A Phase 2 interventional study of Azacitidine and Entinostat in Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia in Remission and Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, sponsored by National Cancer Institute (NCI). Completed at 234 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-02-02.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
This randomized phase II trial studies azacitidine with or without entinostat to see how well they work compared to azacitidine alone in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may work better in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
PRIMARY OBJECTIVES:
I. To estimate the overall response rate (complete, partial, and hematologic improvement-major by International Working Group [IWG] criteria) in response to azacitidine and entinostat.
II. To estimate the major response rate (complete and partial responses by the IWG response criteria) to a 10-day regimen of azacitidine and to the same regimen of azacitidine in combination with entinostat administered orally on days 3 and 10 of each cycle in patients with de novo myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMMoL) (dysplastic) and acute myeloid leukemia with trilineage dysplasia (AML-TLD), as well as in patients with treatment-induced MDS, CMMoL (dysplastic) and AML-TLD.
SECONDARY OBJECTIVES:
I. To evaluate the toxicity of azacitidine and entinostat in this patient population.
II. To identify changes in gene promoter methylation and gene expression which may be associated with response to azacitidine and entinostat.
III. To identify other molecular mechanisms (such as deoxyribonucleic acid [DNA] damage) which may be associated with response to azacitidine and entinostat.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-10.
ARM B: Patients receive azacitidine as in Arm A and entinostat orally (PO) on days 3 and 10.
In both arms, treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 5 years.
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This study's enrollment of 197 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.
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Inclusion Criteria:
Patients receive azacitidine SC QD on days 1-10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine · Other: Laboratory Biomarker Analysis
Patients receive azacitidine as in Arm A and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Drug: Azacitidine · Drug: Entinostat · Other: Laboratory Biomarker Analysis
Given SC
Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza
Given PO
Also known as: HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275
Correlative studies
Proportion of Patients With Clinical Response
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.
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.
| Milestone | 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) |
|---|---|---|---|---|
| Started | 75 | 75 | 24 | 23 |
| Treated | 74 | 75 | 24 | 23 |
| Completed | 5 | 5 | 0 | 0 |
| Not completed | 70 | 70 | 24 | 23 |
| Withdrew: Disease progression | 14 | 19 | 10 | 3 |
| Withdrew: Adverse event | 12 | 18 | 3 | 10 |
| Withdrew: Death | 11 | 8 | 1 | 7 |
| Withdrew: Withdrawal by subject | 13 | 6 | 6 | 2 |
| Withdrew: Alternative therapy | 3 | 6 | 2 | 0 |
| Withdrew: Other complicating disease | 2 | 2 | 0 | 0 |
| Withdrew: Did not achieve hi-major/better response | 10 | 7 | 2 | 1 |
| Withdrew: Physician decision | 2 | 1 | 0 | 0 |
| Withdrew: Absolute neutrophil count not recovered | 2 | 1 | 0 | 0 |
| Withdrew: Lost insurance | 0 | 1 | 0 | 0 |
| Withdrew: Moved | 0 | 1 | 0 | 0 |
| Withdrew: Death before starting treatment | 1 | 0 | 0 | 0 |
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.)
| Proportion of patients | 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) |
|---|---|---|---|---|
| Proportion of Patients With Clinical Response | 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) |
Collected over Assessed every 4 weeks while on treatment and for 30 days after the end of treatment. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm A (Azacitidine) | — | 92/99 (92.9%) | 96/99 (97%) |
| Arm B (Azacitidine + Entinostat) | — | 93/98 (94.9%) | 97/98 (99%) |
| Event | Arm A (Azacitidine) | Arm B (Azacitidine + Entinostat) |
|---|---|---|
| NeutrophilsInvestigations | 78/99 | 72/98 |
| PlateletsInvestigations | 75/99 | 76/98 |
| LeukocytesInvestigations | 69/99 | 65/98 |
| HemoglobinBlood and lymphatic system disorders | 55/99 | 54/98 |
| Febrile neutropeniaBlood and lymphatic system disorders | 20/99 | 25/98 |
| FatigueGeneral disorders | 10/99 | 21/98 |
| HyponatremiaMetabolism and nutrition disorders | 2/99 | 12/98 |
| Infection w/ gr3-4 neut, lungInfections and infestations | 8/99 | 9/98 |
| LymphopeniaInvestigations | 5/99 | 7/98 |
| HypoalbuminemiaMetabolism and nutrition disorders | 1/99 | 7/98 |
| Event | Arm A (Azacitidine) | Arm B (Azacitidine + Entinostat) |
|---|---|---|
| HemoglobinBlood and lymphatic system disorders | 80/99 | 74/98 |
| FatigueGeneral disorders | 71/99 | 71/98 |
| LeukocytesInvestigations | 67/99 | 57/98 |
| PlateletsInvestigations | 63/99 | 57/98 |
| NeutrophilsInvestigations | 56/99 | 49/98 |
| NauseaGastrointestinal disorders | 49/99 | 55/98 |
| AnorexiaMetabolism and nutrition disorders | 27/99 | 49/98 |
| Injection site reactionGeneral disorders | 41/99 | 42/98 |
| HypocalcemiaMetabolism and nutrition disorders | 16/99 | 42/98 |
| HypoalbuminemiaMetabolism and nutrition disorders | 22/99 | 41/98 |
All treated patients were included in the analysis.
| Age, Continuous(years) | 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 |
|---|---|---|---|---|---|
| Median | 72 (25 to 87) | 72 (30 to 86) | 68 (54 to 83) | 71 (39 to 81) | 71 (25 to 87) |
| Gender(Participants) | 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 |
|---|---|---|---|---|---|
| Female | 24 | 23 | 15 | 11 | 73 |
| Male | 50 | 52 | 9 | 12 | 123 |
| Region of Enrollment(participants) | 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 |
|---|---|---|---|---|---|
| United States | 74 | 75 | 24 | 23 | 196 |
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