Entinostat and Anastrozole in Treating Postmenopausal Women With TNBC That Can Be Removed by Surgery
- Conditions
- Triple-negative Breast CancerHER2-negative Breast CancerStage I Breast CancerStage IIIA Breast CancerEstrogen Receptor-negative Breast CancerProgesterone Receptor-negative Breast CancerStage II Breast Cancer
- Interventions
- Other: diagnostic laboratory biomarker analysisProcedure: therapeutic conventional surgery
- Registration Number
- NCT01234532
- Lead Sponsor
- University of Maryland, Baltimore
- Brief Summary
This phase II trial is studying how well giving entinostat and anastrozole together works in treating postmenopausal women with triple-negative breast cancer that can be removed by surgery. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving entinostat together with anastrozole may be an effective treatment for breast cancer.
- Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of entinostat in combination with anastrozole or tamoxifen. (Pilot) II. To determine the optimal dose of entinostat in combination with anastrozole or tamoxifen for phase II. (Pilot) III. To determine baseline and percentage change in proliferative index (Ki67) before and after treatment with entinostat and anastrozole/tamoxifen in triple negative breast cancer (TNBC). (Phase II) IV. To determine the estrogen receptor (ER) expression after treatment with entinostat and anastrozole/tamoxifen in TNBC. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate baseline and change in the expression levels of progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), cytokeratin 5/6 (CK5/6), and aromatase before and after treatment with entinostat and anastrozole/tamoxifen.
II. To assess baseline and change in tumor tissue histone H3 and H4 acetylation before and after treatment with entinostat and anastrozole/tamoxifen.
III. To assess the clinical and pathological response to preoperative combination of entinostat and anastrozole/tamoxifen in TNBC.
TERTIARY OBJECTIVES:
I. To correlate the levels of histone H3 and H4 acetylation in tumors with the changes in Ki67 and ER.
II. To evaluate baseline and change in gene methylation silencing and expression of candidate genes in tissues and in circulating DNA, including estrogen receptor (ER)-alpha, ER-beta, RAR-beta, cyclin D2, Twist, RASSF1A, and HIN-1.
III. To correlate entinostat trough concentrations with histone H3 and H4 acetylation in tumors as well as the change in Ki67 and ER.
IV. To evaluate baseline and change in the global gene expression profile before and after treatment with entinostat and anastrozole/tamoxifen.
OUTLINE: This is a multicenter, pilot study followed by a phase II study.
Patients receive entinostat orally (PO) once daily on days 1, 8, 15, 22, and 29 and anastrozole PO once daily on days 4-29. Patients then undergo mastectomy or lumpectomy.
Tumor tissue samples are collected at baseline or from original diagnosis, and during surgery for correlative studies by IHC and RT-PCR. Blood samples are also collected at baseline, on days 1 and 15, and during surgery for correlative studies.
After completion of study therapy, patients are followed up for 30 days.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Female
- Target Recruitment
- 5
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description entinostat & anastrozole neoadjuvant therapeutic conventional surgery Neoadjuvant entinostat daily on days 1, 8, 15, 22, and 29 + anastrozole daily on days 4-29 followed by surgery ie either lumpectomy or mastectomy. Correlative studies will be performed utilizing tissue and blood. A baseline tumor biopsy is done prior to study entry or archival tissue from diagnosis may be used and a representative tumor sample is submitted at time of surgery. Bloods are drawn for correlative sciences on day 1 and 15 of treatment prior to entinostat dosing and 30 mins post and again on day of surgery. entinostat & anastrozole neoadjuvant diagnostic laboratory biomarker analysis Neoadjuvant entinostat daily on days 1, 8, 15, 22, and 29 + anastrozole daily on days 4-29 followed by surgery ie either lumpectomy or mastectomy. Correlative studies will be performed utilizing tissue and blood. A baseline tumor biopsy is done prior to study entry or archival tissue from diagnosis may be used and a representative tumor sample is submitted at time of surgery. Bloods are drawn for correlative sciences on day 1 and 15 of treatment prior to entinostat dosing and 30 mins post and again on day of surgery. entinostat & anastrozole neoadjuvant entinostat Neoadjuvant entinostat daily on days 1, 8, 15, 22, and 29 + anastrozole daily on days 4-29 followed by surgery ie either lumpectomy or mastectomy. Correlative studies will be performed utilizing tissue and blood. A baseline tumor biopsy is done prior to study entry or archival tissue from diagnosis may be used and a representative tumor sample is submitted at time of surgery. Bloods are drawn for correlative sciences on day 1 and 15 of treatment prior to entinostat dosing and 30 mins post and again on day of surgery. entinostat & anastrozole neoadjuvant anastrozole Neoadjuvant entinostat daily on days 1, 8, 15, 22, and 29 + anastrozole daily on days 4-29 followed by surgery ie either lumpectomy or mastectomy. Correlative studies will be performed utilizing tissue and blood. A baseline tumor biopsy is done prior to study entry or archival tissue from diagnosis may be used and a representative tumor sample is submitted at time of surgery. Bloods are drawn for correlative sciences on day 1 and 15 of treatment prior to entinostat dosing and 30 mins post and again on day of surgery.
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events Participants were followed during the study and for 30 days post treatment, up to 59 days To address the safety of the regimen, a maximum width 90% confidence interval for any grade 3 or higher toxicity will be approximately 30%. For 5 patients in this study, if the true unknown probability of a rare toxicity is 10%, the probability of observing 1 or more toxicities is 97%, and if the true toxicity rate is 5% then the probability of observing one or more rare toxicities is 83%.
Recommended Phase II Dose of Entinostat in Combination With Anastrozole (Pilot) Duration of the study is 29 days followed by 30 days end of study assessment visit, up to 59 days Since the study was terminated early there was insufficient data for analysis and to recommend a phase II dose of entinostat in combination with anastrozole
Change in Proliferative Index (Ki67) (Phase II) Baseline to the time of surgery, within 6 days after the last dose of entinostat, up to 35 days The 95% confidence intervals will be constructed for the observed proportions. Exploratory data analysis and appropriate graphs will be used to decide whether data transformation (e.g. log or square-root) is necessary to assure an approximate normality. All descriptive statistics will be reported for ER and Ki67 expression. The general linear model approach and/or its non parametric alternative, the Wilcoxon test, will be used to assess whether there is any evidence of changes due to treatment.
Change in Estrogen-receptor (ER) Expression (Phase II) Baseline before the study treatment and at the time of surgery, up to 30 days The 95% confidence intervals will be constructed for the observed proportions. Exploratory data analysis and appropriate graphs will be used to decide whether data transformation (e.g. log or square-root) is necessary to assure an approximate normality. All descriptive statistics will be reported for ER and Ki67 expression. The general linear model approach and/or its non parametric alternative, the Wilcoxon test, will be used to assess whether there is any evidence of changes due to treatment.
- Secondary Outcome Measures
Name Time Method The Pathological Response to Entinostat and Anastrozole Pathological response was assessed after the surgery, up to 59 days Rate of Pathologic response % of patients responding
Clinical Response to Entinostat and Anastrozole Clinical response was assessed during the study treatment and before the surgery, up to 29 days Rate of clinical response % of patients responding
Change in HER2 Baseline before study treatment and at the time of surgery, up to 30 days Will be treated as continuous variables. Multivariate analysis of variance may also be used to compare correlated biomarkers' expression. Correlation between biomarkers will be estimated and tested. The repeated measures model approach will be also used. Categorical outcome data (e.g., number of proteins expressed) will be recorded, proportions will be estimated and compared using the Fisher's exact test.
Trial Locations
- Locations (1)
University of Maryland Baltimore
🇺🇸Baltimore, Maryland, United States