Study of Azacitidine to Evaluate Safety and Effectiveness for Chinese Patients With Higher Risk Myelodysplastic Syndrome

Study Overview
=================
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).

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

Conditions
-----------------
Myelodysplastic Syndrome (MDS)

Intervention / Treatment
-----------------
* Drug: Azacitidine


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine<br>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. | Drug: Azacitidine<br>* 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<br>* Other names: Vidaza;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days | 
| 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. | Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days | 
| 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. | Up to 29 January 2015; 894 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days | 
| 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. | 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) | 
| 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 | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| 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. | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| Maximum Observed Plasma Concentration (Cmax) of Azacitidine | The observed maximum plasma concentration obtained directly from the observed concentration versus time data. | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| Time to Maximum Plasma Concentration (Tmax) of Azacitidine | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| 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. | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| Apparent Total Plasma Clearance (CL/F) of Azacitidine | Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞ | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| Apparent Volume of Distribution (Vd/F) of Azacitidine | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | 
| 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. | 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 |