Exemestane With or Without Entinostat in Treating Postmenopausal Patients With Recurrent Hormone Receptor-Positive Breast Cancer That Is Locally Advanced or Metastatic

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02115282
First received: April 14, 2014
Last updated: October 22, 2014
Last verified: July 2014
  Purpose

This randomized phase III trial studies exemestane and entinostat to see how well they work compared to exemestane alone in treating postmenopausal patients with hormone receptor-positive breast cancer that has spread to nearby tissue or lymph nodes or another place in the body. Estrogen can cause the growth of breast cancer cells. Endocrine therapy using exemestane may fight breast cancer by lowering the amount of estrogen the body makes. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether exemestane is more effective with or without entinostat in treating breast cancer.


Condition Intervention Phase
Estrogen Receptor-positive Breast Cancer
HER2-negative Breast Cancer
Hormone-resistant Breast Cancer
Male Breast Cancer
Progesterone Receptor-positive Breast Cancer
Recurrent Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: exemestane
Drug: entinostat
Drug: goserelin acetate
Other: placebo
Other: laboratory biomarker analysis
Other: quality-of-life assessment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo in Postmenopausal Patients With Hormone Receptor-Positive Advanced Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • PFS defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) [ Time Frame: Time from randomization to the earliest of documented disease progression, new primary breast cancer, or death without progression, assessed up to 10 years ] [ Designated as safety issue: No ]
    The distribution of PFS will be estimated using the Kaplan- Meier method, with 95% confidence intervals calculated using Greenwood's formula. In the primary analysis of PFS, differences in treatment effect will be tested using stratified log rank tests, stratifying on the randomization stratification factors. Stratified univariate and multivariable Cox proportional-hazard models will be built to estimate the hazard ratios (HRs) for treatment effect for PFS as a supportive analysis. In all analyses, P-values will be two-sided.

  • OS [ Time Frame: Time from randomization to death from any cause, assessed up to 70 months ] [ Designated as safety issue: No ]
    The distribution of OS will be estimated using the Kaplan- Meier method, with 95% confidence intervals calculated using Greenwood's formula. In the primary analyses of OS, differences in treatment effect will be tested using stratified log rank tests, stratifying on the randomization stratification factors. Stratified univariate and multivariable Cox proportional-hazard models will be built to estimate the HRs for treatment effect for OS as a supportive analysis. In all analyses, P-values will be two-sided.


Secondary Outcome Measures:
  • Objective response, defined as the proportion of patients with complete response (CR) or partial response (PR) among all patients assessed per RESIST v1.1 [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Objective response in the two arms will be evaluated by comparing objective response rate (ORR, PR+CR) using a Fisher's exact test on the intention-to-treat patients with one-sided type I error of 2.5%. ORR will be summarized along with the exact binomial 95% confidence interval. In all analyses, P-values will be two-sided.

  • Incidence of toxicity graded according to National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    All treatment-emergent and baseline adverse events and hematological/biochemical toxicities based on laboratory measurements, as well as drug related AEs, will be summarized by treatment group and worst grade. The incidence of deaths and treatment-emergent serious AEs (defined as number of patients experiencing the AE divided by all treated patients) will be summarized and compared between treatment arms using Fisher's exact test. Also, the incidence of adverse events leading to discontinuation of investigational product and/or withdrawal from the study will be summarized and listed.

  • Time to treatment deterioration (TTD) assessed per RECIST v1.1 [ Time Frame: Time from randomization to disease progression or death or worsening of symptoms, whichever occurs first, assessed up to 10 years ] [ Designated as safety issue: No ]
    The distribution of TTD will be estimated using Kaplan-Meier method, and TTD comparisons between treatment arms will be tested primarily using log-rank test. Cox proportional-hazards models will be conducted to estimate the HR for treatment effect for TTD as a supportive analysis.


Other Outcome Measures:
  • Percent change in protein lysine acetylation [ Time Frame: Baseline to up to 70 months ] [ Designated as safety issue: No ]
    The distribution of the percentage change in protein lysine acetylation will be plotted for the two treatment groups and difference will be compared using the Wilcoxon ranks sum test. Tumor response rate will be compared between the patients with percentage change in acetylation being above or below median using Fisher's exact tests in each treatment arm. In all analyses, P-values will be two-sided and a level of 5% will be considered statistically significant.

  • Overall HRQL score measured by the Trial Outcome Index [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Mixed effect models will be constructed to estimate the time profile of HRQL in the two treatment arms and to evaluate treatment-by-time interactions. Time will be included as a continuous variable if there is a linear trend in HRQL over time or a set of dummy variables if non-linear trend exits for HRQL. PROs will be correlated with PFS (prognostic value of PROs) in the study patients. Kaplan-Meier method, log rank test and Cox models will be used to compare PFS between patients with good quality of life (QOL) and those with poor QOL in the overall patient population.

  • Adherence to study [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    The distribution of the adherence score for each agent will be displayed via box-and-whisker plot. The proportion of high, medium and low adherence to each agent will be calculated along with the binomial exact 95% confidence interval. The proportion of high adherence to entinostat and placebo will be compared between arms A and B using Fisher exact test. The proportion of adherence to exemestane will be compared between treatment arms using Fisher exact test as well.


Estimated Enrollment: 600
Study Start Date: March 2014
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (exemestane, entinostat)

Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Male patients also receive goserelin acetate SC on day 1.

Drug: exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304
  • PNU 155971
Drug: entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: goserelin acetate
Given SC
Other Names:
  • ICI-118630
  • ZDX
  • Zoladex
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Placebo Comparator: Arm B (exemestane, placebo)

Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Male patients also receive goserelin acetate SC on day 1.

Drug: exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304
  • PNU 155971
Drug: goserelin acetate
Given SC
Other Names:
  • ICI-118630
  • ZDX
  • Zoladex
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Estrogen receptor (ER) and/or progesterone receptor (PR) positive histologically confirmed adenocarcinoma of the breast with staining of >= 1% cells will be considered positive; receptor status may be based on any time during treatment prior to study randomization, and from any site (i.e. primary, recurrent, or metastatic)
  • Patients whose tumors have HER2 immunohistochemistry (IHC) 3+, in situ hybridization (ISH) >= 2.0, or average HER2 copy number >= 6.0 signals per cell are not eligible; receptor status may be based on any time during treatment prior to study randomization, and from any site (i.e. primary, recurrent, or metastatic)
  • Patients must have measurable or non-measurable stage III/locally advanced or metastatic carcinoma of the breast where local therapy with curative intent is not possible; lesions must be evaluated =< 4 weeks prior to study randomization; diagnostic-quality computed tomography (CT) scans with both oral and intravenous (IV) contrast are the expected radiologic method, unless an alternative is approved

    • NOTE: Where baseline imaging has already been performed =< 6 weeks prior to study randomization, repeat imaging may not be required
  • Postmenopausal women and all men are eligible for this trial; postmenopausal is defined as:

    • Age >= 55 years and one year or more of amenorrhea
    • Age < 55 years and one year or more of amenorrhea, with estradiol < 20 pg/ml
    • Age < 55 with prior hysterectomy but intact ovaries, with estradiol < 20 pg/ml
    • Prior bilateral oophorectomy NOTE: Men can enroll provided they agree to receive concomitant luteinizing hormone-releasing hormone (LHRH) agonist; LHRH agonist use is not permitted for female patients
  • Sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 3 months after discontinuation of therapy
  • Patients must not have known central nervous system metastasis or a history of central nervous system (CNS) metastases; patients with leptomeningeal disease are not eligible
  • Patients must be disease-free of prior invasive malignancies for > 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix; NOTE: if there is a history of prior malignancy, patients must not be receiving other specific treatment for that cancer
  • Patients must meet at least one of the following criteria:

    • Disease progression after non-steroidal aromatase inhibitor (AI) use in the metastatic setting
    • Relapse while on or within =< 12 months of end of adjuvant non-steroidal AI therapy with no prior or =< 4 weeks of endocrine therapy for metastatic disease
    • NOTE: Prior exemestane or fulvestrant is not allowed; prior everolimus therapy is allowed and must have been completed 2 weeks prior to study entry; other prior endocrine therapy for metastatic disease is allowed (e.g. tamoxifen) and must have been completed 2 weeks prior to study entry
  • Patients may have received one prior chemotherapy regimen for metastatic disease provided treatment was completed >= 3 weeks prior to randomization
  • Patients may be treated with bone modifying agents such as bisphosphonates or receptor activator of nuclear factor kappa-B (RANK)-ligand agents (e.g. denosumab) per American Society of Clinical Oncology (ASCO) guidelines; whenever possible, patients requiring bone modifying agents should start treatment >= 7 days prior to study therapy and should continue the same agent throughout study unless clinically compelled to change
  • Prior radiotherapy must in general have been completed >= 2 weeks prior to randomization and patients must have recovered from the toxicity of the radiation; NOTE: patients may receive concurrent radiation therapy to painful sites of bony disease or areas of impending fracture as long as sites of measurable or non-measurable disease outside the radiation therapy port are available to follow
  • Patients must NOT receive concurrent anti-cancer therapy or investigational agent unless specified in protocol
  • Patients must NOT be receiving valproic acid, an histone deacetylase (HDAC) inhibitor, and may not have previously received any HDAC inhibitor prior to enrollment (e.g. valproic acid, entinostat, vorinostat)
  • Patients must have no known allergies to imidazole drugs (e.g. clotrimazole, ketoconazole, miconazole, econazole, sulconazole, ticonazole, or terconazole), exemestane or entinostat
  • Patients must NOT suffer from medical or psychiatric conditions that would interfere with protocol compliance, the ability to provide informed consent, or assessment of response or anticipated toxicities; this includes uncontrolled intercurrent illness including, but not limited to ongoing or active infection
  • Patients must have recovered from all clinically relevant adverse events to grade 1 or baseline due to previous agents administered (except alopecia)
  • Patients must have adequate hematologic, liver and renal function =< 28 days prior to randomization; NOTE: it is preferred that laboratory values for eligibility be assessed after the last dose of prior treatment, especially in cases where most-recent treatment prior to study entry is chemotherapy
  • Hemoglobin (HgB) >= 9.0 g/dL
  • Platelet count >= 100,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Creatinine =< 2.0 mg/dL
  • Total bilirubin < 1.5 x institutional upper limit of normal (=< 3 mg/dL in case of Gilbert's syndrome)
  • Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =< 2.5 x institutional upper limit normal
  • Known human immunodeficiency virus (HIV)-positive patients should have a cluster of differentiation (CD)4 count > 250/mm^3
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Patients must have a life expectancy >= 12 weeks
  • Patients must be able to swallow tablets
  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: NCT02115282

  Show 254 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Roisin Connolly ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02115282     History of Changes
Other Study ID Numbers: NCI-2014-00746, NCI-2014-00746, ECOG-E2112, E2112, E2112, U10CA021115, U10CA180820
Study First Received: April 14, 2014
Last Updated: October 22, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 22, 2014