Azacitidine and Entinostat in Treating Patients With Advanced Breast Cancer
|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: NCT01349959|
Recruitment Status : Completed
First Posted : May 9, 2011
Results First Posted : March 17, 2016
Last Update Posted : April 18, 2018
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Azacitidine Drug: Entinostat Other: Laboratory Biomarker Analysis Other: Pharmacological Study||Phase 2|
I. To evaluate objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria of the combination of azacitidine (5-AZA) and entinostat in women with advanced breast cancer; triple-negative and hormone-refractory.
I. To determine the safety and tolerability of the combination of 5-AZA and entinostat in women with advanced breast cancer.
II. To determine progression-free survival, overall survival, and clinical benefit rate of the combination of 5-AZA and entinostat.
I. To collect safety and toxicity data as well as the feasibility and response rate where hormonal therapy is added to the combination under investigation at the time of progressive disease. (Exploratory) II. To determine the pharmacokinetic profile of 5-AZA (full profile) and entinostat (trough concentrations) in patients with advanced breast cancer. (Exploratory) III. To assess serum cytidine deaminase pharmacogenetics and phenotypic activity as a potential biomarker of response to 5-AZA. (Exploratory) IV. To evaluate baseline and change in candidate gene re-expression (e.g., estrogen receptor [ER] alpha, retinoic acid receptor [RAR] beta) in malignant tissue obtained from selected patients through fine-needle aspiration (FNA) and core biopsy, prior to and following combination therapy. (Exploratory) V. To evaluate baseline and change in gene methylation silencing in circulating deoxyribonucleic acid (DNA) obtained prior to and following combination therapy. (Exploratory) VI. To evaluate baseline and change in gene methylation in malignant tissue obtained through FNA and core biopsy. (Exploratory)
OUTLINE: This is a multicenter study.
Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10, and entinostat orally (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.
After completion of study therapy, patients are followed up every 3-6 months for up to 3 years.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Azacitidine and Entinostat (SNDX-275) in Patients With Advanced Breast Cancer|
|Actual Study Start Date :||April 21, 2011|
|Actual Primary Completion Date :||March 27, 2014|
Experimental: Treatment (entinostat and azacitidine)
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.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- Confirmed Response Rate (Complete or Partial Response Noted as the Objective Status on Two Consecutive Evaluations at Least 4 Weeks Apart) Assessed by RECIST [ Time Frame: Up to 3 years ]The proportion of successes 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.
- 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 [ Time Frame: Up to 3 years ]All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true clinical benefit rate will be calculated.
- Overall Survival [ Time Frame: Up to 3 years ]Estimated using the method of Kaplan-Meier.
- Progression-free Survival [ Time Frame: At 6 months ]Estimated using the method of Kaplan-Meier.
- Change in Expression of Relevant Genes (e.g., ER Alpha and RAR Beta) Evaluated by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) [ Time Frame: Baseline to up to 8 weeks ]To evaluate baseline and change in candidate gene re-expression such as ER re-expression in malignant tissue, the absolute difference between prior to and following combination therapy (i.e., at 8 weeks) will be estimated and the median difference will be reported. These 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.
- Circulating DNA Evaluated Using QM-MSP [ Time Frame: Up to 8 weeks ]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.
- Confirmed Response Rate to Azacitidine and Entinostat Plus the Addition of Hormone Therapy [ Time Frame: Up to 3 years ]Will be estimated in each cohort. All evaluable patients who receive hormonal therapy will be used for this analysis.
- Feasibility of the Addition of Hormone Therapy, Evaluated by Calculating the Percentage of Patients With Disease Progression That go on to Receive Hormonal Therapy [ Time Frame: Up to 3 years ]
- Gene Methylation Evaluated Using Quantitative Multiple Methylation-specific Polymerase Chain Reaction (QM-MSP) [ Time Frame: Up to 8 weeks ]Wilcoxon rank sum tests will be used to determine the association between azacitidine or entinostat exposure and methylation changes expressed as a categorical variable (i.e.: response or no response). 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01349959
|United States, California|
|City of Hope Comprehensive Cancer Center|
|Duarte, California, United States, 91010|
|USC / Norris Comprehensive Cancer Center|
|Los Angeles, California, United States, 90033|
|University of California Davis Comprehensive Cancer Center|
|Sacramento, California, United States, 95817|
|United States, Maryland|
|Johns Hopkins University/Sidney Kimmel Cancer Center|
|Baltimore, Maryland, United States, 21287|
|United States, Minnesota|
|Fridley, Minnesota, United States, 55432|
|Metro Minnesota Community Oncology Research Consortium|
|Saint Louis Park, Minnesota, United States, 55416|
|United States, Pennsylvania|
|University of Pittsburgh Cancer Institute (UPCI)|
|Pittsburgh, Pennsylvania, United States, 15232|
|Principal Investigator:||Vered Stearns||Johns Hopkins University/Sidney Kimmel Cancer Center|