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Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT00313586
Recruitment Status : Completed
First Posted : April 12, 2006
Results First Posted : November 25, 2014
Last Update Posted : February 2, 2017
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
Alkylating Agent-Related Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndrome
Previously Treated Myelodysplastic Syndrome
Recurrent Adult Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndrome
Untreated Adult Acute Myeloid Leukemia
Interventions Drug: Azacitidine
Drug: Entinostat
Other: Laboratory Biomarker Analysis
Enrollment 197
Recruitment Details Participants were recruited from ECOG member institutions between August 18, 2006 and April 29, 2011. One hundred and fifty non-treatment-induced patients and forty-seven treatment-induced patients were enrolled.
Pre-assignment Details  
Arm/Group Title Arm A (Azacitidine; Non-treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Non-treatment-induced Cohort) Arm A (Azacitidine; Treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Treatment-induced Cohort)
Hide Arm/Group Description Non-treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle. Non-treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle. Treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle. Treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle.
Period Title: Overall Study
Started 75 75 24 23
Treated 74 75 24 23
Completed 5 5 0 0
Not Completed 70 70 24 23
Reason Not Completed
Disease progression             14             19             10             3
Adverse Event             12             18             3             10
Death             11             8             1             7
Withdrawal by Subject             13             6             6             2
Alternative therapy             3             6             2             0
Other complicating disease             2             2             0             0
Did not achieve HI-major/better response             10             7             2             1
Physician Decision             2             1             0             0
Absolute neutrophil count not recovered             2             1             0             0
Lost insurance             0             1             0             0
Moved             0             1             0             0
Death before starting treatment             1             0             0             0
Arm/Group Title Arm A (Azacitidine; Non-treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Non-treatment-induced Cohort) Arm A (Azacitidine; Treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Treatment-induced Cohort) Total
Hide Arm/Group Description Non-treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle. Non-treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle. Treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle. Treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle. Total of all reporting groups
Overall Number of Baseline Participants 74 75 24 23 196
Hide Baseline Analysis Population Description
All treated patients were included in the analysis.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 74 participants 75 participants 24 participants 23 participants 196 participants
72
(25 to 87)
72
(30 to 86)
68
(54 to 83)
71
(39 to 81)
71
(25 to 87)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 74 participants 75 participants 24 participants 23 participants 196 participants
Female
24
  32.4%
23
  30.7%
15
  62.5%
11
  47.8%
73
  37.2%
Male
50
  67.6%
52
  69.3%
9
  37.5%
12
  52.2%
123
  62.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 74 participants 75 participants 24 participants 23 participants 196 participants
74 75 24 23 196
1.Primary Outcome
Title Proportion of Patients With Clinical Response
Hide Description

Clinical response is defined as a complete response (CR), partial response (PR) or trilineage response (TR) graded according to the following criteria:

  1. World Health Organization classification of the acute leukemias and myelodysplastic syndrome (by Bennett)
  2. Myelodysplastic syndromes standardized response criteria: further definition (by Cheson et al.)
  3. Report of an international working group to standardize response criteria for myelodysplastic syndromes (by Cheson et al.)
Time Frame Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2 - 5 years from study entry.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All treated patients are included in the analysis.
Arm/Group Title Arm A (Azacitidine; Non-treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Non-treatment-induced Cohort) Arm A (Azacitidine; Treatment-induced Cohort) Arm B (Azacitidine + Entinostat; Treatment-induced Cohort)
Hide Arm/Group Description:
Non-treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle.
Non-treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle.
Treatment-induced patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle.
Treatment-induced patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle.
Overall Number of Participants Analyzed 74 75 24 23
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of patients
0.32
(0.22 to 0.44)
0.27
(0.17 to 0.39)
0.46
(0.26 to 0.67)
0.17
(0.05 to 0.39)
Time Frame Assessed every 4 weeks while on treatment and for 30 days after the end of treatment
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm A (Azacitidine) Arm B (Azacitidine + Entinostat)
Hide Arm/Group Description Patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle. Patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle.
All-Cause Mortality
Arm A (Azacitidine) Arm B (Azacitidine + Entinostat)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Arm A (Azacitidine) Arm B (Azacitidine + Entinostat)
Affected / at Risk (%) Affected / at Risk (%)
Total   92/99 (92.93%)   93/98 (94.90%) 
Blood and lymphatic system disorders     
Hemoglobin  1  55/99 (55.56%)  54/98 (55.10%) 
Hemolysis  1  0/99 (0.00%)  1/98 (1.02%) 
DIC  1  1/99 (1.01%)  0/98 (0.00%) 
Febrile neutropenia  1  20/99 (20.20%)  25/98 (25.51%) 
Cardiac disorders     
Heart block 3rd degree  1  0/99 (0.00%)  1/98 (1.02%) 
Atrial fibrillation  1  1/99 (1.01%)  2/98 (2.04%) 
Left ventricular diastolic dysfunction  1  0/99 (0.00%)  1/98 (1.02%) 
Pericardial effusion (non-malignant)  1  0/99 (0.00%)  1/98 (1.02%) 
Cardiac/heart, pain  1  0/99 (0.00%)  1/98 (1.02%) 
Eye disorders     
Neuropathy CN II vision  1  0/99 (0.00%)  1/98 (1.02%) 
Gastrointestinal disorders     
Colitis  1  1/99 (1.01%)  1/98 (1.02%) 
Constipation  1  2/99 (2.02%)  0/98 (0.00%) 
Diarrhea w/o prior colostomy  1  4/99 (4.04%)  3/98 (3.06%) 
Ileus  1  0/99 (0.00%)  1/98 (1.02%) 
Muco/stomatitis by exam, oral cavity  1  2/99 (2.02%)  0/98 (0.00%) 
Muco/stomatitis (symptom) oral cavity  1  1/99 (1.01%)  0/98 (0.00%) 
Nausea  1  2/99 (2.02%)  5/98 (5.10%) 
Obstruction, small bowel NOS  1  0/99 (0.00%)  1/98 (1.02%) 
Typhlitis  1  1/99 (1.01%)  0/98 (0.00%) 
Vomiting  1  3/99 (3.03%)  1/98 (1.02%) 
Abdomen, hemorrhage NOS  1  0/99 (0.00%)  1/98 (1.02%) 
Lower GI, hemorrhage NOS  1  0/99 (0.00%)  1/98 (1.02%) 
Oral cavity, hemorrhage  1  0/99 (0.00%)  1/98 (1.02%) 
Abdomen, pain  1  0/99 (0.00%)  1/98 (1.02%) 
General disorders     
Fatigue  1  10/99 (10.10%)  21/98 (21.43%) 
Constitutional, other  1  0/99 (0.00%)  1/98 (1.02%) 
Injection site reaction  1  2/99 (2.02%)  0/98 (0.00%) 
Death - multiorgan failure  1  1/99 (1.01%)  1/98 (1.02%) 
Death - sudden death  1  0/99 (0.00%)  1/98 (1.02%) 
Edema limb  1  0/99 (0.00%)  1/98 (1.02%) 
Chest/thoracic pain NOS  1  0/99 (0.00%)  1/98 (1.02%) 
Immune system disorders     
Autoimmune reaction  1  0/99 (0.00%)  1/98 (1.02%) 
Infections and infestations     
Colitis, infectious (e.g. C.diff)  1  1/99 (1.01%)  2/98 (2.04%) 
Infection w/ gr3-4 neut, abdomen NOS  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ gr3-4 neut, anal/perianal  1  0/99 (0.00%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, bronchus  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ gr3-4 neut, catheter relate  1  2/99 (2.02%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, colon  1  0/99 (0.00%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, foreign body  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ gr3-4 neut, lung  1  8/99 (8.08%)  9/98 (9.18%) 
Infection w/ gr3-4 neut, muscle  1  0/99 (0.00%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, pharynx  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ gr3-4 neut, sinus  1  1/99 (1.01%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, skin  1  1/99 (1.01%)  2/98 (2.04%) 
Infection w/ gr3-4 neut, soft tissue NOS  1  0/99 (0.00%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, upper airway  1  1/99 (1.01%)  1/98 (1.02%) 
Infection w/ gr3-4 neut, urinary tract  1  0/99 (0.00%)  2/98 (2.04%) 
Infection Gr0-2 neut, catheter  1  1/99 (1.01%)  0/98 (0.00%) 
Infection Gr0-2 neut, colon  1  1/99 (1.01%)  0/98 (0.00%) 
Infection Gr0-2 neut, lung  1  1/99 (1.01%)  2/98 (2.04%) 
Infection Gr0-2 neut, muscle  1  0/99 (0.00%)  1/98 (1.02%) 
Infection Gr0-2 neut, skin  1  1/99 (1.01%)  0/98 (0.00%) 
Infection Gr0-2 neut, urinary tract  1  1/99 (1.01%)  0/98 (0.00%) 
Infection Gr0-2 neut, wound  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ unk ANC abdomen NOS  1  1/99 (1.01%)  0/98 (0.00%) 
Infection w/ unk ANC urinary tract NOS  1  1/99 (1.01%)  1/98 (1.02%) 
Opportunistic infection lymphopenia>=gr1  1  0/99 (0.00%)  3/98 (3.06%) 
Infection w/ gr3-4 neut, blood  1  2/99 (2.02%)  5/98 (5.10%) 
Infection Gr0-2 neut, blood  1  1/99 (1.01%)  1/98 (1.02%) 
Infection-other  1  0/99 (0.00%)  2/98 (2.04%) 
Investigations     
Leukocytes  1  69/99 (69.70%)  65/98 (66.33%) 
Lymphopenia  1  5/99 (5.05%)  7/98 (7.14%) 
Neutrophils  1  78/99 (78.79%)  72/98 (73.47%) 
Platelets  1  75/99 (75.76%)  76/98 (77.55%) 
Weight loss  1  0/99 (0.00%)  1/98 (1.02%) 
Coagulation-other  1  0/99 (0.00%)  1/98 (1.02%) 
Alkaline phosphatase  1  1/99 (1.01%)  0/98 (0.00%) 
ALT, SGPT  1  0/99 (0.00%)  4/98 (4.08%) 
AST, SGOT  1  1/99 (1.01%)  5/98 (5.10%) 
Bilirubin  1  2/99 (2.02%)  2/98 (2.04%) 
Creatinine  1  1/99 (1.01%)  3/98 (3.06%) 
Lipase  1  0/99 (0.00%)  1/98 (1.02%) 
Metabolism and nutrition disorders     
Anorexia  1  2/99 (2.02%)  4/98 (4.08%) 
Dehydration  1  2/99 (2.02%)  2/98 (2.04%) 
Hypoalbuminemia  1  1/99 (1.01%)  7/98 (7.14%) 
Hypocalcemia  1  0/99 (0.00%)  3/98 (3.06%) 
Hyperglycemia  1  3/99 (3.03%)  7/98 (7.14%) 
Hypomagnesemia  1  1/99 (1.01%)  1/98 (1.02%) 
Hypophosphatemia  1  2/99 (2.02%)  3/98 (3.06%) 
Hyperkalemia  1  0/99 (0.00%)  1/98 (1.02%) 
Hypokalemia  1  3/99 (3.03%)  2/98 (2.04%) 
Hyponatremia  1  2/99 (2.02%)  12/98 (12.24%) 
Hyperuricemia  1  1/99 (1.01%)  0/98 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  0/99 (0.00%)  2/98 (2.04%) 
Nonneuropathic generalized weakness  1  0/99 (0.00%)  1/98 (1.02%) 
Chest wall, pain  1  0/99 (0.00%)  1/98 (1.02%) 
Extremity-limb, pain  1  1/99 (1.01%)  1/98 (1.02%) 
Joint, pain  1  0/99 (0.00%)  1/98 (1.02%) 
Muscle, pain  1  0/99 (0.00%)  1/98 (1.02%) 
Nervous system disorders     
CNS, hemorrhage  1  0/99 (0.00%)  1/98 (1.02%) 
Ataxia  1  1/99 (1.01%)  0/98 (0.00%) 
Dizziness  1  0/99 (0.00%)  1/98 (1.02%) 
Neuropathy-sensory  1  0/99 (0.00%)  1/98 (1.02%) 
Syncope  1  0/99 (0.00%)  1/98 (1.02%) 
Head/headache  1  1/99 (1.01%)  4/98 (4.08%) 
Psychiatric disorders     
Confusion  1  1/99 (1.01%)  1/98 (1.02%) 
Renal and urinary disorders     
Renal failure  1  0/99 (0.00%)  3/98 (3.06%) 
Respiratory, thoracic and mediastinal disorders     
Nose, hemorrhage  1  0/99 (0.00%)  1/98 (1.02%) 
Dyspnea  1  3/99 (3.03%)  5/98 (5.10%) 
Hypoxia  1  2/99 (2.02%)  1/98 (1.02%) 
Pulmonary/Upper Respiratory-other  1  0/99 (0.00%)  1/98 (1.02%) 
Skin and subcutaneous tissue disorders     
Rash/desquamation  1  0/99 (0.00%)  2/98 (2.04%) 
Rash: acne/acneiform  1  0/99 (0.00%)  1/98 (1.02%) 
Vascular disorders     
Hypotension  1  4/99 (4.04%)  3/98 (3.06%) 
Visceral arterial ischemia  1  0/99 (0.00%)  1/98 (1.02%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE 3.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm A (Azacitidine) Arm B (Azacitidine + Entinostat)
Affected / at Risk (%) Affected / at Risk (%)
Total   96/99 (96.97%)   97/98 (98.98%) 
Blood and lymphatic system disorders     
Hemoglobin  1  80/99 (80.81%)  74/98 (75.51%) 
Gastrointestinal disorders     
Constipation  1  37/99 (37.37%)  39/98 (39.80%) 
Diarrhea w/o prior colostomy  1  28/99 (28.28%)  40/98 (40.82%) 
Dyspepsia  1  7/99 (7.07%)  10/98 (10.20%) 
Muco/stomatitis by exam, oral cavity  1  4/99 (4.04%)  5/98 (5.10%) 
Nausea  1  49/99 (49.49%)  55/98 (56.12%) 
Vomiting  1  22/99 (22.22%)  30/98 (30.61%) 
Abdomen, pain  1  9/99 (9.09%)  13/98 (13.27%) 
General disorders     
Fatigue  1  71/99 (71.72%)  71/98 (72.45%) 
Fever w/o neutropenia  1  10/99 (10.10%)  7/98 (7.14%) 
Rigors/chills  1  4/99 (4.04%)  5/98 (5.10%) 
Injection site reaction  1  41/99 (41.41%)  42/98 (42.86%) 
Edema limb  1  7/99 (7.07%)  23/98 (23.47%) 
Injury, poisoning and procedural complications     
Bruising  1  6/99 (6.06%)  6/98 (6.12%) 
Investigations     
Leukocytes  1  67/99 (67.68%)  57/98 (58.16%) 
Lymphopenia  1  11/99 (11.11%)  8/98 (8.16%) 
Neutrophils  1  56/99 (56.57%)  49/98 (50.00%) 
Platelets  1  63/99 (63.64%)  57/98 (58.16%) 
Weight loss  1  8/99 (8.08%)  15/98 (15.31%) 
Alkaline phosphatase  1  11/99 (11.11%)  17/98 (17.35%) 
ALT, SGPT  1  15/99 (15.15%)  12/98 (12.24%) 
AST, SGOT  1  14/99 (14.14%)  11/98 (11.22%) 
Bilirubin  1  11/99 (11.11%)  11/98 (11.22%) 
Creatinine  1  18/99 (18.18%)  26/98 (26.53%) 
Metabolism and nutrition disorders     
Anorexia  1  27/99 (27.27%)  49/98 (50.00%) 
Dehydration  1  3/99 (3.03%)  9/98 (9.18%) 
Hypoalbuminemia  1  22/99 (22.22%)  41/98 (41.84%) 
Hypocalcemia  1  16/99 (16.16%)  42/98 (42.86%) 
Hyperglycemia  1  30/99 (30.30%)  40/98 (40.82%) 
Hypomagnesemia  1  3/99 (3.03%)  5/98 (5.10%) 
Hypophosphatemia  1  2/99 (2.02%)  8/98 (8.16%) 
Hypokalemia  1  7/99 (7.07%)  14/98 (14.29%) 
Hyponatremia  1  24/99 (24.24%)  36/98 (36.73%) 
Musculoskeletal and connective tissue disorders     
Nonneuropathic generalized weakness  1  1/99 (1.01%)  7/98 (7.14%) 
Joint, pain  1  3/99 (3.03%)  10/98 (10.20%) 
Muscle, pain  1  1/99 (1.01%)  7/98 (7.14%) 
Nervous system disorders     
Taste disturbance  1  9/99 (9.09%)  18/98 (18.37%) 
Dizziness  1  3/99 (3.03%)  11/98 (11.22%) 
Neuropathy-sensory  1  2/99 (2.02%)  8/98 (8.16%) 
Head/headache  1  9/99 (9.09%)  16/98 (16.33%) 
Psychiatric disorders     
Insomnia  1  8/99 (8.08%)  10/98 (10.20%) 
Respiratory, thoracic and mediastinal disorders     
Allergic rhinitis  1  5/99 (5.05%)  4/98 (4.08%) 
Nose, hemorrhage  1  3/99 (3.03%)  12/98 (12.24%) 
Cough  1  6/99 (6.06%)  9/98 (9.18%) 
Dyspnea  1  15/99 (15.15%)  22/98 (22.45%) 
Skin and subcutaneous tissue disorders     
Sweating  1  6/99 (6.06%)  6/98 (6.12%) 
Alopecia  1  6/99 (6.06%)  9/98 (9.18%) 
Pruritus/itching  1  5/99 (5.05%)  7/98 (7.14%) 
Rash/desquamation  1  11/99 (11.11%)  13/98 (13.27%) 
Petechiae  1  4/99 (4.04%)  9/98 (9.18%) 
Vascular disorders     
Hypotension  1  2/99 (2.02%)  8/98 (8.16%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE 3.0
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.
Results Point of Contact
Name/Title: Study Statistician
Organization: ECOG Statistical Office
Phone: 617-632-3012
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00313586     History of Changes
Other Study ID Numbers: NCI-2009-01077
NCI-2009-01077 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ECOG-E1905
CDR0000466186
E1905 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E1905 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
U10CA021115 ( U.S. NIH Grant/Contract )
First Submitted: April 11, 2006
First Posted: April 12, 2006
Results First Submitted: November 18, 2014
Results First Posted: November 25, 2014
Last Update Posted: February 2, 2017