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An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation (IDHENTIFY)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02577406
Recruitment Status : Active, not recruiting
First Posted : October 16, 2015
Results First Posted : September 10, 2022
Last Update Posted : February 23, 2023
Sponsor:
Information provided by (Responsible Party):
Celgene

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Leukemia, Myeloid
Isocitrate Dehydrogenase
Interventions Drug: AG-221
Other: BSC
Drug: Azacitidine
Drug: Low-dose cytarabine (LDAC)
Drug: Intermediate-dose cytarabine (IDAC)
Enrollment 319
Recruitment Details  
Pre-assignment Details 319 participants were randomized and 298 participants received treatment
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC: Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Period Title: Randomized Period
Started 158 161
Completed [1] 157 141
Not Completed 1 20
Reason Not Completed
Death             1             0
Other reasons             0             20
[1]
Continuing to treatment period
Period Title: Treatment Period
Started 157 141
Completed [1] 10 4
Not Completed 147 137
Reason Not Completed
Transition to commercially available treatment             1             0
Progressive disease             47             36
Death             36             23
Other reasons             3             37
Withdrawal by Subject             10             24
Adverse Event             17             12
Disease relapse             27             1
HSCT             6             2
Lost to Follow-up             0             1
Protocol Violation             0             1
[1]
Ongoing treatment
Arm/Group Title AG-221 Conventional Care Regimens (CCRs) Total
Hide Arm/Group Description Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC: Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.

 Total of all reporting groups
Overall Number of Baseline Participants 158 161 319
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 158 participants 161 participants 319 participants
71.4  (6.04) 70.5  (6.17) 70.9  (6.11)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 161 participants 319 participants
≥ 60 to < 70 years
61
  38.6%
72
  44.7%
133
  41.7%
≥ 70 to < 80 years
80
  50.6%
77
  47.8%
157
  49.2%
≥ 80 years
17
  10.8%
12
   7.5%
29
   9.1%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 161 participants 319 participants
Female
67
  42.4%
65
  40.4%
132
  41.4%
Male
91
  57.6%
96
  59.6%
187
  58.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 161 participants 319 participants
Hispanic or Latino
4
   2.5%
3
   1.9%
7
   2.2%
Not Hispanic or Latino
126
  79.7%
128
  79.5%
254
  79.6%
Unknown or Not Reported
28
  17.7%
30
  18.6%
58
  18.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 158 participants 161 participants 319 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
12
   7.6%
12
   7.5%
24
   7.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
2
   1.3%
6
   3.7%
8
   2.5%
White
115
  72.8%
110
  68.3%
225
  70.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
29
  18.4%
33
  20.5%
62
  19.4%
1.Primary Outcome
Title Overall Survival (OS)
Hide Description The time between randomization and death from any cause. Participants who drop-out or are alive at the end of trial will have their OS times censored at the time of last contact, as appropriate.
Time Frame From randomization to death due to any cause (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC: Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Mean (95% Confidence Interval)
Unit of Measure: Months
6.5
(5.5 to 9.5)
6.2
(4.6 to 7.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2288
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.67 to 1.10
Estimation Comments The hazard ratio was from a Cox proportional hazards model stratified by prior intensive therapy for AML and primary refractory
2.Secondary Outcome
Title Overall Response Rate
Hide Description Number of participants with MLFS + CR + CRi + CRp + PR according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria. Complete response (CR) and morphologic leukemia-free state (MLFS) are defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. Partial remission (PR) is defined as all hematologic criteria of CR with a >50% decrease in the percentage of BM blasts to 5% to 25%. (<5% considered if Auer rods are present).
Time Frame From randomization up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
25
  15.8%
7
   4.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments p-value from a Cochran-Mantel-Haenszel test comparing the response rates between the AG-221 group and the combined CCR group with stratification factors of prior intensive therapy for AML and primary refractory status
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.12
Confidence Interval (2-Sided) 95%
1.73 to 9.81
Estimation Comments Odds ratio from logistic regression
3.Secondary Outcome
Title Event-Free Survival
Hide Description Time from randomization to documented morphologic relapse after complete remission/complete remission with incomplete neutrophil recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp), progressive disease (PD) or death from any cause, whichever occurs first. Morphologic Relapse after CR/CRi/CRp is defined as either reappearance of ≥ 5% blasts in the BM not attributable to any other cause or the development of extramedullary disease. PD is defined as a > 50% increase of BM blast count percentage from baseline to ≥ 20% for participants with 5 to 70% BM blasts at baseline or a doubling of absolute blast count in peripheral blood from baseline to ≥ 10 x 109/L (10,000/μL) for participants with > 70% BM blasts at baseline or the development of new extramedullary disease.
Time Frame From randomization to the date of documented morphologic relapse after CR/CRi/CRp, PD or death from any cause, whichever occurs first. (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Median (95% Confidence Interval)
Unit of Measure: Months
3.2
(2.4 to 4.4)
2.5
(1.9 to 3.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2625
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.57 to 1.17
Estimation Comments The hazard ratio is from a Cox proportional hazards model stratified by prior intensive therapy for AML and primary refractory status.
4.Secondary Outcome
Title Duration of Response
Hide Description Time from first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse after CR/CRi/CRp/ PD or death due to any cause, whichever occurs first. CR and MLFS are defined as <5% blasts in a BM aspirate sample with marrow spicules + a count of ≥200 nucleated cells with no blasts with Auer rods + no extramedullary disease. CR must also include: ANC ≥ 1,000/μL, Platelet count ≥100,000/μL, + independent of red cell transfusions for ≥1 week before assessment. CRi is all criteria of CR except ANC. CRp is all criteria of CR except platelet count. PR is defined as all hematologic criteria of CR with >50% decrease in BM blasts to 5%-25%. Relapse after CR/CRi/CRp is defined as reappearance of ≥ 5% blasts in the BM not attributable to other cause or development of extramedullary disease. PD is defined as > 50% increase of BM blast count from baseline to ≥ 20% or a doubling of absolute blast count in peripheral blood from baseline to ≥ 10,000/μL or development of new extramedullary disease.
Time Frame From randomization to documented morphologic relapse after CR/CRi/CRp/ PD or death due to any cause, whichever occurs first (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who achieved CR/CRi/CRp/PR/MLFS
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 25 7
Median (95% Confidence Interval)
Unit of Measure: Months
3.9
(1.9 to 7.4)
4.5 [1] 
(1.9 to NA)
[1]
Insufficient number of participants with events
5.Secondary Outcome
Title Time to Response
Hide Description Time from randomization to first documented MLFS/CR/CRi/CRp/PR. Complete remission (CR) and morphologic leukemia-free state (MLFS) are defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include the following conditions: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. partial remission (PR) is defined as all hematologic criteria of CR with a >50% decrease in the percentage of BM blasts to 5% to 25%. (<5% considered if Auer rods are present).
Time Frame From randomization to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who achieved CR/CRi/CRp/PR/MLFS
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 25 7
Median (Full Range)
Unit of Measure: Days
58.0
(23 to 242)
56.0
(27 to 63)
6.Secondary Outcome
Title Treatment Mortality at 30 Days
Hide Description The number of participant deaths from any cause within 30 days of initiation of study treatment.
Time Frame From first dose to 30 days after first dose
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
10
   6.3%
13
   8.1%
7.Secondary Outcome
Title Treatment Mortality at 60 Days
Hide Description The number of participant deaths from any cause within 60 days of initiation of study treatment.
Time Frame From first dose to 60 days after first dose
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
27
  17.1%
30
  18.6%
8.Secondary Outcome
Title One-Year Survival Rate
Hide Description The proportion of participants alive at 1 year after randomization
Time Frame From randomization to 1 year after randomization
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0.375
(0.299 to 0.451)
0.261
(0.191 to 0.336)
9.Secondary Outcome
Title Overall Remission Rate
Hide Description The number of participants with CR + CRi + CRp according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria. Complete remission (CR) is defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include the following conditions: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count.
Time Frame From randomization up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
17
  10.8%
7
   4.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0344
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
10.Secondary Outcome
Title Complete Remission Rate
Hide Description The number of participants with morphologic complete remission (CR) according to modified International Working Group Acute Myeloid Leukemia Response Criteria (IWG AML). CR is defined as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease; plus the following conditions: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment.
Time Frame From randomization up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
11
   7.0%
1
   0.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0027
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
11.Secondary Outcome
Title Hematologic Improvement Rate
Hide Description The number of participants with hematologic improvement neutrophil response (HI-N) + hematologic improvement platelet response (HI-P) + hematologic improvement erythroid response (HI-E) according to the International Working Group for Myelodysplastic Syndromes for Hematologic Improvement (IWG MDS HI) criteria. HI-E is defined as a hemoglobin increase by ≥ 1.5 g/dL and a relevant reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 week compared with the pretreatment transfusion number in the previous 8 week. HI-P is defined as an absolute increase of ≥ 30 X 10^9/L for participants starting with > 20 X and an increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-N is defined as At least 100% increase and an absolute increase > 0.5 X 10^9/L.
Time Frame From randomization up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
33
  20.9%
9
   5.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
12.Secondary Outcome
Title The Number of Participants That Underwent Hematopoietic Stem Cell Transplantation (HSCT)
Hide Description The number of participants that underwent hematopoietic stem cell transplantation during the study.
Time Frame From randomization up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Measure Type: Count of Participants
Unit of Measure: Participants
7
   4.4%
2
   1.2%
13.Secondary Outcome
Title Time to Treatment Failure
Hide Description Time from randomization to discontinuation of study treatment due to any cause
Time Frame From randomization to discontinuation of study treatment due to any cause (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 158 161
Median (95% Confidence Interval)
Unit of Measure: Months
4.9
(4.0 to 6.0)
1.9
(1.4 to 2.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection AG-221, Conventional Care Regimens (CCRs)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Stratified Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
0.41 to 0.67
Estimation Comments The hazard ratio was from a Cox proportional hazards model stratified by prior intensive therapy for AML and primary refractory status
14.Secondary Outcome
Title The Number of Participants Experiencing Adverse Events (AEs)
Hide Description The number of participants experiencing different types of adverse events (AE). An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A Serious Adverse Event (SAE) is any AE occurring at any dose that: 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, or constitutes an important medical event. All AEs were coded using the MedDRA Version 22.0. Adverse events were analyzed in terms of treatment-emergent AEs (TEAEs). A treatment-related TEAE was defined as a TEAE that was suspected by the investigator to be related to study treatment. The severity was graded by the study personnel based on NCI National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Time Frame From first dose up to 28 days after last dose (up to approximately 49 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 157 141
Measure Type: Count of Participants
Unit of Measure: Participants
Treatment-Emergent Adverse Event (TEAE)
157
 100.0%
131
  92.9%
TEAE Related to Study Drug
121
  77.1%
86
  61.0%
Grade ≥ 3 TEAE
146
  93.0%
112
  79.4%
Grade ≥ 3 TEAE Related to Study Drug
74
  47.1%
49
  34.8%
Serious TEAE
138
  87.9%
92
  65.2%
Serious TEAE Related to Study Drug
34
  21.7%
30
  21.3%
TEAE Leading to Discontinuation of Study Drug
35
  22.3%
16
  11.3%
Treatment-related TEAE Leading to Discontinuation of Study Drug
5
   3.2%
6
   4.3%
TEAE Leading to Study Drug Dose Reduction Only
22
  14.0%
3
   2.1%
Treatment-related TEAE Leading to Study Drug Dose Reduction Only
18
  11.5%
3
   2.1%
TEAE Leading to Study Drug Dose Interruption Only
84
  53.5%
35
  24.8%
Treatment-related TEAE Leading to Study Drug Dose Interruption Only
46
  29.3%
20
  14.2%
TEAE Leading to Study Drug Dose Reduction or Dose Interruption
92
  58.6%
36
  25.5%
Treatment-related TEAE Leading to Study Drug Dose Reduction or Dose Interruption
56
  35.7%
21
  14.9%
TEAE Leading to Death
77
  49.0%
33
  23.4%
Treatment-related TEAE Leading to Death
1
   0.6%
5
   3.5%
15.Secondary Outcome
Title The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Serum Chemistry
Hide Description The percent of participants with clinically significant serum chemistry laboratory abnormalities. A clinically significant laboratory abnormality is defined as meeting Grade 3 or Grade 4 criteria according to the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is defined as severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4 is defined as life-threatening consequences; urgent intervention indicated. The chemistry panel includes sodium, potassium, calcium, magnesium, chloride, phosphorus, CO2, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase (ALP), bilirubin (total and direct), uric acid, lactate dehydrogenase (LDH), AST/SGOT, ALT/SGPT, gamma glutamyl transpeptidase (GGT), amylase and lipase.
Time Frame From first dose up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 157 141
Measure Type: Number
Unit of Measure: Percent of Participants
42.7 21.3
16.Secondary Outcome
Title The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Hematology
Hide Description The percent of participants with clinically significant hematology laboratory abnormalities. A clinically significant laboratory abnormality is defined as meeting Grade 3 or Grade 4 criteria according to the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is defined as severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4 is defined as life-threatening consequences; urgent intervention indicated. The hematology panel includes complete blood count (CBC) with differential, including red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell (WBC) count (with differential), absolute neutrophil count (ANC) and platelet count.
Time Frame From first dose up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 157 141
Measure Type: Number
Unit of Measure: Percent of Participants
94.3 89.4
17.Secondary Outcome
Title The Percent of Participants Experiencing Clinically Significant Vital Sign Abnormalities
Hide Description The percent of participants with clinically significant vital sign abnormalities including weight, temperature, blood pressure, pulse rate, and respiratory rate.
Time Frame From first dose up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 157 141
Measure Type: Number
Unit of Measure: Percent of Participants
0 0
18.Secondary Outcome
Title The Percentage of Participants Experiencing Clinically Significant Electrocardiogram (ECG) Abnormalities
Hide Description The percent of participants with clinically significant ECG abnormalities. 12-lead ECG was assessed by a physician trained in ECG interpretation. Intervals including PR, QRS, QT and RR were collected, as well as heart rate and rhythm.
Time Frame From first dose up to approximately 49 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants with evaluable measurements
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 147 120
Measure Type: Number
Unit of Measure: Percentage of Participants
7.6 2.1
19.Secondary Outcome
Title Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)
Hide Description The change from baseline in the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning. Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered meaningful. Results obtained just prior to the start of study treatment on Day 1 of Cycle 1 will serve as the baseline values. If not available, the most recent screening results prior to the start of study treatment on Day 1 of Cycle 1 will be considered the baseline values.
Time Frame From baseline to cycle 2 day 1 (up to approximately 1 month)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed at least 15 of the 30 items at baseline and at least one post-baseline assessment based on EORTC QLQ-C30
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 106 62
Mean (Standard Deviation)
Unit of Measure: Change from baseline in QLQ-C30 score
Global QoL -4.7  (20.18) -4.0  (18.46)
Physical Functioning -3.1  (17.19) -6.7  (21.32)
Role Functioning -3.8  (27.63) -7.8  (29.98)
Cognitive Functioning -0.6  (16.89) -5.1  (18.00)
Emotional Functioning 0.9  (15.72) -0.7  (18.44)
Social Functioning -0.6  (29.27) -10.2  (31.56)
Fatigue 5.5  (18.73) 7.5  (25.59)
Nausea / Vomiting 9.0  (20.21) 1.9  (15.12)
Pain 6.0  (23.37) 7.0  (30.11)
Dyspnea -1.3  (23.42) 0.0  (27.66)
Insomnia 8.5  (26.85) 1.1  (33.04)
Appetite Loss 10.7  (28.19) 8.6  (31.33)
Constipation 2.8  (24.82) 1.6  (24.46)
Diarrhea 4.1  (24.21) 1.6  (18.53)
Financial Difficulties -0.3  (24.12) -3.2  (21.52)
20.Secondary Outcome
Title Change From Baseline in EQ-5D-5L Health Utility Index
Hide Description The EQ-5D is a standardized instrument for use as a measure of health outcome. The descriptive system comprises 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort and Anxiety/Depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses from the 5 dimensions are coded so that a '1' indicates no problem on that dimension, and '5' indicates the most serious problem. Results obtained just prior to the start of study treatment on Day 1 of Cycle 1 will serve as the baseline values. If not available, the most recent screening results prior to the start of study treatment on Day 1 of Cycle 1 will be considered the baseline values. The responses for the 5 dimensions can be combined in a 5-digit number describing the respondent's health state. Score was converted to a single index value using the cross-walk method to the EQ-5D-3L value set.
Time Frame From baseline up to cycle 2 day 1 (up to approximately 1 month)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants with non-missing score of EQ-5D-5L Health Utility Index (i.e. all five items were completed) at baseline
Arm/Group Title AG-221 Conventional Care Regimens (CCRs)
Hide Arm/Group Description:
Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
Overall Number of Participants Analyzed 106 62
Mean (Standard Deviation)
Unit of Measure: Change from baseline in EQ-5D score
-0.0738  (0.2128) -0.0598  (0.2500)
Time Frame Serious Adverse Events and Other (Not Including Serious) Adverse Events were collected form from first dose to 28 days after last dose (up to approximately 49 months). All-Cause Mortality was assessed from randomization up to approximately 50 months.
Adverse Event Reporting Description Serious Adverse Events and Other (Not Including Serious) Adverse Events were assessed/monitored for the treated population. All-Cause Mortality was assessed for the randomized population.
 
Arm/Group Title AG-221 BSC Only Azacitidine + BSC LDAC + BSC IDAC + BSC
Hide Arm/Group Description Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC). Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support. Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day subcutaneous (SC) for 7 days, plus best supportive care (BSC) Participants receive continuous 28-day cycles of cytarabine 20 mg subcutaneous (SC) twice a day (BID) for 10 days, plus best supportive care (BSC). Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day Intravenously (IV) for 3 to 6 days, per standard institutional practice, plus best supportive care (BSC); only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.
All-Cause Mortality
AG-221 BSC Only Azacitidine + BSC LDAC + BSC IDAC + BSC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   126/158 (79.75%)   19/22 (86.36%)   48/69 (69.57%)   30/37 (81.08%)   21/33 (63.64%) 
Hide Serious Adverse Events
AG-221 BSC Only Azacitidine + BSC LDAC + BSC IDAC + BSC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   138/157 (87.90%)   10/22 (45.45%)   38/58 (65.52%)   27/33 (81.82%)   17/28 (60.71%) 
Blood and lymphatic system disorders           
AGRANULOCYTOSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ANAEMIA † 1  6/157 (3.82%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
FEBRILE BONE MARROW APLASIA † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
FEBRILE NEUTROPENIA † 1  31/157 (19.75%)  5/22 (22.73%)  14/58 (24.14%)  13/33 (39.39%)  7/28 (25.00%) 
HAEMORRHAGIC DISORDER † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HYPERLEUKOCYTOSIS † 1  2/157 (1.27%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LEUKAEMOID REACTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LEUKOCYTOSIS † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
LEUKOSTASIS SYNDROME † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
NEUTROPENIA † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
PANCYTOPENIA † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
THROMBOCYTOPENIA † 1  6/157 (3.82%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  0/28 (0.00%) 
Cardiac disorders           
ACUTE CORONARY SYNDROME † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ACUTE MYOCARDIAL INFARCTION † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
ANGINA PECTORIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
ATRIAL FIBRILLATION † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ATRIAL FLUTTER † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BRADYCARDIA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CARDIAC ARREST † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CARDIAC FAILURE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CARDIAC FAILURE CONGESTIVE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CARDIAC HYPERTROPHY † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CARDIOMYOPATHY † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CORONARY ARTERY DISEASE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PERICARDIAL EFFUSION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PERICARDITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
SINUS BRADYCARDIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Eye disorders           
RETINAL HAEMORRHAGE † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
Gastrointestinal disorders           
ABDOMINAL PAIN † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
ANGINA BULLOSA HAEMORRHAGICA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ASCITES † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
COLITIS † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
CONSTIPATION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CROHN'S DISEASE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
DIARRHOEA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
DIARRHOEA HAEMORRHAGIC † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ENTEROCOLITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
ENTEROCOLITIS HAEMORRHAGIC † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
GASTROINTESTINAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  0/28 (0.00%) 
GINGIVAL HYPERTROPHY † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
INGUINAL HERNIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LOWER GASTROINTESTINAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
MELAENA † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
MOUTH HAEMORRHAGE † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
NAUSEA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ODYNOPHAGIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
OESOPHAGEAL ULCER † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
OESOPHAGITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RECTAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
STOMATITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
UPPER GASTROINTESTINAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
VOMITING † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
General disorders           
ASTHENIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
FATIGUE † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
GENERAL PHYSICAL HEALTH DETERIORATION † 1  14/157 (8.92%)  1/22 (4.55%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
INFLUENZA LIKE ILLNESS † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
MALAISE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
MUCOSAL INFLAMMATION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
MULTIPLE ORGAN DYSFUNCTION SYNDROME † 1  3/157 (1.91%)  1/22 (4.55%)  1/58 (1.72%)  0/33 (0.00%)  1/28 (3.57%) 
ORGAN FAILURE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
PHYSICAL DECONDITIONING † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PYREXIA † 1  15/157 (9.55%)  0/22 (0.00%)  2/58 (3.45%)  3/33 (9.09%)  5/28 (17.86%) 
Hepatobiliary disorders           
CHOLANGITIS ACUTE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CHOLELITHIASIS MIGRATION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CHRONIC HEPATIC FAILURE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HEPATIC FAILURE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HEPATOCELLULAR INJURY † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
HEPATOTOXICITY † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
HYPERBILIRUBINAEMIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Immune system disorders           
GRAFT VERSUS HOST DISEASE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
Infections and infestations           
ACARODERMATITIS † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
ACUTE SINUSITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ANAL ABSCESS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
APPENDICITIS † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
BACTERAEMIA † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
BREVIBACTERIUM INFECTION † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
BRONCHITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
BRONCHOPULMONARY ASPERGILLOSIS † 1  0/157 (0.00%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
CAMPYLOBACTER INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CELLULITIS † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
CLOSTRIDIAL SEPSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CLOSTRIDIUM DIFFICILE COLITIS † 1  4/157 (2.55%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
CLOSTRIDIUM DIFFICILE INFECTION † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
DEVICE RELATED INFECTION † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  0/28 (0.00%) 
ENTEROCOCCAL INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
ENTEROCOLITIS INFECTIOUS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
EPIGLOTTITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
ESCHERICHIA BACTERAEMIA † 1  1/157 (0.64%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ESCHERICHIA SEPSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ESCHERICHIA URINARY TRACT INFECTION † 1  2/157 (1.27%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
FURUNCLE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
GASTROENTERITIS † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
GASTROINTESTINAL INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
GINGIVITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HEPATIC INFECTION † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
HEPATOSPLENIC CANDIDIASIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HERPES SIMPLEX † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
INFECTION † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
INFLUENZA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
INJECTION SITE CELLULITIS † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
INTERVERTEBRAL DISCITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
KLEBSIELLA BACTERAEMIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LIVER ABSCESS † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
LOCALISED INFECTION † 1  0/157 (0.00%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LOWER RESPIRATORY TRACT INFECTION † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
LUNG INFECTION † 1  10/157 (6.37%)  0/22 (0.00%)  2/58 (3.45%)  1/33 (3.03%)  0/28 (0.00%) 
MENINGITIS LISTERIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
MUCORMYCOSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
NEUTROPENIC SEPSIS † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
NOCARDIA SEPSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
NOCARDIOSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
OTITIS EXTERNA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PERIORBITAL CELLULITIS † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PERIRECTAL ABSCESS † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
PHARYNGITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
PNEUMONIA † 1  16/157 (10.19%)  2/22 (9.09%)  6/58 (10.34%)  3/33 (9.09%)  3/28 (10.71%) 
PNEUMONIA BACTERIAL † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PNEUMONIA FUNGAL † 1  4/157 (2.55%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
PNEUMONIA INFLUENZAL † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PNEUMONIA LEGIONELLA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PSEUDOMONAS INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PULMONARY MYCOSIS † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
PYELONEPHRITIS ACUTE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RESPIRATORY SYNCYTIAL VIRUS INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RESPIRATORY TRACT INFECTION † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
SEPSIS † 1  17/157 (10.83%)  0/22 (0.00%)  3/58 (5.17%)  2/33 (6.06%)  1/28 (3.57%) 
SEPTIC SHOCK † 1  6/157 (3.82%)  2/22 (9.09%)  1/58 (1.72%)  0/33 (0.00%)  1/28 (3.57%) 
SINUSITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
SKIN INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
STAPHYLOCOCCAL BACTERAEMIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
STAPHYLOCOCCAL SEPSIS † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
STENOTROPHOMONAS INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
SUBCUTANEOUS ABSCESS † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TOOTH ABSCESS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
UPPER RESPIRATORY TRACT INFECTION † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
URETHRITIS † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
URINARY TRACT INFECTION † 1  4/157 (2.55%)  1/22 (4.55%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
URINARY TRACT INFECTION ENTEROCOCCAL † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
VASCULAR DEVICE INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Injury, poisoning and procedural complications           
ANAPHYLACTIC TRANSFUSION REACTION † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
ANKLE FRACTURE † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  2/28 (7.14%) 
FALL † 1  5/157 (3.18%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
FEMUR FRACTURE † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
INFUSION RELATED REACTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LOWER LIMB FRACTURE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
OVERDOSE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
POST PROCEDURAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
SUBDURAL HAEMATOMA † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
SUBDURAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TRANSFUSION REACTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Investigations           
ALANINE AMINOTRANSFERASE INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BLAST CELL COUNT INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
BLOOD BILIRUBIN INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BLOOD CREATININE INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
EJECTION FRACTION DECREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
GENERAL PHYSICAL CONDITION ABNORMAL † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LIVER FUNCTION TEST INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PLATELET COUNT DECREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TRANSAMINASES INCREASED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Metabolism and nutrition disorders           
DECREASED APPETITE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
DEHYDRATION † 1  5/157 (3.18%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
DIABETIC METABOLIC DECOMPENSATION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HYPERGLYCAEMIA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HYPOKALAEMIA † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
HYPONATRAEMIA † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TUMOUR LYSIS SYNDROME † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Musculoskeletal and connective tissue disorders           
ARTHRALGIA † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BACK PAIN † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BONE PAIN † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
JOINT EFFUSION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
MUSCULAR WEAKNESS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
NECK PAIN † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PAIN IN EXTREMITY † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TENDONITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
ACUTE LEUKAEMIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ACUTE LYMPHOCYTIC LEUKAEMIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ACUTE MYELOID LEUKAEMIA † 1  6/157 (3.82%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  1/28 (3.57%) 
ACUTE MYELOID LEUKAEMIA RECURRENT † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
DIFFERENTIATION SYNDROME † 1  9/157 (5.73%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ENDOMETRIAL CANCER † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ONCOLOGIC COMPLICATION † 1  2/157 (1.27%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
SQUAMOUS CELL CARCINOMA † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
SQUAMOUS CELL CARCINOMA OF SKIN † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Nervous system disorders           
ATAXIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CEREBRAL HAEMORRHAGE † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
CEREBRAL INFARCTION † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
DYSARTHRIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HAEMORRHAGE INTRACRANIAL † 1  5/157 (3.18%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
INTRAVENTRICULAR HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ISCHAEMIC STROKE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LOSS OF CONSCIOUSNESS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
LUMBOSACRAL RADICULOPATHY † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
NORMAL PRESSURE HYDROCEPHALUS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
SYNCOPE † 1  4/157 (2.55%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
Psychiatric disorders           
CONFUSIONAL STATE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Renal and urinary disorders           
ACUTE KIDNEY INJURY † 1  4/157 (2.55%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  0/28 (0.00%) 
HAEMATURIA † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
OLIGURIA † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
RENAL COLIC † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RENAL FAILURE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  1/28 (3.57%) 
RENAL IMPAIRMENT † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
URINARY RETENTION † 1  0/157 (0.00%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Reproductive system and breast disorders           
BENIGN PROSTATIC HYPERPLASIA † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
ACUTE RESPIRATORY FAILURE † 1  0/157 (0.00%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
DYSPNOEA † 1  2/157 (1.27%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
EPISTAXIS † 1  3/157 (1.91%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
LUNG DISORDER † 1  2/157 (1.27%)  1/22 (4.55%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
LUNG INFILTRATION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ORGANISING PNEUMONIA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PLEURAL EFFUSION † 1  1/157 (0.64%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
PNEUMONITIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RESPIRATORY DISTRESS † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
RESPIRATORY FAILURE † 1  4/157 (2.55%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Skin and subcutaneous tissue disorders           
ECCHYMOSIS † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PURPURA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RASH † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
RASH GENERALISED † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
TOXIC SKIN ERUPTION † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Vascular disorders           
HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
HYPOTENSION † 1  6/157 (3.82%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
1
Term from vocabulary, 22.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AG-221 BSC Only Azacitidine + BSC LDAC + BSC IDAC + BSC
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   153/157 (97.45%)   11/22 (50.00%)   51/58 (87.93%)   30/33 (90.91%)   24/28 (85.71%) 
Blood and lymphatic system disorders           
ANAEMIA † 1  44/157 (28.03%)  2/22 (9.09%)  7/58 (12.07%)  7/33 (21.21%)  7/28 (25.00%) 
FEBRILE NEUTROPENIA † 1  13/157 (8.28%)  0/22 (0.00%)  7/58 (12.07%)  2/33 (6.06%)  4/28 (14.29%) 
LEUKOCYTOSIS † 1  20/157 (12.74%)  2/22 (9.09%)  3/58 (5.17%)  3/33 (9.09%)  2/28 (7.14%) 
LEUKOPENIA † 1  13/157 (8.28%)  0/22 (0.00%)  3/58 (5.17%)  1/33 (3.03%)  1/28 (3.57%) 
NEUTROPENIA † 1  27/157 (17.20%)  2/22 (9.09%)  14/58 (24.14%)  7/33 (21.21%)  4/28 (14.29%) 
THROMBOCYTOPENIA † 1  45/157 (28.66%)  2/22 (9.09%)  16/58 (27.59%)  5/33 (15.15%)  7/28 (25.00%) 
Cardiac disorders           
TACHYCARDIA † 1  1/157 (0.64%)  2/22 (9.09%)  1/58 (1.72%)  1/33 (3.03%)  0/28 (0.00%) 
Eye disorders           
CONJUNCTIVAL HAEMORRHAGE † 1  4/157 (2.55%)  0/22 (0.00%)  1/58 (1.72%)  2/33 (6.06%)  0/28 (0.00%) 
DRY EYE † 1  4/157 (2.55%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  0/28 (0.00%) 
Gastrointestinal disorders           
ABDOMINAL DISTENSION † 1  10/157 (6.37%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
ABDOMINAL PAIN † 1  18/157 (11.46%)  0/22 (0.00%)  5/58 (8.62%)  2/33 (6.06%)  1/28 (3.57%) 
ABDOMINAL PAIN UPPER † 1  10/157 (6.37%)  2/22 (9.09%)  4/58 (6.90%)  0/33 (0.00%)  0/28 (0.00%) 
CONSTIPATION † 1  30/157 (19.11%)  2/22 (9.09%)  23/58 (39.66%)  4/33 (12.12%)  6/28 (21.43%) 
DIARRHOEA † 1  61/157 (38.85%)  0/22 (0.00%)  13/58 (22.41%)  7/33 (21.21%)  6/28 (21.43%) 
DRY MOUTH † 1  2/157 (1.27%)  0/22 (0.00%)  3/58 (5.17%)  2/33 (6.06%)  0/28 (0.00%) 
DYSPEPSIA † 1  9/157 (5.73%)  1/22 (4.55%)  1/58 (1.72%)  1/33 (3.03%)  1/28 (3.57%) 
GINGIVAL BLEEDING † 1  10/157 (6.37%)  1/22 (4.55%)  2/58 (3.45%)  1/33 (3.03%)  0/28 (0.00%) 
HAEMORRHOIDS † 1  5/157 (3.18%)  1/22 (4.55%)  5/58 (8.62%)  1/33 (3.03%)  0/28 (0.00%) 
MELAENA † 1  1/157 (0.64%)  0/22 (0.00%)  0/58 (0.00%)  2/33 (6.06%)  0/28 (0.00%) 
MOUTH HAEMORRHAGE † 1  10/157 (6.37%)  1/22 (4.55%)  3/58 (5.17%)  1/33 (3.03%)  0/28 (0.00%) 
NAUSEA † 1  67/157 (42.68%)  2/22 (9.09%)  16/58 (27.59%)  10/33 (30.30%)  7/28 (25.00%) 
STOMATITIS † 1  15/157 (9.55%)  1/22 (4.55%)  4/58 (6.90%)  7/33 (21.21%)  5/28 (17.86%) 
VOMITING † 1  39/157 (24.84%)  1/22 (4.55%)  9/58 (15.52%)  5/33 (15.15%)  1/28 (3.57%) 
General disorders           
ASTHENIA † 1  28/157 (17.83%)  2/22 (9.09%)  13/58 (22.41%)  5/33 (15.15%)  4/28 (14.29%) 
FATIGUE † 1  44/157 (28.03%)  0/22 (0.00%)  9/58 (15.52%)  6/33 (18.18%)  4/28 (14.29%) 
GENERAL PHYSICAL HEALTH DETERIORATION † 1  10/157 (6.37%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
INFLUENZA LIKE ILLNESS † 1  5/157 (3.18%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  0/28 (0.00%) 
INJECTION SITE PAIN † 1  0/157 (0.00%)  0/22 (0.00%)  5/58 (8.62%)  0/33 (0.00%)  0/28 (0.00%) 
NON-CARDIAC CHEST PAIN † 1  5/157 (3.18%)  1/22 (4.55%)  3/58 (5.17%)  0/33 (0.00%)  0/28 (0.00%) 
OEDEMA PERIPHERAL † 1  32/157 (20.38%)  1/22 (4.55%)  12/58 (20.69%)  6/33 (18.18%)  2/28 (7.14%) 
PYREXIA † 1  37/157 (23.57%)  4/22 (18.18%)  14/58 (24.14%)  5/33 (15.15%)  5/28 (17.86%) 
Hepatobiliary disorders           
HYPERBILIRUBINAEMIA † 1  15/157 (9.55%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
Infections and infestations           
BRONCHITIS † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  2/33 (6.06%)  1/28 (3.57%) 
CELLULITIS † 1  3/157 (1.91%)  1/22 (4.55%)  2/58 (3.45%)  2/33 (6.06%)  1/28 (3.57%) 
INFECTION † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  2/28 (7.14%) 
ORAL CANDIDIASIS † 1  9/157 (5.73%)  1/22 (4.55%)  2/58 (3.45%)  1/33 (3.03%)  0/28 (0.00%) 
PHARYNGITIS † 1  3/157 (1.91%)  0/22 (0.00%)  0/58 (0.00%)  2/33 (6.06%)  0/28 (0.00%) 
PNEUMONIA † 1  7/157 (4.46%)  0/22 (0.00%)  5/58 (8.62%)  0/33 (0.00%)  1/28 (3.57%) 
RHINITIS † 1  4/157 (2.55%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
TOOTH INFECTION † 1  2/157 (1.27%)  0/22 (0.00%)  0/58 (0.00%)  2/33 (6.06%)  0/28 (0.00%) 
UPPER RESPIRATORY TRACT INFECTION † 1  13/157 (8.28%)  0/22 (0.00%)  6/58 (10.34%)  0/33 (0.00%)  1/28 (3.57%) 
URINARY TRACT INFECTION † 1  12/157 (7.64%)  2/22 (9.09%)  1/58 (1.72%)  0/33 (0.00%)  0/28 (0.00%) 
Injury, poisoning and procedural complications           
CONTUSION † 1  12/157 (7.64%)  0/22 (0.00%)  3/58 (5.17%)  1/33 (3.03%)  0/28 (0.00%) 
FALL † 1  13/157 (8.28%)  0/22 (0.00%)  4/58 (6.90%)  1/33 (3.03%)  0/28 (0.00%) 
Investigations           
ALANINE AMINOTRANSFERASE INCREASED † 1  7/157 (4.46%)  0/22 (0.00%)  3/58 (5.17%)  2/33 (6.06%)  2/28 (7.14%) 
ASPARTATE AMINOTRANSFERASE INCREASED † 1  6/157 (3.82%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  2/28 (7.14%) 
BLOOD ALKALINE PHOSPHATASE INCREASED † 1  5/157 (3.18%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
BLOOD BILIRUBIN INCREASED † 1  40/157 (25.48%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  2/28 (7.14%) 
BLOOD CREATININE INCREASED † 1  20/157 (12.74%)  0/22 (0.00%)  5/58 (8.62%)  0/33 (0.00%)  1/28 (3.57%) 
C-REACTIVE PROTEIN INCREASED † 1  8/157 (5.10%)  0/22 (0.00%)  4/58 (6.90%)  3/33 (9.09%)  1/28 (3.57%) 
WEIGHT DECREASED † 1  13/157 (8.28%)  0/22 (0.00%)  4/58 (6.90%)  1/33 (3.03%)  2/28 (7.14%) 
WEIGHT INCREASED † 1  0/157 (0.00%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  3/28 (10.71%) 
Metabolism and nutrition disorders           
DECREASED APPETITE † 1  49/157 (31.21%)  1/22 (4.55%)  13/58 (22.41%)  5/33 (15.15%)  2/28 (7.14%) 
HYPERGLYCAEMIA † 1  11/157 (7.01%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  2/28 (7.14%) 
HYPERKALAEMIA † 1  2/157 (1.27%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
HYPERURICAEMIA † 1  17/157 (10.83%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  1/28 (3.57%) 
HYPOALBUMINAEMIA † 1  12/157 (7.64%)  2/22 (9.09%)  4/58 (6.90%)  0/33 (0.00%)  2/28 (7.14%) 
HYPOCALCAEMIA † 1  15/157 (9.55%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  2/28 (7.14%) 
HYPOKALAEMIA † 1  51/157 (32.48%)  1/22 (4.55%)  10/58 (17.24%)  2/33 (6.06%)  7/28 (25.00%) 
HYPOMAGNESAEMIA † 1  18/157 (11.46%)  1/22 (4.55%)  3/58 (5.17%)  2/33 (6.06%)  6/28 (21.43%) 
HYPONATRAEMIA † 1  10/157 (6.37%)  0/22 (0.00%)  2/58 (3.45%)  1/33 (3.03%)  1/28 (3.57%) 
HYPOPHOSPHATAEMIA † 1  9/157 (5.73%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
Musculoskeletal and connective tissue disorders           
ARTHRALGIA † 1  11/157 (7.01%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
BACK PAIN † 1  19/157 (12.10%)  0/22 (0.00%)  3/58 (5.17%)  2/33 (6.06%)  1/28 (3.57%) 
MUSCULAR WEAKNESS † 1  11/157 (7.01%)  1/22 (4.55%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
PAIN IN EXTREMITY † 1  19/157 (12.10%)  0/22 (0.00%)  6/58 (10.34%)  5/33 (15.15%)  1/28 (3.57%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
DIFFERENTIATION SYNDROME † 1  16/157 (10.19%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
Nervous system disorders           
DIZZINESS † 1  23/157 (14.65%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
DYSGEUSIA † 1  12/157 (7.64%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  1/28 (3.57%) 
HEADACHE † 1  23/157 (14.65%)  0/22 (0.00%)  3/58 (5.17%)  5/33 (15.15%)  2/28 (7.14%) 
PERIPHERAL SENSORY NEUROPATHY † 1  3/157 (1.91%)  0/22 (0.00%)  3/58 (5.17%)  1/33 (3.03%)  0/28 (0.00%) 
Psychiatric disorders           
ANXIETY † 1  8/157 (5.10%)  0/22 (0.00%)  0/58 (0.00%)  0/33 (0.00%)  0/28 (0.00%) 
CONFUSIONAL STATE † 1  9/157 (5.73%)  0/22 (0.00%)  0/58 (0.00%)  2/33 (6.06%)  2/28 (7.14%) 
INSOMNIA † 1  23/157 (14.65%)  1/22 (4.55%)  10/58 (17.24%)  2/33 (6.06%)  2/28 (7.14%) 
Renal and urinary disorders           
CHRONIC KIDNEY DISEASE † 1  2/157 (1.27%)  0/22 (0.00%)  3/58 (5.17%)  1/33 (3.03%)  0/28 (0.00%) 
DYSURIA † 1  2/157 (1.27%)  0/22 (0.00%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
Reproductive system and breast disorders           
VAGINAL HAEMORRHAGE † 1  1/157 (0.64%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  2/28 (7.14%) 
Respiratory, thoracic and mediastinal disorders           
COUGH † 1  26/157 (16.56%)  3/22 (13.64%)  8/58 (13.79%)  8/33 (24.24%)  2/28 (7.14%) 
DYSPNOEA † 1  32/157 (20.38%)  2/22 (9.09%)  3/58 (5.17%)  3/33 (9.09%)  1/28 (3.57%) 
EPISTAXIS † 1  27/157 (17.20%)  3/22 (13.64%)  10/58 (17.24%)  4/33 (12.12%)  4/28 (14.29%) 
OROPHARYNGEAL PAIN † 1  8/157 (5.10%)  0/22 (0.00%)  2/58 (3.45%)  4/33 (12.12%)  2/28 (7.14%) 
PLEURAL EFFUSION † 1  8/157 (5.10%)  1/22 (4.55%)  3/58 (5.17%)  0/33 (0.00%)  0/28 (0.00%) 
Skin and subcutaneous tissue disorders           
ERYTHEMA † 1  6/157 (3.82%)  0/22 (0.00%)  5/58 (8.62%)  1/33 (3.03%)  1/28 (3.57%) 
PETECHIAE † 1  13/157 (8.28%)  0/22 (0.00%)  4/58 (6.90%)  4/33 (12.12%)  0/28 (0.00%) 
PRURITUS † 1  9/157 (5.73%)  0/22 (0.00%)  0/58 (0.00%)  1/33 (3.03%)  0/28 (0.00%) 
RASH † 1  9/157 (5.73%)  0/22 (0.00%)  6/58 (10.34%)  0/33 (0.00%)  1/28 (3.57%) 
RASH MACULO-PAPULAR † 1  9/157 (5.73%)  0/22 (0.00%)  1/58 (1.72%)  1/33 (3.03%)  1/28 (3.57%) 
Vascular disorders           
HAEMATOMA † 1  11/157 (7.01%)  0/22 (0.00%)  2/58 (3.45%)  0/33 (0.00%)  0/28 (0.00%) 
HYPERTENSION † 1  8/157 (5.10%)  0/22 (0.00%)  4/58 (6.90%)  1/33 (3.03%)  2/28 (7.14%) 
HYPOTENSION † 1  14/157 (8.92%)  0/22 (0.00%)  1/58 (1.72%)  0/33 (0.00%)  1/28 (3.57%) 
PHLEBITIS † 1  2/157 (1.27%)  1/22 (4.55%)  3/58 (5.17%)  0/33 (0.00%)  1/28 (3.57%) 
1
Term from vocabulary, 22.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
Phone: 855-907-3286
EMail: Clinical.Trials@bms.com
Layout table for additonal information
Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02577406    
Other Study ID Numbers: AG-221-AML-004
First Submitted: October 14, 2015
First Posted: October 16, 2015
Results First Submitted: June 29, 2022
Results First Posted: September 10, 2022
Last Update Posted: February 23, 2023