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Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer

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ClinicalTrials.gov Identifier: NCT01349959
Recruitment Status : Active, not recruiting
First Posted : May 9, 2011
Results First Posted : March 17, 2016
Last Update Posted : June 10, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Estrogen Receptor Negative
Estrogen Receptor Positive
HER2/Neu Negative
Male Breast Carcinoma
Progesterone Receptor Negative
Recurrent Breast Carcinoma
Stage IIIC Breast Cancer AJCC v7
Stage IV Breast Cancer AJCC v6 and v7
Triple-Negative Breast Carcinoma
Interventions Drug: Azacitidine
Drug: Entinostat
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Enrollment 58
Recruitment Details  
Pre-assignment Details 58 consented, 18 screen failed and did not receive study treatment
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Period Title: Overall Study
Started 40
Completed 33
Not Completed 7
Reason Not Completed
Adverse Event             7
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Baseline Participants 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
<=18 years
0
   0.0%
Between 18 and 65 years
35
  87.5%
>=65 years
5
  12.5%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
Female
40
 100.0%
Male
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
Hispanic or Latino
4
  10.0%
Not Hispanic or Latino
35
  87.5%
Unknown or Not Reported
1
   2.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
6
  15.0%
White
31
  77.5%
More than one race
3
   7.5%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 40 participants
40
 100.0%
1.Primary Outcome
Title Confirmed Response Rate (Percentage of Participants With Complete or Partial Response Noted as the Objective Status on Two Consecutive Evaluations at Least 4 Weeks Apart) Assessed by RECIST
Hide Description Percentage of participants with complete or partial response will be estimated independently for each cohort by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Triple-negative Breast Cancer (TNBC) Number Analyzed 13 participants
0 [1] 
(NA to NA)
Hormone-resistant Breast Cancer (HRBC) Number Analyzed 27 participants
4
(0 to 19)
[1]
No clinical response was observed in participants with TNBC.
2.Secondary Outcome
Title Clinical Benefit Rate
Hide Description Clinical benefit rate estimated by the number of patients who achieve a confirmed response plus the number of patients who have stable disease for a duration of at least 6 months divided by the total number of evaluable patients. All evaluable patients will be used for this analysis.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Measure Type: Count of Participants
Unit of Measure: Participants
TNBC Number Analyzed 13 participants
0
   0.0%
HRBC Number Analyzed 27 participants
1
   3.7%
3.Secondary Outcome
Title Overall Survival
Hide Description Median number of months alive, estimated by Kaplan-Meier method.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Median (95% Confidence Interval)
Unit of Measure: months
TNBC Number Analyzed 13 participants
6.6
(2.0 to 10.3)
HRBC Number Analyzed 27 participants
12.6
(6.3 to 16.3)
4.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description Median number of months without progression. Estimated using the method of Kaplan-Meier.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Median (95% Confidence Interval)
Unit of Measure: months
TNBC Number Analyzed 13 participants
1.4
(0.9 to 1.8)
HRBC Number Analyzed 27 participants
1.8
(1.7 to 1.9)
5.Other Pre-specified Outcome
Title Number of Participants With Change in Expression of Relevant Genes (e.g., ER Alpha and RAR Beta) Evaluated by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)
Hide Description Number of participants with a change in candidate gene re-expression of ER-alpha and RAR beta evaluated by reverse transcriptase polymerase chain reaction (RT-PCR).
Time Frame Baseline to up to 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC). However, data was only evaluable in 19/40 participants (5/13 TNBC, and 14/40 HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 19
Measure Type: Count of Participants
Unit of Measure: Participants
TNBC Number Analyzed 5 participants
0
   0.0%
HRBC Number Analyzed 14 participants
14
 100.0%
6.Other Pre-specified Outcome
Title Circulating DNA Evaluated Using QM-MSP
Hide Description Data will also be graphically displayed showing trend in median values across time. Nonparametric Wilcoxon signed rank tests will be used to determine whether or not the data shows evidence of changes from baseline.
Time Frame Up to 8 weeks
Outcome Measure Data Not Reported
7.Other Pre-specified Outcome
Title Confirmed Response Rate to Azacitidine and Entinostat Plus the Addition of Hormone Therapy
Hide Description Will be estimated in each cohort. All evaluable patients who receive hormonal therapy will be used for this analysis.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Measure Type: Count of Participants
Unit of Measure: Participants
TNBC Number Analyzed 13 participants
0
   0.0%
HRBC Number Analyzed 27 participants
1
   3.7%
8.Other Pre-specified Outcome
Title Feasibility of the Addition of Hormone Therapy, Evaluated by Calculating the Number of Patients With Disease Progression That go on to Receive Hormonal Therapy
Hide Description [Not Specified]
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Measure Type: Count of Participants
Unit of Measure: Participants
TNBC Number Analyzed 13 participants
4
  30.8%
HRBC Number Analyzed 27 participants
12
  44.4%
9.Other Pre-specified Outcome
Title Number of Participants With Change in Gene Methylation Evaluated Using Quantitative Multiple Methylation-specific Polymerase Chain Reaction (QM-MSP)
Hide Description [Not Specified]
Time Frame Up to 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13/40 participants with triple-negative breast cancer (TNBC) and 27/40 participants with hormone-resistant breast cancer (HRBC).
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description:

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Overall Number of Participants Analyzed 40
Measure Type: Count of Participants
Unit of Measure: Participants
TNBC Number Analyzed 13 participants
0
   0.0%
HRBC Number Analyzed 27 participants
14
  51.9%
Time Frame 1 year
Adverse Event Reporting Description CTCAE criteria
 
Arm/Group Title Treatment (Entinostat and Azacitidine)
Hide Arm/Group Description

Patients receive azacitidine SC on days 1-5 and 8-10, and entinostat PO on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease may continue azacitidine and entinostat in combination with hormonal therapy, at treating physician discretion, or undergo event monitoring.

Azacitidine: Given SC

Entinostat: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

All-Cause Mortality
Treatment (Entinostat and Azacitidine)
Affected / at Risk (%)
Total   33/40 (82.50%)    
Show Serious Adverse Events Hide Serious Adverse Events
Treatment (Entinostat and Azacitidine)
Affected / at Risk (%) # Events
Total   2/40 (5.00%)    
Gastrointestinal disorders   
Nausea  1  2/40 (5.00%)  2
Vomiting  1  2/40 (5.00%)  2
General disorders   
Death  1  1/40 (2.50%)  1
Infections and infestations   
Skin Infection  1  1/40 (2.50%)  1
Investigations   
White blood cell decreased  1  1/40 (2.50%)  1
Neutrophil count decreased  1  1/40 (2.50%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Disease Progression  1  2/40 (5.00%)  2
Respiratory, thoracic and mediastinal disorders   
Dyspnea  1  2/40 (5.00%)  2
Pleural Effusion  1  1/40 (2.50%)  1
Vascular disorders   
Thromboembolic event  1  2/40 (5.00%)  2
1
Term from vocabulary, CTCAE (2.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Treatment (Entinostat and Azacitidine)
Affected / at Risk (%) # Events
Total   6/40 (15.00%)    
Blood and lymphatic system disorders   
Neutropenia  1  6/40 (15.00%) 
1
Term from vocabulary, CTCAE (2.0)
Indicates events were collected by systematic assessment
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: Clinical Research Office
Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Phone: 410-955-8866
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01349959     History of Changes
Other Study ID Numbers: NCI-2011-02585
NCI-2011-02585 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000698726
SKCCC J1107 ( Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center )
8822 ( Other Identifier: CTEP )
N01CM00038 ( U.S. NIH Grant/Contract )
N01CM62205 ( U.S. NIH Grant/Contract )
P30CA006973 ( U.S. NIH Grant/Contract )
U01CA062505 ( U.S. NIH Grant/Contract )
U01CA070095 ( U.S. NIH Grant/Contract )
First Submitted: May 6, 2011
First Posted: May 9, 2011
Results First Submitted: February 19, 2016
Results First Posted: March 17, 2016
Last Update Posted: June 10, 2019