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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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. VIII. To evaluate the pharmacokinetics of entinostat in patients with advanced breast cancer. IX. To evaluate what, if any, patient variables alter the pharmacokinetic profile of entinostat in patients with advanced breast cancer. EXPLORATORY 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. ARM B: 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. Patients also undergo CT or MRI at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. In both arms, pre/perimenopausal female patients and all 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.

Official Title
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A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo in Patients With Hormone Receptor-Positive Advanced Breast Cancer

Conditions
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Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Breast Adenocarcinoma, HER2/Neu Negative, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Recurrent Breast Carcinoma

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Drug: Entinostat
* Drug: Exemestane
* Drug: Goserelin
* Drug: Goserelin Acetate
* Procedure: Magnetic Resonance Imaging
* Other: Placebo Administration
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (exemestane, entinostat)<br>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. Patients also undergo CT or MRI at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. | Procedure: Biospecimen Collection<br>* Undergo collection of blood and archived tissue samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Entinostat<br>* Given PO<br>* Other names: SNDX-275;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Drug: Goserelin<br>* Given PO<br>* Other names: ICI-118630;Drug: Goserelin Acetate<br>* Given SC<br>* Other names: Zoladex;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Placebo Comparator: Arm B (exemestane, placebo)<br>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. Patients also undergo CT or MRI at baseline, at the end of cycle 3, every 3 cycles, at treatment discontinuation, and during follow-up, collection of blood samples at baseline and day 15 of cycle 1, and collection of archived tissue at baseline. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. | Procedure: Biospecimen Collection<br>* Undergo collection of blood and archived tissue samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Drug: Goserelin<br>* Given PO<br>* Other names: ICI-118630;Drug: Goserelin Acetate<br>* Given SC<br>* Other names: Zoladex;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Other: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | 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. | 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 | 
| Overall Survival (OS) | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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). | 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) | 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. | 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 | 
| Lysine Acetylation Change in CD45 Blood Mononuclear Cells Between C1D1 and C1D15 and PFS in Patients on Arm A | 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. | 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 | 
| Patient-reported Health-related Quality of Life | 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. | Assessed at baseline and end of cycle 3 | 
| Patient-reported Diarrhea | 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. | Assessed at baseline and end of cycle 3 | 
| Patient-reported Fatigue | 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. | Assessed at baseline and end of cycle 3 | 
| Patient-reported Nausea and Anorexia | 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. | Assessed at baseline and end of cycle 3 |