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RENAL: Pharmacokinetics and Safety Study of Azacitidine in Cancer Patients With and Without Impaired Renal Function

Sponsor
Celgene (Industry)
Overall Status
Completed
CT.gov ID
NCT00652626
Collaborator
(none)
31
Enrollment
11
Locations
5
Arms
44
Actual Duration (Months)
2.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate three things. The first being whether azacitidine is absorbed in the body at the same rate or proportion for different concentrations. The second is to determine the effect renal impairment has or does not have on the absorption of azacitidine. The third is to determine if azacitidine is safe and well tolerated in patients with renal function impairment.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
31 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Phase 1, Open-Label, Multi-Center, Parallel Group Study to the Pharmacokinetics and Safety of Subcutaneous Azacitidine in Adult Cancer Patients With and Without Impaired Renal Function
Actual Study Start Date :
Nov 1, 2008
Actual Primary Completion Date :
Jul 1, 2012
Actual Study Completion Date :
Jul 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Azacitidine 25 mg/m^2

Participants with normal renal function received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle.

Drug: azacitidine
Other Names:
  • Vidaza

    		•
    Experimental: Azacitidine 50 mg/m^2

    Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle.

    Drug: azacitidine
    Other Names:
  • Vidaza

    		•
    Experimental: Azacitidine 75 mg/m^2

    Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle.

    Drug: azacitidine
    Other Names:
  • Vidaza

    		•
    Experimental: Azacitidine 100 mg/m^2

    Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle.

    Drug: azacitidine
    Other Names:
  • Vidaza

    		•
    Experimental: Severe RI: azacitidine 75 mg/m^2

    Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants could continue treatment in the extension phase, which allowed up to 6 cycles of treatment with 75 mg/m^2 daily on Days 1-7 of each 28-day cycle.

    Drug: azacitidine
    Other Names:
  • Vidaza

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

    2. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.

    3. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.

    4. Maximum Plasma Concentration of Azacitidine (Cmax) [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The maximum observed plasma concentration of azacitidine after a single dose on Day 1.

    5. Time to Maximum Plasma Concentration of Azacitidine (Tmax) [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.

    6. Terminal Phase Half-life of Azacitidine (t½) [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.

    7. Apparent Total Clearance of Azacitidine (CL/F) [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.

    8. Apparent Volume of Distribution of Azacitidine (Vz/F) [Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz)

    9. Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule.

    10. Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment.

    11. Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.

    12. Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment.

    13. Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment.

    14. Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.

    15. Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf.

    16. Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine [Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose]

      The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz).

    17. Number of Participants With Adverse Events (AEs) [Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months).]

      A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: Results in death; Is life threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).

    Eligibility Criteria

    Criteria

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

    • Diagnosis of one of the following:

    • MDS according to the French-American-British (FAB) classification system: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML); or

    • Acute myelogenous leukemia (AML) in remission,

    • Malignant solid tumor,

    • Multiple myeloma (MM),

    • Non-Hodgkin lymphoma (NHL), or

    • Hodgkin lymphoma (HD)

    • Patients with a history of treated brain metastases should be clinically stable for greater than 4 weeks prior to signing the informed consent form and off glucocorticoid therapy for central nervous system (CNS) edema for at least 4 weeks

    • Be capable of giving informed consent

    • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

    • Have a life expectancy ≥ 3 months

    • Have stable renal function for at least 2 months

    • Have average calculated creatinine clearance of:

    • 80 mL/min/1.73m^2 for Cohorts 1, 2, 3, and 4

    • <30 mL/min/1.73m^2 for Cohort 5 - Severe renal impairment,

    • 50-80 mL/min/1.73m^2 for Cohort 6 - Mild renal impairment,

    • 30 to <50 mL/min/1.73m^2 for Cohort 7 - Moderate renal impairment

    • Have organ and marrow function at the screening and pre-dose visits as defined below:

    • Hemoglobin ≥8 g/dL,

    • Absolute neutrophil count ≥0.75 x 10^3/µL,

    • Platelets ≥30 x 10^3/µL,

    • Total bilirubin ≤1.5 times the upper limit of normal (ULN),

    • Aspartate aminotransferase (AST) ≤2 times the ULN, and

    • Alanine transaminase (ALT) ≤2 times the ULN;

    • Have a 12-lead electrocardiogram (ECG) that is not clinically significant, as determined by the Investigator, at screening

    • Have serum bicarbonate:

    • 20 mEq/L for patients with normal renal function (cohorts 1, 2, 3 and 4),

    • 16 mEq/L for patients with impaired renal function (cohorts 5, 6 and 7)

    • Women of childbearing potential may participate, providing are not pregnant and agree to use at least 2 effective contraceptive methods throughout the study

    • Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and to avoid fathering a child for 6 months following the date of the last dose of study medication

    • Be a nonsmoker or must not have smoked for at least 30 days before the screening visit and agree to abstain from smoking during study participation

    Exclusion Criteria:

    • Women who are pregnant or nursing;

    • Had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin

    1. prior to signing informed consent

    • Have been treated with an investigational agent within 4 weeks prior to signing the informed consent form

    • Have ongoing clinically significant adverse event(s) due to chemotherapy, radiotherapy or investigational agents administered more than 4 weeks prior to signing the informed consent as determined by the Investigator

    • Have known or suspected hypersensitivity to azacitidine or mannitol

    • Have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia

    • Have low blood pressure (supine blood pressure <90/60 mmHg)

    • Have human immunodeficiency virus (HIV), or active hepatitis virus B or C

    • Have advanced malignant hepatic tumors

    • Have end stage renal disease requiring dialysis

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Sutter East Bay Hospitals Berkeley California United States 94704
    2 Palm Springs Research Institute Hialeah Florida United States 33012
    3 MCG Cancer Center Augusta Georgia United States 30912
    4 Joliet Oncology-Hematology Associates, Ltd. Joliet Illinois United States 60435
    5 University of Kentucky-Markey Cancer Center Clinical Research Organization Lexington Kentucky United States 40536
    6 Nevada Cancer Institute Las Vegas Nevada United States 89135
    7 Montefiore Medical Center Bronx New York United States 10461
    8 Mid Dakota Clinical P.C. - Cancer Treatment and Research Center Bismarck North Dakota United States 58501
    9 Gabrail Cancer Center Canton Ohio United States 44718
    10 Pharma Resource East Providence Rhode Island United States 02915
    11 Cancer Therapy and Research Center San Antonio Texas United States 78229

    Sponsors and Collaborators

    • Celgene

    Investigators

    • Study Director: Jay Backstrom, MD, Celgene Corporation

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT00652626
    Other Study ID Numbers:
    • AZA PH US 2007 PK006
    First Posted:
    Apr 4, 2008
    Last Update Posted:
    Nov 19, 2019
    Last Verified:
    Nov 1, 2019
    Keywords provided by Celgene
    MDS
    AML
    Solid Tumors
    Azacitidine
    PK
    Pharmacokinetics
    Renal Impairment
    Multiple Myeloma
    Non-Hodgkin's Lymphoma
    Hodgkin's Disease
    Additional relevant MeSH terms:
    Multiple Myeloma
    Lymphoma, Non-Hodgkin
    Hodgkin Disease
    Renal Insufficiency
    Azacitidine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle. Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle.
    Period Title: Initial Treatment Phase
    STARTED 5 5 7 6 8 0 0
    Received Study Drug 5 5 6 5 6 0 0
    COMPLETED 5 5 6 5 5 0 0
    NOT COMPLETED 0 0 1 1 3 0 0
    Period Title: Initial Treatment Phase
    STARTED 0 0 0 0 0 14 4
    COMPLETED 0 0 0 0 0 2 1
    NOT COMPLETED 0 0 0 0 0 12 3

    Baseline Characteristics

    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI Total
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle. Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle. Total of all reporting groups
    Overall Participants 5 5 6 5 6 14 4 45
    Age (years) [Mean (Standard Deviation) ]
    Initial Treatment Period
    67.6
    (3.78)
    64.6
    (9.63)
    53.5
    (10.19)
    57.0
    (12.02)
    74.5
    (12.58)
    NA
    (NA)
    NA
    (NA)
    63.5
    (12.32)
    Extension Treatment Period
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    60.6
    (9.52)
    68.8
    (11.0)
    62.4
    (10.15)
    Sex/Gender, Customized (participants) [Number]
    Female
    3
    60%
    3
    60%
    3
    50%
    4
    80%
    3
    50%
    0
    0%
    0
    0%
    16
    35.6%
    Male
    2
    40%
    2
    40%
    3
    50%
    1
    20%
    3
    50%
    0
    0%
    0
    0%
    11
    24.4%
    Race/Ethnicity, Customized (participants) [Number]
    Black
    1
    20%
    2
    40%
    1
    16.7%
    2
    40%
    2
    33.3%
    0
    0%
    0
    0%
    8
    17.8%
    White
    4
    80%
    3
    60%
    5
    83.3%
    3
    60%
    4
    66.7%
    0
    0%
    0
    0%
    19
    42.2%
    Region of Enrollment (participants) [Number]
    United States
    5
    100%
    5
    100%
    6
    100%
    5
    100%
    6
    100%
    0
    0%
    0
    0%
    27
    60%
    Gender of Extension Period Participants (participants) [Number]
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    8
    57.1%
    2
    50%
    10
    22.2%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    6
    42.9%
    2
    50%
    8
    17.8%
    Race: Extension Phase (participants) [Number]
    Black
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    5
    35.7%
    0
    0%
    5
    11.1%
    White
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    9
    64.3%
    4
    100%
    13
    28.9%
    Eastern Cooperative Oncology Group (ECOG) Performance Status: Initial Treatment Phase (participants) [Number]
    0
    2
    40%
    2
    40%
    1
    16.7%
    0
    0%
    2
    33.3%
    0
    0%
    0
    0%
    7
    15.6%
    1
    3
    60%
    3
    60%
    4
    66.7%
    5
    100%
    3
    50%
    0
    0%
    0
    0%
    18
    40%
    2
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    2
    4.4%
    Eastern Cooperative Oncology Group (ECOG) Performance Status: Extension Phase (participants) [Number]
    0
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    14.3%
    1
    25%
    3
    6.7%
    1
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    11
    78.6%
    3
    75%
    14
    31.1%
    2
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    1
    2.2%
    Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
    Initial Treatment Period
    2.0
    (0.20)
    1.9
    (0.28)
    1.9
    (0.42)
    1.6
    (0.15)
    1.8
    (0.15)
    NA
    (NA)
    NA
    (NA)
    1.9
    (0.27)
    Extension Period
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    1.9
    (0.35)
    1.9
    (0.06)
    1.9
    (0.31)
    Cancer Diagnosis: Initial Treatment Phase (participants) [Number]
    Myelodysplastic syndrome-RA
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    2
    4.4%
    Myelodysplastic syndrome-RARS
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.2%
    Myelodysplastic syndrome-RAEB-T
    1
    20%
    1
    20%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    4.4%
    Chronic myelomonocytic leukemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    1
    2.2%
    Solid tumor
    3
    60%
    3
    60%
    5
    83.3%
    5
    100%
    4
    66.7%
    0
    0%
    0
    0%
    20
    44.4%
    Multiple myeloma
    1
    20%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.2%
    Cancer Diagnosis: Extension Phase (participants) [Number]
    Myelodysplastic syndrome-RA
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    1
    2.2%
    Myelodysplastic syndrome-RARS
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    1
    2.2%
    Myelodysplastic syndrome-RAEB-T
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    1
    2.2%
    Chronic myelomonocytic leukemia
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Solid tumor
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    12
    85.7%
    3
    75%
    15
    33.3%
    Multiple myeloma
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose
    Description Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    455.86
    (26.04)
    897.43
    (31.00)
    921.87
    (39.215)
    1502.86
    (25.57)
    2. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point
    Description Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    454.80
    (26.22)
    895.38
    (31.20)
    920.76
    (39.20)
    1505.16
    (25.57)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Geometric means, ratio and 90% confidence interval (CI) of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 98.4
    Confidence Interval (2-Sided) 90%
    64.0 to 151.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 50 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 75 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 67.5
    Confidence Interval (2-Sided) 90%
    44.7 to 101.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 75 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 100 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 82.7
    Confidence Interval (2-Sided) 90%
    53.8 to 127.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 100 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    3. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time Zero to Infinity
    Description The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]
    460.47
    (25.79)
    897.42
    (30.93)
    945.50
    (39.05)
    1533.37
    (23.96)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 97.4
    Confidence Interval (2-Sided) 90%
    63.8 to 148.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 50 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 75 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 68.5
    Confidence Interval (2-Sided) 90%
    45.7 to 102.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 75 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 100 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 83.2
    Confidence Interval (2-Sided) 90%
    54.5 to 127.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 100 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    4. Primary Outcome
    Title Maximum Plasma Concentration of Azacitidine (Cmax)
    Description The maximum observed plasma concentration of azacitidine after a single dose on Day 1.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    293.38
    (34.11)
    749.04
    (61.03)
    745.50
    (57.90)
    1261.96
    (39.19)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 127.7
    Confidence Interval (2-Sided) 90%
    66.3 to 245.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 50 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 75 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 84.7
    Confidence Interval (2-Sided) 90%
    45.3 to 158.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 75 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 100 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 107.5
    Confidence Interval (2-Sided) 90%
    55.9 to 207.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric means is calculated as Azacitidine 100 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    5. Primary Outcome
    Title Time to Maximum Plasma Concentration of Azacitidine (Tmax)
    Description The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Median (Full Range) [hours]
    0.25
    0.25
    0.25
    0.27
    6. Primary Outcome
    Title Terminal Phase Half-life of Azacitidine (t½)
    Description The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    1.38
    (27.31)
    0.63
    (35.72)
    1.19
    (102.56)
    1.03
    (78.48)
    7. Primary Outcome
    Title Apparent Total Clearance of Azacitidine (CL/F)
    Description The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [liters/hour]
    104.58
    (25.00)
    105.76
    (17.03)
    151.55
    (30.88)
    106.00
    (25.64)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 101.1
    Confidence Interval (2-Sided) 90%
    71.2 to 143.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 50 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 75 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 144.9
    Confidence Interval (2-Sided) 90%
    103.6 to 202.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 75 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 100 mg/m^2
    Comments Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m^2 is the reference group for comparisons.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 101.4
    Confidence Interval (2-Sided) 90%
    71.4 to 143.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Azacitidine 100 mg/m^2 / Azacitidine 25 mg/m^2 and expressed as a percentage.
    8. Primary Outcome
    Title Apparent Volume of Distribution of Azacitidine (Vz/F)
    Description The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz)
    Time Frame Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1.
    Measure Participants 5 5 6 5
    Geometric Mean (Geometric Coefficient of Variation) [liters]
    208.69
    (45.57)
    96.74
    (36.75)
    259.44
    (121.71)
    456.69
    (99.41)
    9. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine
    Description The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    921.87
    (39.15)
    1558.32
    (64.95)
    Day 5
    843.03
    (12.00)
    1183.61
    (51.92)
    10. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine
    Description The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    920.76
    (39.20)
    1558.72
    (65.02)
    Day 5
    841.62
    (11.83)
    1181.83
    (51.98)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of AUC0-t after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 169.3
    Confidence Interval (2-Sided) 90%
    109.2 to 262.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of AUC0-t after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 140.4
    Confidence Interval (2-Sided) 90%
    90.6 to 217.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    11. Primary Outcome
    Title Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine
    Description The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    946.22
    (39.05)
    1573.82
    (63.46)
    Day 5
    857.64
    (9.94)
    1210.92
    (49.07)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of AUC0-inf after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 166.3
    Confidence Interval (2-Sided) 90%
    108.6 to 254.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of AUC0-inf after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 141.2
    Confidence Interval (2-Sided) 90%
    92.2 to 216.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    12. Primary Outcome
    Title Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine
    Description The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    745.50
    (57.90)
    1056.66
    (93.01)
    Day 5
    632.56
    (45.86)
    668.11
    (91.64)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of Cmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 141.7
    Confidence Interval (2-Sided) 90%
    73.2 to 274.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of Cmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment. Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Ratio (%) of Geometric Means
    Estimated Value 105.6
    Confidence Interval (2-Sided) 90%
    54.5 to 204.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Ratio of geometric mean is calculated as Severe RI/Normal RF and expressed as a percentage.
    13. Primary Outcome
    Title Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine
    Description The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    0.25
    0.50
    Day 5
    0.38
    0.64
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of Tmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1342
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value 0.25
    Confidence Interval (2-Sided) 90%
    0 to 0.52
    Parameter Dispersion Type:
    Value:
    Estimation Comments Median difference is Severe RI - Normal RF.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Azacitidine 25 mg/m^2, Azacitidine 50 mg/m^2
    Comments Comparison of Tmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1017
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value 0.25
    Confidence Interval (2-Sided) 90%
    0 to 0.50
    Parameter Dispersion Type:
    Value:
    Estimation Comments Median difference is Severe RI - Normal RF.
    14. Primary Outcome
    Title Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine
    Description The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    1.19
    (102.56)
    0.97
    (43.88)
    Day 5
    1.03
    (76.95)
    1.15
    (53.86)
    15. Primary Outcome
    Title Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine
    Description The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf.
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    151.55
    (30.88)
    85.76
    (68.83)
    Day 5
    166.95
    (27.59)
    111.55
    (51.75)
    16. Primary Outcome
    Title Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine
    Description The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz).
    Time Frame Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
    Arm/Group Title Normal RF: Azacitidine 75 mg/m^2 Severe RI: Azacitidine 75 mg/m^2
    Arm/Group Description Participants with normal renal function (RF) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with severe renal impairment (RI) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5.
    Measure Participants 6 6
    Day 1
    259.44
    (121.71)
    120.47
    (120.45)
    Day 5
    248.57
    (115.10)
    184.54
    (104.34)
    17. Primary Outcome
    Title Number of Participants With Adverse Events (AEs)
    Description A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: Results in death; Is life threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).
    Time Frame Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months).

    Outcome Measure Data

    Analysis Population Description
    Safety population, all enrolled patients who received at least one dose of azacitidine and who had at least one post-treatment safety assessment.
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle. Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle.
    Measure Participants 5 5 6 5 6 14 4
    Any adverse event
    4
    80%
    3
    60%
    6
    100%
    5
    100%
    6
    100%
    14
    100%
    4
    100%
    Adverse event related to study drug
    2
    40%
    3
    60%
    4
    66.7%
    4
    80%
    3
    50%
    8
    57.1%
    2
    50%
    Serious adverse event
    0
    0%
    0
    0%
    4
    66.7%
    1
    20%
    1
    16.7%
    8
    57.1%
    3
    75%
    Serious adverse event related to study drug
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    0
    0%
    1
    7.1%
    1
    25%
    Grade 3 or 4 adverse event
    0
    0%
    0
    0%
    4
    66.7%
    1
    20%
    3
    50%
    10
    71.4%
    3
    75%
    AE leading to study drug discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    28.6%
    2
    50%
    AE leading to study drug interruption
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    28.6%
    1
    25%
    AE leading to a dose reduction
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    AE leading to other action taken
    2
    40%
    1
    20%
    6
    100%
    4
    80%
    5
    83.3%
    10
    71.4%
    3
    75%
    Death
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    7.1%
    1
    25%

    Adverse Events

    Time Frame Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months).
    Adverse Event Reporting Description
    Arm/Group Title Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Arm/Group Description Participants with normal renal function (defined as creatinine clearance > 80 mL/min/1.73m^2) received a single subcutaneous dose of azacitidine 25 mg/m^2 on Day 1. Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m^2 on Day 1. Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m^2 on Day 1. Participants with severe renal impairment (RI; defined as creatinine clearance < 30 mL/min/1.73 m^2) received subcutaneous doses of azacitidine 75 mg/m^2 on Days 1 to 5. Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle. Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m^2 azacitidine daily on Days 1-7 of each 28-day cycle.
    All Cause Mortality
    Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/5 (0%) 0/5 (0%) 4/6 (66.7%) 1/5 (20%) 1/6 (16.7%) 8/14 (57.1%) 3/4 (75%)
    Blood and lymphatic system disorders
    Anemia 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Pancytopenia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Gastrointestinal disorders
    Nausea 0/5 (0%) 0/5 (0%) 2/6 (33.3%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Small intestinal obstruction 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 1/4 (25%)
    Vomiting 0/5 (0%) 0/5 (0%) 2/6 (33.3%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    General disorders
    Device dislocation 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Fatigue 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Non-cardiac chest pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Pyrexia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Infections and infestations
    Urinary tract infection 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injury, poisoning and procedural complications
    Post procedural fistula 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Investigations
    Hemoglobin decreased 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Metabolism and nutrition disorders
    Dehydration 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Hyponatremia 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Nervous system disorders
    Dizziness 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Psychiatric disorders
    Confusional state 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Renal and urinary disorders
    Renal failure 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Renal vein thrombosis 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Renal failure acute 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 1/4 (25%)
    Dyspnea 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 2/4 (50%)
    Other (Not Including Serious) Adverse Events
    Azacitidine 25 mg/m^2 Azacitidine 50 mg/m^2 Azacitidine 75 mg/m^2 Azacitidine 100 mg/m^2 Severe RI: Azacitidine 75 mg/m^2 Extension Phase: Normal RF Extension Phase: Severe RI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/5 (80%) 3/5 (60%) 5/6 (83.3%) 5/5 (100%) 6/6 (100%) 9/14 (64.3%) 4/4 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 2/6 (33.3%) 1/14 (7.1%) 1/4 (25%)
    Leukopenia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 2/14 (14.3%) 1/4 (25%)
    Lymphadenopathy 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Neutropenia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 2/6 (33.3%) 2/14 (14.3%) 2/4 (50%)
    Pancytopenia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Thrombocytopenia 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 2/14 (14.3%) 0/4 (0%)
    Cardiac disorders
    Bradycardia 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Cardiac failure congestive 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Palpitations 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Gastrointestinal disorders
    Constipation 1/5 (20%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 4/14 (28.6%) 1/4 (25%)
    Diarrhoea 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 1/4 (25%)
    Dyspepsia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Dysphagia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 2/14 (14.3%) 0/4 (0%)
    Eructation 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Gastric ulcer 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Gastrooesophageal reflux disease 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 2/14 (14.3%) 0/4 (0%)
    Nausea 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 2/5 (40%) 0/6 (0%) 2/14 (14.3%) 2/4 (50%)
    Vomiting 0/5 (0%) 0/5 (0%) 3/6 (50%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    General disorders
    Asthenia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 1/4 (25%)
    Catheter site erythema 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Catheter site pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Chills 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 1/4 (25%)
    Fatigue 0/5 (0%) 0/5 (0%) 2/6 (33.3%) 3/5 (60%) 2/6 (33.3%) 3/14 (21.4%) 1/4 (25%)
    Gait disturbance 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Hernia pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Influenza like illness 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Injection site discomfort 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Injection site erythema 1/5 (20%) 1/5 (20%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/4 (0%)
    Injection site haematoma 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injection site haemorrhage 0/5 (0%) 1/5 (20%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injection site induration 1/5 (20%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Injection site pain 0/5 (0%) 2/5 (40%) 1/6 (16.7%) 1/5 (20%) 2/6 (33.3%) 0/14 (0%) 0/4 (0%)
    Injection site pruritus 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Injection site rash 0/5 (0%) 1/5 (20%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injection site reaction 0/5 (0%) 0/5 (0%) 2/6 (33.3%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injection site swelling 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Injection site vesicles 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Non-cardiac chest pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Pyrexia 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Infections and infestations
    Bronchitis 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Oral candidiasis 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Otitis media 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Postoperative wound infection 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Urinary tract infection 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 1/4 (25%)
    Injury, poisoning and procedural complications
    Procedural site reaction 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Investigations
    Cardiac murmur 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Neutrophil count decreased 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Platelet count increased 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Weight decreased 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/5 (0%) 0/5 (0%) 2/6 (33.3%) 1/5 (20%) 0/6 (0%) 2/14 (14.3%) 0/4 (0%)
    Dehydration 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Hyperkalaemia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 1/4 (25%)
    Hypomagnesaemia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Hyponatraemia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Malnutrition 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 2/14 (14.3%) 0/4 (0%)
    Back pain 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Bone pain 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Flank pain 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Muscular weakness 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Musculoskeletal pain 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Vaginal neoplasm 0/5 (0%) 1/5 (20%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Nervous system disorders
    Headache 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 2/14 (14.3%) 0/4 (0%)
    Hypoaesthesia 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Neuropathy peripheral 1/5 (20%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Psychiatric disorders
    Depression 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Psychiatric symptom 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Renal and urinary disorders
    Haematuria 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Reproductive system and breast disorders
    Vaginal haemorrhage 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Vulval disorder 0/5 (0%) 0/5 (0%) 1/6 (16.7%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 1/14 (7.1%) 0/4 (0%)
    Dyspnoea 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 2/14 (14.3%) 1/4 (25%)
    Hiccups 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)
    Pulmonary oedema 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 1/4 (25%)
    Rales 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Rhinorrhoea 1/5 (20%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Skin and subcutaneous tissue disorders
    Erythema 0/5 (0%) 1/5 (20%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Pruritus generalised 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 1/6 (16.7%) 0/14 (0%) 0/4 (0%)
    Vascular disorders
    Hot flush 0/5 (0%) 0/5 (0%) 0/6 (0%) 1/5 (20%) 0/6 (0%) 0/14 (0%) 0/4 (0%)
    Peripheral coldness 0/5 (0%) 0/5 (0%) 0/6 (0%) 0/5 (0%) 0/6 (0%) 1/14 (7.1%) 0/4 (0%)

    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 thirty (30) 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.

    Results Point of Contact

    Name/Title Associate Director, Clinical Trials Disclosure
    Organization Celgene Corporation
    Phone 1-888-260-1599
    Email clinicaltrialdisclosure@celgene.com
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT00652626
    Other Study ID Numbers:
    • AZA PH US 2007 PK006
    First Posted:
    Apr 4, 2008
    Last Update Posted:
    Nov 19, 2019
    Last Verified:
    Nov 1, 2019