigational drugs, including thalidomide and arsenic trioxide, 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; and
- Pregnant or lactating females;
- Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study;
- Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study;
- Any condition that confounds the ability to interpret data from the study.
Sites / Locations
- Peking University People's Hospital
- The 301 Hospital- Chinese PLA General Hospital
- The Third Hospital of Peking University
- West China Hospital of Sichuan University
- Guangdong General Hospital
- 1st Hospital Zhejiang University (The First Affiliated Hospital of Zhejiang University )
- Ruijin Hospital Shanghai Jiaotong University
- Shanghai 6th Hospital
- The 1st Hospital of Soochow University
- Blood Disease Hospital, Chinese Academy of Medical Science and Peking Union Medical College
- Wuhan Union Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Azacitidine
Arm Description
Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days until disease progression (DP), adverse events (AE), withdrawal of consent from further treatment, withdrawal of consent, death, lost to follow-up, or protocol violation.
Outcomes
Primary Outcome Measures
Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.5x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.5x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major >20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of >0.5x10^9/L. Minor: ≥100% increase and absolute increase of <0.5x10^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin <100g/L or RBC transfusion-dependent, platelet count <100x10^9/L or platelet transfusion dependent, absolute neutrophil count <1.5x10^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI.
Secondary Outcome Measures
The Number of Units of Platelet Transfusions by Cycle
The number of units of platelet transfusions received 56 days prior to treatment, considered the baseline period, (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
The Number of Platelet Transfusions by Cycle
The number of platelet transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle
The number of units of RBC received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for RBC. 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.
The Number of RBC Transfusions by Cycle
The number of RBC transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle
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.
Kaplan Meier Estimates for Overall Survival (OS)
Overall survival is defined as time to death from any cause, is calculated using date of first dose and date of death, or date of last follow-up for censored participants. Those, who die regardless of the cause of death, will be considered to have an event.
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
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 will be performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ will not be reported
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.
Maximum Observed Plasma Concentration (Cmax) of Azacitidine
The observed maximum plasma concentration obtained directly from the observed concentration versus time data.
Time to Maximum Plasma Concentration (Tmax) of Azacitidine
Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.
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.
Apparent Total Plasma Clearance (CL/F) of Azacitidine
Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞
Apparent Volume of Distribution (Vd/F) of Azacitidine
Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01599325
Brief Title
Study of Azacitidine to Evaluate Safety and Effectiveness for Chinese Patients With Higher Risk Myelodysplastic Syndrome
Official Title
A Phase 2, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Azacitidine in Adult Chinese Subjects With Higher-Risk Myelodysplastic Syndromes
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
July 24, 2012 (Actual)
Primary Completion Date
January 29, 2015 (Actual)
Study Completion Date
March 13, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Celgene
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of the study is to determine whether azacitidine is safe and effective in the treatment of Chinese patients with higher risk Myelodysplastic Syndromes (MDS).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome (MDS)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
72 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Azacitidine
Arm Type
Experimental
Arm Description
Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days until disease progression (DP), adverse events (AE), withdrawal of consent from further treatment, withdrawal of consent, death, lost to follow-up, or protocol violation.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
Subcutaneous administration of azacitidine 75 mg/m^2/day for 7 days every 28 days optimally for at least 6 cycles until disease progression, unacceptable toxicity, or treatment discontinuation for any other reason
Primary Outcome Measure Information:
Title
Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Description
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.5x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Time Frame
Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Title
Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator
Description
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows <5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (>110 g/L), neutrophils (≥1.5x10^9/L), platelets (≥100x10^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Time Frame
Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Title
Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Description
Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major >20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of >0.5x10^9/L. Minor: ≥100% increase and absolute increase of <0.5x10^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin <100g/L or RBC transfusion-dependent, platelet count <100x10^9/L or platelet transfusion dependent, absolute neutrophil count <1.5x10^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI.
Time Frame
Up to 29 January 2015; 894 days
Secondary Outcome Measure Information:
Title
The Number of Units of Platelet Transfusions by Cycle
Description
The number of units of platelet transfusions received 56 days prior to treatment, considered the baseline period, (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
Time Frame
Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Title
The Number of Platelet Transfusions by Cycle
Description
The number of platelet transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
Time Frame
Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Title
The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle
Description
The number of units of RBC received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for RBC. 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.
Time Frame
Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Title
The Number of RBC Transfusions by Cycle
Description
The number of RBC transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) 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.
Time Frame
Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Title
The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle
Description
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.
Time Frame
Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Title
Kaplan Meier Estimates for Overall Survival (OS)
Description
Overall survival is defined as time to death from any cause, is calculated using date of first dose and date of death, or date of last follow-up for censored participants. Those, who die regardless of the cause of death, will be considered to have an event.
Time Frame
Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days
Title
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase
Description
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
Time Frame
Up to 29 January 2015; from the first dose of study drug to 28 days after the date of the last dose of study drug (maximum time on study was 244 days)
Title
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine
Description
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 will be performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ will not be reported
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine
Description
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
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Maximum Observed Plasma Concentration (Cmax) of Azacitidine
Description
The observed maximum plasma concentration obtained directly from the observed concentration versus time data.
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Time to Maximum Plasma Concentration (Tmax) of Azacitidine
Description
Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Terminal Phase of Half-life (T1/2) of Azacitidine
Description
The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz.
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Apparent Total Plasma Clearance (CL/F) of Azacitidine
Description
Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Apparent Volume of Distribution (Vd/F) of Azacitidine
Description
Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Time Frame
PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Title
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase
Description
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
Time Frame
Up to final data cut off date of 25 April 2018; from the first dose of study drug extesnion of 29 December 2014 to 28 days after the date of the last dose of study drug; median duration of any dose of study drug was 169 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
Chinese males and females of Asian descent ≥ 18 years of age at the time of signing the informed consent document;
Must have a documented diagnosis of refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T) according to French-American-British (FAB) classification for Myelodysplastic Syndrome (MDS) and with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk or a diagnosis of myelodysplastic chronic myelomonocytic leukemia (CMML) per modified FAB criteria meeting the following:
Monocytosis in peripheral blood > 1 x 10^9/L;
Dysplasia in one or more myeloid cell lines;
10% to 29% blasts in the bone marrow; and White blood cell (WBC) count < 13 x 10^9/L
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ;
Adequate organ function, defined as:
Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN);
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 times the ULN;
Serum Creatinine ≤ 1.5 times the ULN;
Females of childbearing potential (FCBP) must:
Agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine; and
for 3 months following the last dose of azacitidine; and have a negative serum pregnancy test within 72 hours prior to starting Investigational Product (IP).
Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine;
Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted;
Able to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
Previous treatment with azacitidine or decitabine;
Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, "in-situ" carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure);
Uncorrected red cell folate deficiency or vitamin B12 deficiency;
Diagnosis of metastatic disease;
Malignant hepatic tumors;
Known or suspected hypersensitivity to azacitidine or mannitol;
Candidate to proceed to bone marrow or stem cell transplant during the study;
Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS;
Treatment with erythropoietin or myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) during the 21 days prior to Day 1 of Cycle 1;
Treatment with androgenic hormones during the 14 days prior to Day 1 of Cycle 1;
Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C;
Treatment with other investigational drugs, including thalidomide and arsenic trioxide, 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; and
Pregnant or lactating females;
Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study;
Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study;
Any condition that confounds the ability to interpret data from the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
C L Beach
Organizational Affiliation
Celgene
Official's Role
Study Director
Facility Information:
Facility Name
Peking University People's Hospital
City
Beijing
ZIP/Postal Code
100044
Country
China
Facility Name
The 301 Hospital- Chinese PLA General Hospital
City
Beijing
ZIP/Postal Code
300200
Country
China
Facility Name
The Third Hospital of Peking University
City
Beijing
Country
China
Facility Name
West China Hospital of Sichuan University
City
Chengdu
ZIP/Postal Code
610041
Country
China
Facility Name
Guangdong General Hospital
City
Guangzhou
ZIP/Postal Code
510080
Country
China
Facility Name
1st Hospital Zhejiang University (The First Affiliated Hospital of Zhejiang University )
City
Hangzhou
ZIP/Postal Code
310003
Country
China
Facility Name
Ruijin Hospital Shanghai Jiaotong University
City
Shanghai
ZIP/Postal Code
200025
Country
China
Facility Name
Shanghai 6th Hospital
City
Shanghai
ZIP/Postal Code
200233
Country
China
Facility Name
The 1st Hospital of Soochow University
City
Suzhou
ZIP/Postal Code
215006
Country
China
Facility Name
Blood Disease Hospital, Chinese Academy of Medical Science and Peking Union Medical College
City
Tianjin
ZIP/Postal Code
300041
Country
China
Facility Name
Wuhan Union Hospital
City
Wuhan
ZIP/Postal Code
430000
Country
China
12. IPD Sharing Statement
Learn more about this trial
Study of Azacitidine to Evaluate Safety and Effectiveness for Chinese Patients With Higher Risk Myelodysplastic Syndrome
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