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

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01599325
• Collaborator: (none)
• Enrollment: 72
• Locations: 11
• Arm: 1
• Actual Duration (Months): 67.6
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.1

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome (MDS)	Drug: Azacitidine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jul 24, 2012
• Actual Primary Completion Date: Jan 29, 2015
• Actual Study Completion Date: Mar 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azacitidine 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; 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; Other Names: Vidaza

Outcome Measures

Primary Outcome Measures

1. 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. [Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days]

   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.

2. Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator [Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days]

   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.

3. 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. [Up to 29 January 2015; 894 days]

   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

1. The Number of Units of Platelet Transfusions by 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]

   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.

2. The Number of Platelet Transfusions by 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]

   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.

3. The Number of Units of Red Blood Cell (RBC) Transfusions by 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]

   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.

4. The Number of RBC Transfusions by 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]

   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.

5. The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by 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]

   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.

6. Kaplan Meier Estimates for Overall Survival (OS) [Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days]

   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.

7. Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase [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)]

   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.

8. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine [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 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

9. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine [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 quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.

10. Maximum Observed Plasma Concentration (Cmax) of Azacitidine [PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7]

    The observed maximum plasma concentration obtained directly from the observed concentration versus time data.

11. Time to Maximum Plasma Concentration (Tmax) of Azacitidine [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 observed plasma concentration obtained directly from the observed concentration versus time data.

12. Terminal Phase of Half-life (T1/2) of Azacitidine [PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7]

    The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz.

13. Apparent Total Plasma Clearance (CL/F) of Azacitidine [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 was calculated as Dose/AUC∞

14. Apparent Volume of Distribution (Vd/F) of Azacitidine [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, was calculated according to the equation: Vd/F = (CL/F)/λz

15. Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase [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]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University People's Hospital	Beijing		China	100044
2	The 301 Hospital- Chinese PLA General Hospital	Beijing		China	300200
3	The Third Hospital of Peking University	Beijing		China
4	West China Hospital of Sichuan University	Chengdu		China	610041
5	Guangdong General Hospital	Guangzhou		China	510080
6	1st Hospital Zhejiang University (The First Affiliated Hospital of Zhejiang University )	Hangzhou		China	310003
7	Ruijin Hospital Shanghai Jiaotong University	Shanghai		China	200025
8	Shanghai 6th Hospital	Shanghai		China	200233
9	The 1st Hospital of Soochow University	Suzhou		China	215006
10	Blood Disease Hospital, Chinese Academy of Medical Science and Peking Union Medical College	Tianjin		China	300041
11	Wuhan Union Hospital	Wuhan		China	430000

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: C L Beach, Celgene

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT01599325
• Other Study ID Numbers: AZA-MDS-002
• First Posted: May 16, 2012
• Last Update Posted: Mar 19, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Azacitidine

Study Results

Participant Flow

Arm/Group Title	Azacitidine
Arm/Group 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.
Period Title: Primary Parent Phase
STARTED	72
Intent to Treat (ITT) Population	72
Pharmacokinetic (PK) Population	12
COMPLETED	15
NOT COMPLETED	57
Period Title: Primary Parent Phase
STARTED	15
COMPLETED	0
NOT COMPLETED	15

Baseline Characteristics

Arm/Group Title	Azacitidine
Arm/Group 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.
Overall Participants	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.3 (11.78)
Sex: Female, Male (Count of Participants)
Female	34 47.2%
Male	38 52.8%
International Prognostic Scoring System (IPSS) Risk Classification (Count of Participants)
Low (0)	0 0%
Intermediate 1 (0.5-1.0)	0 0%
Intermediate 2 (1.5-2.0)	47 65.3%
High (>=2.5)	25 34.7%
French-American-British classification (FAB) (Count of Participants)
RAEB=Refractory anemia with excess blasts	63 87.5%
RAEB in transformation	8 11.1%
Modified CMML=Chronic myelomonocytic leukemia	1 1.4%
MDS World Health Organization (WHO) Classification (Count of Participants)
RAEB-1=Refractory anemia with excess blasts	14 19.4%
RAEB -2 with MPD=Myeloproliferative disease	50 69.4%
Acute Myelogenous Leukemia (AML)	7 9.7%
CMML	1 1.4%
MDS and myeloproliferative disease (MPD)	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Overall CR+PR	1.4 1.9%
Overall CR+PR+SD	95.8 133.1%
Complete Remission (CR)	1.4 1.9%
Partial Remission (PR)	0 0%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Overall CR+PR	12.5 17.4%
Overall CR+PR+SD	70.8 98.3%
CR	6.9 9.6%
PR	5.6 7.8%

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Any improvement	52.8 73.3%
Hematologic Improvement-E (major)	35.8 49.7%
Hematologic Improvement-E (minor)	9.0 12.5%
Hematologic Improvement-P (major)	37.9 52.6%
Hematologic Improvement-P (minor)	0.0 0%
Hematologic Improvement-N (major)	21.8 30.3%
Hematologic Improvement-N (minor)	0.0 0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Baseline N = 72	1.9 (4.91)
Overall Post-Baseline Average N = 72	4.7 (17.79)
Overall Change from Baseline N = 72	2.8 (17.89)
Cycle 1 N = 72	5.2 (18.83)
Cycle 2	2.4 (5.86)
Cycle 3	3.3 (11.44)
Cycle 4	2.7 (6.13)
Cycle 5	2.5 (7.69)
Cycle 6	1.5 (4.15)
Cycle 7	1.0 (2.84)
Cycle 8	1.1 (2.05)
Cycle 9	0.8 (2.46)
Cycle 10	0.8 (2.08)
Cycle 11	0.5 (1.00)
Cycle 12	0.3 (0.78)
Cycle 13	0.3 (0.72)
Cycle 14	0.1 (0.35)
Cycle 15	0.3 (0.90)
Cycle 16	0.3 (0.90)
Cycle 17	0.3 (0.73)
Cycle 18	0.6 (1.51)
Cycle 19	0.3 (0.64)
Cycle 20	0.2 (0.37)
Cycle 21	0.0 (0.00)
Cycle 22	0.0 (NA)
Cycle 23	0.0 (NA)
Cycle 24	0.0 (NA)
Cycle 25	0.0 (NA)
Cycle 26	0.0 (NA)
Cycle 27	0.0 (NA)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Baseline N = 72	0.8 (2.36)
Overall Post-Baseline Average N = 72	1.6 (2.83)
Overall Change from Baseline N = 72	0.8 (3.29)
Cycle 1 N = 72	1.8 (2.89)
Cycle 2	1.3 (2.59)
Cycle 3	1.2 (2.28)
Cycle 4	1.3 (2.18)
Cycle 5	0.9 (1.58)
Cycle 6	0.7 (1.34)
Cycle 7	0.8 (2.50)
Cycle 8	0.8 (1.66)
Cycle 9	0.8 (2.46)
Cycle 10	0.8 (2.08)
Cycle 11	0.5 (1.00)
Cycle 12	0.3 (0.78)
Cycle 13	0.3 (0.72)
Cycle 14	0.1 (0.35)
Cycle 15	0.3 (0.90)
Cycle 16	0.3 (0.90)
Cycle 17	0.3 (0.73)
Cycle 18	0.6 (1.51)
Cycle 19	0.3 (0.64)
Cycle 20	0.2 (0.37)
Cycle 21	0.0 (0.00)
Cycle 22	0.0 (NA)
Cycle 23	0.0 (NA)
Cycle 24	0.0 (NA)
Cycle 25	0.0 (NA)
Cycle 26	0.0 (NA)
Cycle 27	0.0 (NA)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT includes all participants who were enrolled into the study

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Baseline N = 72	2.3 (3.55)
Overall Post-Baseline Average N = 72	3.5 (3.88)
Overall Change from Baseline N = 72	1.2 (4.34)
Cycle 1 N = 72	3.6 (3.41)
Cycle 2	3.6 (4.88)
Cycle 3	3.0 (3.68)
Cycle 4	2.7 (3.73)
Cycle 5	2.5 (3.94)
Cycle 6	2.0 (3.46)
Cycle 7	1.7 (3.84)
Cycle 8	1.7 (2.68)
Cycle 9	0.9 (1.56)
Cycle 10	1.2 (2.25)
Cycle 11	1.3 (1.97)
Cycle 12	1.1 (2.21)
Cycle 13	1.2 (2.62)
Cycle 14	0.4 (1.05)
Cycle 15	1.1 (2.07)
Cycle 16	0.9 (1.61)
Cycle 17	1.2 (3.28)
Cycle 18	1.6 (3.07)
Cycle 19	0.8 (1.37)
Cycle 20	1.1 (1.42)
Cycle 21	0.4 (0.62)
Cycle 22 N	0 (NA)
Cycle 23	0.0 (NA)
Cycle 24	0.0 (NA)
Cycle 25	0.0 (NA)
Cycle 26	0.0 (NA)
Cycle 27	0.0 (NA)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Baseline N = 72	1.1 (1.79)
Overall Post-Baseline Average N = 72	1.6 (1.97)
Overall Change from Baseline N = 72	0.5 (2.12)
Cycle 1 N = 72	1.7 (1.64)
Cycle 2	1.7 (2.56)
Cycle 3	1.4 (1.81)
Cycle 4	1.2 (1.73)
Cycle 5	1.1 (1.81)
Cycle 6	0.9 (1.63)
Cycle 7	0.8 (1.97)
Cycle 8	0.8 (1.23)
Cycle 9	0.4 (0.74)
Cycle 10	0.5 (0.94)
Cycle 11	0.5 (0.78)
Cycle 12	0.4 (0.87)
Cycle 13	0.5 (0.94)
Cycle 14	0.2 (0.53)
Cycle 15	0.4 (0.77)
Cycle 16	0.4 (0.57)
Cycle 17	0.3 (0.91)
Cycle 18	0.7 (1.17)
Cycle 19	0.4 (0.64)
Cycle 20	0.6 (0.71)
Cycle 21	0.2 (0.31)
Cycle 22	0.0 (NA)
Cycle 23	0.0 (NA)
Cycle 24	0.0 (NA)
Cycle 25	0.0 (NA)
Cycle 26	0.0 (NA)
Cycle 27	0.0 (NA)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Baseline N = 72	0.0 (0.20)
Overall Post Baseline Average N = 72	0.6 (1.43)
Overall Change from Baseline N =72	0.5 (1.45)
Cycle 1 N = 72	0.6 (1.32)
Cycle 2	0.5 (1.67)
Cycle 3	0.4 (0.86)
Cycle 4	0.5 (1.03)
Cycle 5	0.4 (0.72)
Cycle 6	0.2 (0.61)
Cycle 7	0.3 (1.01)
Cycle 8	0.2 (0.47)
Cycle 9	0.1 (0.32)
Cycle 10	0.2 (0.44)
Cycle 11	0.1 (0.31)
Cycle12	0.1 (0.27)
Cycle 13	0.1 (0.24)
Cycle 14 15	0.1 (0.32)
Cycle 15	0.3 (0.70)
Cycle 16	0.3 (0.42)
Cycle 17	0.4 (0.75)
Cycle 18	0.4 (0.74)
Cycle 19	0.2 (0.41)
Cycle 20	0.0 (0.00)
Cycle 21	0.0 (0.00)
Cycle 22	0.9 (NA)
Cycle 23	1.0 (NA)
Cycle 24	0.0 (NA)
Cycle 25	0.0 (NA)
Cycle 26 N	0.0 (NA)
Cycle 27	0.0 (NA)

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) includes all participants who were enrolled into the study.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
Median OS	22.0
25th percentile OS	8.5
75th Percentile OS	NA

10. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of azacitidine and had at least one post-dose safety assessment

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	72
≥ 1 TEAE	72 100%
≥ 1 Grade 3 or 4 TEAE	70 97.2%
≥ 1 TEAE related to study drug	68 94.4%
≥ 1 Grade 3 or 4 TEAE related to study drug	59 81.9%
≥ 1 serious TEAE	38 52.8%
≥ 1 Grade 3 or 4 serious TEAE	33 45.8%
≥ 1 serious TEAE related to study drug	28 38.9%
≥ 1 TEAE leading to discontinuation of study drug	14 19.4%
≥ 1 TEAE leading to dose reduction of study drug	19 26.4%
≥1 TEAE leading to dose interruption of study drug	49 68.1%
≥1 TEAE leading to dose reduction/interruption	50 69.4%
≥1 TEAE with outcome of death	11 15.3%

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1172.6 (18.0)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	1161.9 (17.7)

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1264.6 (30.7)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Median (Full Range) [hours]	0.25 (27.66)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [hours]	0.8 (69.0)

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [Liters/hours]	107.2 (19.1)

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [Liters]	121.5 (65.1)

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of azacitidine and had at least one post-dose safety assessment

Arm/Group Title	Azacitidine
Arm/Group 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.
Measure Participants	15
≥ 1 TEAE	14 19.4%
≥ 1 TEAE related to study drug	8 11.1%
≥ 1 Grade 3 or 4 TEAE	13 18.1%
≥ 1 Grade 3 or 4 TEAE related to study drug	6 8.3%
≥ 1 serious TEAE	5 6.9%
≥ 1 serious TEAE related to study drug	1 1.4%
≥ 1 Grade 3 or 4 serious TEAE	5 6.9%
≥1 TEAE leading to dose interruption of study drug	4 5.6%
≥1 TEAE leading to dose reduction/interruption	4 5.6%

Adverse Events

Time Frame	Azacitidine Exposure across all cycles: median duration of azacitidine treatment was 786 days (range 428 to 1507).
Adverse Event Reporting Description	For extension phase: From 29 December 2014 to 28 days after the date of the last dose of study drug; median treatment duration of any dose of azacitidine was 169 days; range: 7 to 1112 days.
Arm/Group Title	Azacitidine - Parent Phase		Azacitdine - Extension Phase
Arm/Group 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.		Azacitidine 75 mg/m^2/day subcutaneously 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
All Cause Mortality
	Azacitidine - Parent Phase		Azacitdine - Extension Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/72 (18.1%)		0/15 (0%)
Serious Adverse Events
	Azacitidine - Parent Phase		Azacitdine - Extension Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/72 (52.8%)		5/15 (33.3%)
Blood and lymphatic system disorders
Agranulocytosis	4/72 (5.6%)		0/15 (0%)
Anaemia	1/72 (1.4%)		2/15 (13.3%)
Bone marrow failure	2/72 (2.8%)		0/15 (0%)
Febrile neutropenia	5/72 (6.9%)		0/15 (0%)
Granulocytopenia	1/72 (1.4%)		0/15 (0%)
Leukopenia	1/72 (1.4%)		0/15 (0%)
Thrombocytopenia	4/72 (5.6%)		1/15 (6.7%)
Erythropenia	0/72 (0%)		1/15 (6.7%)
Cardiac disorders
Atrioventricular block	1/72 (1.4%)		0/15 (0%)
Cardiac failure	2/72 (2.8%)		1/15 (6.7%)
Gastrointestinal disorders
Abdominal pain upper	1/72 (1.4%)		0/15 (0%)
Gastrointestinal haemorrhage	1/72 (1.4%)		0/15 (0%)
Ileus	1/72 (1.4%)		0/15 (0%)
Mouth haemorrhage	3/72 (4.2%)		0/15 (0%)
Enteritis	0/72 (0%)		1/15 (6.7%)
General disorders
Oedema peripheral	1/72 (1.4%)		0/15 (0%)
Pyrexia	3/72 (4.2%)		0/15 (0%)
Immune system disorders
Drug hypersensitivity	1/72 (1.4%)		0/15 (0%)
Infections and infestations
Abdominal infection	1/72 (1.4%)		0/15 (0%)
Abscess limb	1/72 (1.4%)		0/15 (0%)
Anal abscess	1/72 (1.4%)		0/15 (0%)
Anal infection	1/72 (1.4%)		0/15 (0%)
Bronchopneumonia	1/72 (1.4%)		0/15 (0%)
Cellulitis	2/72 (2.8%)		0/15 (0%)
Fungal sepsis	1/72 (1.4%)		0/15 (0%)
Gingival infection	1/72 (1.4%)		0/15 (0%)
Lung infection	2/72 (2.8%)		2/15 (13.3%)
Myelitis	1/72 (1.4%)		0/15 (0%)
Neutropenic infection	1/72 (1.4%)		0/15 (0%)
Pneumonia	11/72 (15.3%)		1/15 (6.7%)
Pneumonia fungal	1/72 (1.4%)		0/15 (0%)
Pneumonia staphylococcal	1/72 (1.4%)		0/15 (0%)
Pulmonary mycosis	1/72 (1.4%)		0/15 (0%)
Respiratory tract infection	1/72 (1.4%)		0/15 (0%)
Sepsis	1/72 (1.4%)		0/15 (0%)
Skin bacterial infection	1/72 (1.4%)		0/15 (0%)
Skin infection	1/72 (1.4%)		0/15 (0%)
Soft tissue infection	1/72 (1.4%)		0/15 (0%)
Upper respiratory tract infection	4/72 (5.6%)		0/15 (0%)
Injury, poisoning and procedural complications
Subdural haematoma	1/72 (1.4%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	1/72 (1.4%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome	1/72 (1.4%)		0/15 (0%)
Pancreatic carcinoma	1/72 (1.4%)		0/15 (0%)
Nervous system disorders
Cerebral haemorrhage	1/72 (1.4%)		0/15 (0%)
Cerebral ischaemia	1/72 (1.4%)		0/15 (0%)
Subarachnoid haemorrhage	1/72 (1.4%)		0/15 (0%)
Renal and urinary disorders
Renal Failure, Acute	0/72 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Hydrothorax	1/72 (1.4%)		0/15 (0%)
Interstitial lung disease	1/72 (1.4%)		0/15 (0%)
Rhinitis Allergic	0/72 (0%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Henoch-Schonlein Purpura	0/72 (0%)		1/15 (6.7%)
Vascular disorders
Shock haemorrhagic	1/72 (1.4%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Azacitidine - Parent Phase		Azacitdine - Extension Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/72 (100%)		14/15 (93.3%)
Blood and lymphatic system disorders
Anaemia	38/72 (52.8%)		6/15 (40%)
Leukopenia	48/72 (66.7%)		10/15 (66.7%)
Neutropenia	48/72 (66.7%)		6/15 (40%)
Thrombocytopenia	52/72 (72.2%)		10/15 (66.7%)
Cardiac disorders
Palpitations	0/72 (0%)		1/15 (6.7%)
Pericardial effusion	0/72 (0%)		1/15 (6.7%)
Eye disorders
Conjunctival haemorrhage	4/72 (5.6%)		1/15 (6.7%)
Gastrointestinal disorders
Abdominal discomfort	8/72 (11.1%)		2/15 (13.3%)
Abdominal distension	4/72 (5.6%)		0/15 (0%)
Abdominal pain	5/72 (6.9%)		0/15 (0%)
Constipation	22/72 (30.6%)		1/15 (6.7%)
Diarrhoea	15/72 (20.8%)		3/15 (20%)
Gingival bleeding	8/72 (11.1%)		1/15 (6.7%)
Mouth ulceration	6/72 (8.3%)		0/15 (0%)
Nausea	19/72 (26.4%)		3/15 (20%)
Toothache	4/72 (5.6%)		0/15 (0%)
Vomiting	15/72 (20.8%)		0/15 (0%)
Dysphagia	0/72 (0%)		1/15 (6.7%)
Haemorrhoids	0/72 (0%)		1/15 (6.7%)
Enteritis	0/72 (0%)		1/15 (6.7%)
General disorders
Asthenia	6/72 (8.3%)		3/15 (20%)
Fatigue	4/72 (5.6%)		0/15 (0%)
Oedema peripheral	9/72 (12.5%)		2/15 (13.3%)
Pyrexia	21/72 (29.2%)		2/15 (13.3%)
Localized Oedema	0/72 (0%)		1/15 (6.7%)
Nodule	0/72 (0%)		1/15 (6.7%)
Hepatobiliary disorders
Hyperbilirubinaemia	4/72 (5.6%)		0/15 (0%)
Hepatic Stenosis	0/72 (0%)		1/15 (6.7%)
Infections and infestations
Cellulitis	4/72 (5.6%)		0/15 (0%)
Gingival infection	5/72 (6.9%)		0/15 (0%)
Gingivitis	16/72 (22.2%)		2/15 (13.3%)
Lung infection	8/72 (11.1%)		1/15 (6.7%)
Pneumonia	19/72 (26.4%)		1/15 (6.7%)
Skin infection	4/72 (5.6%)		1/15 (6.7%)
Upper respiratory tract infection	27/72 (37.5%)		1/15 (6.7%)
Abscess Limb	0/72 (0%)		1/15 (6.7%)
Sinusitis	0/72 (0%)		1/15 (6.7%)
Soft Tissue Infection	0/72 (0%)		1/15 (6.7%)
Urinary Tract Infection	0/72 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Transfusion reaction	6/72 (8.3%)		0/15 (0%)
Spinal Compression Fracture	0/72 (0%)		1/15 (6.7%)
Investigations
Alanine aminotransferase increased	10/72 (13.9%)		2/15 (13.3%)
Aspartate aminotransferase increased	6/72 (8.3%)		2/15 (13.3%)
Weight decreased	12/72 (16.7%)		0/15 (0%)
Bilirubin Conjugated Increased	0/72 (0%)		1/15 (6.7%)
Blood Bilirubin Increased	0/72 (0%)		1/15 (6.7%)
Blood Fibrinogen Decreased	0/72 (0%)		1/15 (6.7%)
Blood Urea Increased	0/72 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
Decreased appetite	6/72 (8.3%)		0/15 (0%)
Hyperglycaemia	8/72 (11.1%)		1/15 (6.7%)
Hypoalbuminaemia	7/72 (9.7%)		2/15 (13.3%)
Hypocalcaemia	4/72 (5.6%)		1/15 (6.7%)
Hypokalaemia	10/72 (13.9%)		3/15 (20%)
Hypoproteinaemia	4/72 (5.6%)		0/15 (0%)
Acidosis	0/72 (0%)		1/15 (6.7%)
Hypercreatininaemia	0/72 (0%)		1/15 (6.7%)
Hyperuricaemia	0/72 (0%)		2/15 (13.3%)
Hyponatraemia	0/72 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/72 (0%)		1/15 (6.7%)
Back Pain	0/72 (0%)		1/15 (6.7%)
Nervous system disorders
Dizziness	5/72 (6.9%)		0/15 (0%)
Psychiatric disorders
Insomnia	12/72 (16.7%)		0/15 (0%)
Renal and urinary disorders
Haemoglobinuria	0/72 (0%)		1/15 (6.7%)
Proteinuria	0/72 (0%)		1/15 (6.7%)
Renal Failure Acute	0/72 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	0/72 (0%)		1/15 (6.7%)
Dysmenorrhoea	0/72 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	7/72 (9.7%)		1/15 (6.7%)
Epistaxis	6/72 (8.3%)		1/15 (6.7%)
Oropharyngeal pain	9/72 (12.5%)		1/15 (6.7%)
Dyspnoea	0/72 (0%)		1/15 (6.7%)
Pleural Effusion	0/72 (0%)		1/15 (6.7%)
Rhinitis allergic	0/72 (0%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Ecchymosis	6/72 (8.3%)		0/15 (0%)
Pruritus	5/72 (6.9%)		0/15 (0%)
Purpura	5/72 (6.9%)		0/15 (0%)
Pain of Skin	0/72 (0%)		1/15 (6.7%)
Rash	0/72 (0%)		1/15 (6.7%)
Skin Ulcer	0/72 (0%)		1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator shall have the right to publish and/or present study data provided that the investigator shall (i) furnish the sponsor a copy of any proposed publication or presentation generally sixty (60) days in advance of the submission, (ii) delete any confidential information of the sponsor, and (iii) delay submission for generally up to ninety (90) days to permit the preparation and filing of intellectual property applications or until sponsor gives its consent in a timely manner.