Entinostat and Anastrozole in Treating Postmenopausal Women With Triple-Negative Breast Cancer That Can Be Removed by Surgery

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01234532
First received: November 3, 2010
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Estrogen Receptor-negative Breast Cancer
HER2-negative Breast Cancer
Progesterone Receptor-negative Breast Cancer
Stage I Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Triple-negative Breast Cancer
Drug: entinostat
Drug: anastrozole
Other: diagnostic laboratory biomarker analysis
Procedure: therapeutic conventional surgery
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot and Phase II Study of Entinostat and Anastrozole/Tamoxifen in Women With Triple Negative Breast Cancer to Evaluate Biomarkers and Surrogates for Response

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recommended phase II dose of entinostat in combination with anastrozole (pilot) [ Time Frame: 29 days ] [ Designated as safety issue: Yes ]
  • Safety and tolerability of entinostat in combination with anastrozole (pilot) [ Time Frame: Up to 30 days post treatment ] [ Designated as safety issue: Yes ]
    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 35 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%.

  • Change in proliferative index (Ki67) (phase II) [ Time Frame: Baseline to the time of surgery, within 6 days after the last dose of entinostat ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline to the time of surgery, within 6 days after the last dose of entinostat ] [ Designated as safety issue: No ]
    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:
  • Change in PR, HER2, EGFR, CK5/6, aromatase, tissue histone H3 and H4 acetylation [ Time Frame: Baseline to the time of surgery, within 6 days after the last dose of entinostat ] [ Designated as safety issue: No ]
    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.

  • Response to entinostat and anastrozole [ Time Frame: Up to the time of surgery, within 6 days after the last dose of entinostat ] [ Designated as safety issue: No ]
    Clinical and pathological response rate with the corresponding 90% or 95% CI will be estimated for all eligible patients. The possible association between response rate and dose level will also be assessed.


Enrollment: 41
Study Start Date: October 2010
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (entinostat, anastrozole, and surgery)

Patients receive entinostat 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.

Drug: entinostat
Given PO
Drug: anastrozole
Given PO
Other: diagnostic laboratory biomarker analysis
Correlative studies
Procedure: therapeutic conventional surgery
Undergo mastectomy or lumpectomy

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the breast

    • Unresected breast cancer amenable to surgery
    • Clinical stage

      • T1c, T2, or T3
      • Any N
      • M0 (no distant metastasis)
    • Hormone insensitivity

      • Evidence of hormone insensitivity (ER and PR negative) of primary tumor tissue; ER negative is define as ER 0 or < 1% staining by immunohistochemistry; PR negativity is defined as PR =< 10% staining by immunohistochemistry
    • HER2 negative in the primary tumor tissue by:

      • Grade 0 or 1+ staining intensity (on a scale of 0 to 3) by IHC analysis
      • Grade 2+ staining intensity by IHC with gene amplification on fluorescent in situ hybridization (FISH) < 2.2
  • Patients must have adequate tumor tissue sample prior to the enrolment available for correlative studies as defined below:

    • Core needle biopsy or incisional biopsy samples that can provide >= 3 unstained sections of 5 micron thickness; fine needle aspiration (FNA) sample alone is not sufficient except in the second cohort
    • Additional core needle biopsy needs to be performed in the patients who agree to participate in this study and do not have adequate tumor tissue sample
    • Patients must have an accessible tumor lesion from which a fine needle aspirate or preferably a core biopsy specimen can be obtained; patients with FNA only samples are allowed in this cohort; ascites or pleural/pericardial effusion alone is not sufficient
    • Patients must be willing to provide consents for 2 research biopsies; however, the pretreatment biopsy can be omitted in patients who have recent biopsy but have not been started on breast cancer treatment within 12 weeks prior to the registration and there is adequate tumor tissue sample
  • Postmenopausal
  • ECOG performance status 0-2
  • WBC ≥ 2,500/mm³
  • ANC ≥ 1,100/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 9.0 g/dL
  • Total bilirubin normal
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • No history of allergic reactions or hypersensitivity to compounds of similar chemical or biologic composition to entinostat, benzamide, or anastrozole
  • No medical conditions that, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on this study, including any of the following:

    • HIV infection
    • Unstable angina
    • Uncontrolled heart failure or hypertension
    • Hyperlipidemia
    • Diabetes mellitus
    • Systemic infection
  • No systemic malignancy within the past 3 years except adequately treated cervical carcinoma in situ or basal/squamous cell carcinoma of the skin
  • No other concurrent anticancer agents including approved luteinizing-hormone releasing-hormone agonists (e.g., goserelin or leuprolide)
  • No prior histone deacetylase inhibitors (HDACs)

    • Prior valproic acid allowed provided patient has ≥ 30 days wash-out period
  • No prior chemotherapy, radiotherapy, or endocrine therapy for the current breast cancer

    • Prior tamoxifen, raloxifene, or another agent for the prevention of breast cancer allowed provided patient has discontinued treatment within the past 30 days prior to baseline study biopsy.
  • No bisphosphonates initiated within 4 weeks of study start
  • No other concurrent investigational agents
  • No concurrent valproic acid, vorinostat, or other HDAC inhibitor
  • No concurrent DNA methyltransferase inhibitors
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01234532

Locations
United States, California
City of Hope
Duarte, California, United States, 91010
USC Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
City of Hope Medical Group Inc
Pasadena, California, United States, 91105
University of California Davis Phase 2 Consortium
Sacramento, California, United States, 95817
United States, Illinois
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637-1470
Evanston CCOP-NorthShore University HealthSystem
Evanston, Illinois, United States, 60201
Ingalls Memorial Hospital
Harvey, Illinois, United States, 60426
Illinois CancerCare-Peoria
Peoria, Illinois, United States, 61615
Central Illinois Hematology Oncology Center
Springfield, Illinois, United States, 60702
United States, Indiana
Fort Wayne Medical Oncology and Hematology Inc - State Boulevard
Fort Wayne, Indiana, United States, 46845
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
University of Maryland Baltimore
Baltimore, Maryland, United States, 21201
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Pennsylvania
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
Magee-Womens Hospital of UPMC
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Investigators
Principal Investigator: Saranya Chumsri University of Chicago Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01234532     History of Changes
Other Study ID Numbers: NCI-2011-02542, NCI-2011-02542, CDR0000687507, 10-466-A, 8597, N01CM00071
Study First Received: November 3, 2010
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Anastrozole
Entinostat
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on September 29, 2014