Clinical Trials /

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

NCT02115282

Description:

This randomized phase III trial studies exemestane and entinostat to see how well they work compared to exemestane alone in treating 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Exemestane</span> With or Without <span class="go-doc-concept go-doc-intervention">Entinostat</span> in Treating Postmenopausal Patients With Recurrent Hormone Receptor-Positive <span class="go-doc-concept go-doc-disease">Breast Cancer</span> That is Locally Advanced or Metastatic

Title

  • Brief Title: Exemestane With or Without Entinostat in Treating Postmenopausal Patients With Recurrent Hormone Receptor-Positive Breast Cancer That is Locally Advanced or Metastatic
  • Official Title: A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo in Men and Postmenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02115282

    ORG ID: NCI-2014-00746

    NCI ID: NCI-2014-00746

    Trial Conditions

    Estrogen Receptor Positive

    HER2/Neu Negative

    Hormone-Resistant Breast Cancer

    Male Breast Carcinoma

    Progesterone Receptor Positive

    Recurrent Breast Carcinoma

    Stage IIIB Breast Cancer

    Stage IIIC Breast Cancer

    Stage IV Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Entinostat ENTINOSTAT, HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275 Arm A (exemestane, entinostat)
    Exemestane Aromasin, EXEMESTANE, FCE-24304 Arm A (exemestane, entinostat), Arm B (exemestane, placebo)
    Goserelin Acetate GOSERELIN ACETATE, ZDX, Zoladex Arm A (exemestane, entinostat), Arm B (exemestane, placebo)

    Trial 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.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate whether the addition of entinostat to endocrine therapy (exemestane) improves
    progression-free survival (PFS) and/or overall survival (OS) in postmenopausal patients with
    hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative
    locally advanced or metastatic breast cancer who have previously progressed on a
    non-steroidal aromatase inhibitor (Al).

    SECONDARY OBJECTIVES:

    I. To evaluate the safety and tolerability of entinostat in combination with exemestane, and
    to compare the safety profile to that of endocrine therapy with placebo.

    II. To evaluate the objective response rate of exemestane in combination with entinostat or
    placebo.

    III. To evaluate whether the efficacy of exemestane with entinostat varies with changes in
    acetylation status in peripheral blood mononuclear cells (PBMCs).

    IV. To evaluate the time to treatment deterioration (as defined by decrease in
    health-related quality of life [HRQL], progression, death) of exemestane + entinostat versus
    exemestane + placebo arms.

    V. To evaluate the differences in overall health-related quality of life (HRQL) between the
    exemestane + entinostat versus exemestane + placebo arms.

    VI. To evaluate the difference with respect to specific symptoms that are associated with
    entinostat, i.e., fatigue, nausea, anorexia and diarrhea, between the exemestane +
    entinostat versus exemestane + placebo arms.

    VII. To measure adherence to protocol therapy.

    TERTIARY OBJECTIVES:

    I. To collect archival tumor samples and germline deoxyribonucleic acid (DNA) to explore
    other potential biomarkers of therapeutic efficacy.

    II. To collect patient ratings of adverse events (AEs) using select patient-reported
    outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) items to evaluate the
    psychometric properties of PRO-CTCAE items and explore the incorporation of PRO-CTCAE items
    into a phase III double-blind placebo-controlled trial.

    OUTLINE: Patients are randomized to 1 of 2 treatment arms.

    ARM A: Patients receive exemestane orally (PO) once daily (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.

    ARM B: 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.

    In both arms, male patients also receive goserelin acetate subcutaneously (SC) on day 1.

    After completion of study treatment, patients are followed up every 3 months for 2 years,
    every 6 months for 3 years, and then annually for 5 years.

    Trial Arms

    Name Type Description Interventions
    Arm A (exemestane, entinostat) Experimental 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. Entinostat, Exemestane, Goserelin Acetate
    Arm B (exemestane, placebo) Placebo Comparator 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. Exemestane, Goserelin Acetate

    Eligibility 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 any time after non-steroidal aromatase inhibitor (AI) use in
    the advanced disease setting

    - Relapse while on or within =< 12 months of end of adjuvant non-steroidal AI
    therapy with no prior endocrine therapy for advanced disease

    - NOTE: Treatment with any prior endocrine therapy must be completed >= 2 weeks
    prior to randomization, with the exception of exemestane which is allowed in the
    advanced disease setting for =< 4 weeks immediately prior to study entry
    (defined as date of randomization); prior exemestane (other than =< 4 weeks as
    above) or fulvestrant in any setting is not allowed; prior everolimus therapy is
    allowed and must have been completed 2 weeks prior to randomization

    - 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    OS

    PFS defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1)

    Secondary Outcome Measures

    Incidence of toxicity graded according to National Cancer Institute CTCAE version 4.0

    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 to treatment deterioration (TTD) assessed per RECIST v1.1

    Trial Keywords