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

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: NCT02115282
Recruitment Status : Active, not recruiting
First Posted : April 16, 2014
Results First Posted : November 16, 2021
Last Update Posted : May 26, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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 (locally advanced) or another place in the body (metastatic). 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 or disease Intervention/treatment Phase
Breast Adenocarcinoma HER2/Neu Negative Locally Advanced Breast Carcinoma Metastatic Breast Carcinoma Recurrent Breast Carcinoma Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7 Drug: Entinostat Drug: Exemestane Drug: Goserelin Drug: Goserelin Acetate Other: Placebo Administration Other: Quality-of-Life Assessment Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 608 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo in Patients With Hormone Receptor-Positive Advanced Breast Cancer
Actual Study Start Date : March 29, 2014
Actual Primary Completion Date : May 5, 2020
Estimated Study Completion Date : October 28, 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Exemestane

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (exemestane, entinostat)

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

Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1.

 Drug: Entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

Drug: Exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304

Drug: Goserelin
Given PO
Other Name: ICI-118630

Drug: Goserelin Acetate
Given SC
Other Names:
  • ZDX
  • Zoladex

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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1.

 Drug: Exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304

Drug: Goserelin
Given PO
Other Name: ICI-118630

Drug: Goserelin Acetate
Given SC
Other Names:
  • ZDX
  • Zoladex

Other: Placebo Administration
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression ]
    Progression-free survival (PFS) was defined to be time from randomization to the earliest documented disease progression as defined by the RECIST criteria, new primary breast cancer, or death without progression. Disease assessment was to continue until disease progression, even after non-protocol anti-cancer therapy was started. Cases with incomplete follow up or without adequate disease evaluations were censored at the date last documented to be free of progression, regardless of whether non-protocol anti-cancer therapy was started or not. Disease progression was based on central review, and defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. In addition, the appearance of one or more new lesions was also considered progression. Kaplan-Meier method was used to estimate PFS rate.

  2. Overall Survival (OS) [ Time Frame: Assessed every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until death ]
    Overall survival (OS) was defined to be time from randomization to death from any cause. Cases who were still alive were censored at the date last known alive.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: Assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression ]
    Objective response rate was defined as number of patients with complete response (CR) or partial response (PR) divided by all randomized patients. Responses were evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR was defined as disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).

  2. Time-to-treatment Deterioration (TTD) [ Time Frame: Disease assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression ]
    Time-to-treatment deterioration (TTD) was defined as time from randomization to disease progression or death or worsening of symptoms, whichever occurred first. Disease progression was assessed per RECIST v1.1. Symptoms deterioration was measured by 6 items (GP1, GP2, GP4, GF7, B1, P2, scored 0-24) from the 8-item FACT-Breast Symptom Index (FBSI). Symptom deterioration was defined as two consecutive available decreases of at least 3 points from baseline using the 6-item FBSI in this trial, and the second visit time was used as the time of symptom deterioration in this case, unless it was the final score, for which one decrease was sufficient. Kaplan-Meier method was used to estimate the median TTD and TTD rate at a certain time point. Symptoms were assessed every cycle for the first six months after randomization, every two cycles between 6 months and 1 year. It then were assessed based on the same schedule for tumor assessments until disease progression as specified below.

  3. Lysine Acetylation Change in CD45 Blood Mononuclear Cells Between C1D1 and C1D15 and PFS in Patients on Arm A [ Time Frame: Disease assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression ]
    Peripheral blood samples (PBMCs) were collected prior to therapy and on Days 8 and 15 of cycle 1, for assessment of lysine acetylation, using an assay developed by the Trepel Laboratory, NCI/NIH. CD45 blood mononuclear cells were measured. Patients with lysine acetylation change of 1.5 folds or higher were compared to patients with lysine acetylation change of less than 1.5 folds.

  4. Patient-reported Health-related Quality of Life [ Time Frame: Assessed at baseline and end of cycle 3 ]
    Health-related quality of life (HRQL) was measured using Functional Assessment of Cancer Therapy - General (FACT-G). The primary endpoint for HRQL was the FACT-G Trial Outcome Index (TOI) which was an aggregate score of 5 items from the FACT-G-Physical subscale (GP2, GP3, GP4, GP6, and GP7) and 6 items from the FACT-G-Functional subscale (GF1, GF2, GF3, GF4, GF6, and GF7). All items were rated on a 5-point Likert scale from 0 to 4. FACT-G TOI subscale score was calculated based on the scoring manual, subscale score ranges from 0 to 44, and higher scores indicate better quality of life. The primary comparison of HRQL between treatment arms was based on the end of cycle 3 assessment.

  5. Patient-reported Diarrhea [ Time Frame: Assessed at baseline and end of cycle 3 ]
    Diarrhea was measured by Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea (FACIT-Diarrhea) subscale form, which had 11 items, all items were rated on a 5-point Likert scale from 0 to 4. FACIT-Diarrhea subscale score was calculated based on the scoring manual, subscale score ranges from 0 to 44, and higher score indicates less diarrhea. The primary comparison of patient-reported diarrhea between treatment arms was based on the end of cycle 3 assessment.

  6. Patient-reported Fatigue [ Time Frame: Assessed at baseline and end of cycle 3 ]
    Fatigue was measured by PROMIS Fatigue short form, it had 7 items and all items were rated on a 5-point Likert scale from 1 to 5. The PROMIS Fatigue total score and T score were calculated based on the scoring manual. The total score ranges from 7 to 35, the T score ranges from 29.4 to 83.2, higher scores indicate more fatigue. The PROMIS Fatigue T score was used for arm comparison. The primary comparison of patient-reported fatigue between treatment arms was based on the end of cycle 3 assessment.

  7. Patient-reported Nausea and Anorexia [ Time Frame: Assessed at baseline and end of cycle 3 ]
    Nausea and anorexia were measured by The Functional Assessment of Anorexia/Cachexia Treatment (FAACT)-additional concerns, which had 12 items, all items were rated on a 5-point Likert scale from 0 to 4. FAACT-additional concerns subscale score was calculated based on scoring manual. Subscale score ranges from 0 to 48, and higher scores indicate less nausea and anorexia. The primary comparison of patient-reported nausea and anorexia between treatment arms was based on the end of cycle 3 assessment.

  8. Proportion of High Adherence Score at End of Cycle 3 [ Time Frame: Assessed at end of cycle 3 ]
    Patient's adherence was assessed using the modified Morisky 8-Item Medication Adherence Questionnaire. The total Morisky scale score was calculated per the scoring guidance, range from 0 to 8. A Morisky total score of 0 was considered as high adherence, a total score of 1-2 was considered as medium adherence, and a total score of 3-8 was considered as poor adherence.


Eligibility Criteria
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Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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
    • NOTE: As of October 16, 2016, accrual of new patients having non-measurable disease has stopped; the planned accrual for this target population has been reached

  • Pre/peri- and 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: Women who do not fit the criteria for being postmenopausal as above are deemed pre-or peri-menopausal; pre/perimenopausal women and all men can enroll provided they agree to receive concomitant luteinizing hormone-releasing hormone (LHRH) agonist; pre/perimenopausal women must have commenced treatment with LHRH agonist at least 4 weeks prior to randomization; if patients have received alternative LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial
  • Sexually active males and pre/perimenopausal women must agree 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

  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study =< 2 weeks prior to randomization

    • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • 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 AI use in the advanced disease setting
    • Relapse while on or within =< 12 months of end of adjuvant non-steroidal AI therapy with or without prior endocrine therapy for advanced disease
    • NOTE: In either setting, treatment with any prior endocrine therapy must be completed >= 2 weeks prior to cycle 1 day 1 (C1D1) of study treatment with the exception of exemestane which is permitted in the advanced disease setting within =< 4 weeks immediately prior to C1D1; prior adjuvant exemestane is allowed if the disease free interval is > 12 months from the discontinuation of exemestane; prior faslodex, everolimus, palbociclib or other cyclin-dependent kinase (CDK) inhibitor (e.g. ribociclib, abemaciclib) use are allowed and must have been completed >= 2 weeks prior to C1D1; failure to adhere to this washout guideline will result in a protocol violation
  • Patients may have received only 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 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) unless discussed with the study chair; patients must not have received prior HDAC therapy for the treatment of their malignancy
  • Patients must have no known allergies to exemestane, entinostat, or medications that have a benzamide structure (e.g., tiapride, remoxipride, clebropride)
  • 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 (=< 28 days prior to randomization)
  • Platelet count >= 100,000/mcL (=< 28 days prior to randomization)
  • Absolute neutrophil count >= 1,500/mcL (=< 28 days prior to randomization)
  • Creatinine =< 2.0 mg/dL (=< 28 days prior to randomization)
  • Total bilirubin < 1.5 x institutional upper limit of normal (=< 3 mg/dL in case of Gilbert's syndrome) (=< 28 days prior to randomization)
  • Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =< 2.5 x institutional upper limit normal (=< 28 days prior to randomization)
  • 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
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Information from the National Library of Medicine

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): NCT02115282


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Roisin M Connolly ECOG-ACRIN Cancer Research Group
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
Study Protocol and Statistical Analysis Plan  [PDF] May 22, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02115282    
Other Study ID Numbers: NCI-2014-00746
NCI-2014-00746 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ECOG-E2112
E2112 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E2112 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
U10CA021115 ( U.S. NIH Grant/Contract )
U24CA196172 ( U.S. NIH Grant/Contract )
First Posted: April 16, 2014    Key Record Dates
Results First Posted: November 16, 2021
Last Update Posted: May 26, 2023
Last Verified: January 2023
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Exemestane
Goserelin
Entinostat
 Histone Deacetylase Inhibitors
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal