Entinostat in Patients With Recurrent Advanced Hormone Receptor-Positive Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02115282
• Collaborator: (none)
• Enrollment: 608
• Locations: 663
• Arms: 2
• Anticipated Duration (Months): 174.9
• Patients Per Site: 0.9
• Patients Per Site Per Month: 0

Study Details

Study Description

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 Acetate; Other: Placebo Administration	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

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

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

4. 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.

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

6. 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.

7. To measure adherence to protocol therapy.

EXPLORATORY OBJECTIVES:

1. To evaluate the pharmacokinetics of entinostat in patients with advanced breast cancer.

2. To evaluate what, if any, patient variables alter the pharmacokinetic profile of entinostat in patients with advanced breast cancer.

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

4. 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.

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.

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.

Study Design

• Study Type: Interventional
• 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: Mar 29, 2014
• Actual Primary Completion Date: May 5, 2020
• Anticipated Study Completion Date: Oct 23, 2028

Arms and Interventions

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 Acetate; Given SC; Other Names: ZDX Zoladex
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 Acetate; Given SC; Other Names: ZDX Zoladex ; Other: Placebo Administration; Given PO

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [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) [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) [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) [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 [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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Estrogen receptor (ER) and/or progesterone receptor (PR) positive histologically confirmed adenocarcinoma of the breast with staining of >= 1% cells is 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 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 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

Exclusion Criteria:

• 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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro	Jonesboro	Arkansas	United States	72401
3	Mercy San Juan Medical Center	Carmichael	California	United States	95608
4	Enloe Medical Center	Chico	California	United States	95926
5	Adventist Health Cancer Care Center Chico	Chico	California	United States	95973
6	Community Cancer Institute	Clovis	California	United States	93611
7	University Oncology Associates	Clovis	California	United States	93611
8	Eisenhower Medical Center	Rancho Mirage	California	United States	92270
9	Mercy Cancer Center - Sacramento	Sacramento	California	United States	95816
10	Saint Helena Hospital	Saint Helena	California	United States	94574
11	Presbyterian Intercommunity Hospital	Whittier	California	United States	90602
12	Woodland Memorial Hospital	Woodland	California	United States	95695
13	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado	United States	80012
14	The Medical Center of Aurora	Aurora	Colorado	United States	80012
15	Boulder Community Hospital	Boulder	Colorado	United States	80301
16	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado	United States	80304
17	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
18	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado	United States	80907
19	UCHealth Memorial Hospital Central	Colorado Springs	Colorado	United States	80909
20	Porter Adventist Hospital	Denver	Colorado	United States	80210
21	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
22	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
23	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado	United States	80218
24	SCL Health Saint Joseph Hospital	Denver	Colorado	United States	80218
25	Rocky Mountain Cancer Centers-Rose	Denver	Colorado	United States	80220
26	Rose Medical Center	Denver	Colorado	United States	80220
27	Mercy Medical Center	Durango	Colorado	United States	81301
28	Southwest Oncology PC	Durango	Colorado	United States	81301
29	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado	United States	80113
30	Swedish Medical Center	Englewood	Colorado	United States	80113
31	Mountain Blue Cancer Care Center	Golden	Colorado	United States	80401
32	North Colorado Medical Center	Greeley	Colorado	United States	80631
33	Rocky Mountain Cancer Centers-Greenwood Village	Greenwood Village	Colorado	United States	80111
34	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado	United States	80228
35	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
36	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado	United States	80120
37	Littleton Adventist Hospital	Littleton	Colorado	United States	80122
38	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado	United States	80124
39	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
40	Longmont United Hospital	Longmont	Colorado	United States	80501
41	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado	United States	80501
42	McKee Medical Center	Loveland	Colorado	United States	80539
43	Parker Adventist Hospital	Parker	Colorado	United States	80138
44	Rocky Mountain Cancer Centers-Parker	Parker	Colorado	United States	80138
45	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
46	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado	United States	81008
47	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado	United States	80260
48	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
49	Smilow Cancer Hospital Care Center - Guiford	Guilford	Connecticut	United States	06437
50	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
51	Manchester Memorial Hospital	Manchester	Connecticut	United States	06040
52	Middlesex Hospital	Middletown	Connecticut	United States	06457
53	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
54	Yale University	New Haven	Connecticut	United States	06520
55	Smilow Cancer Hospital-Orange Care Center	Orange	Connecticut	United States	06477
56	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut	United States	06790
57	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut	United States	06385
58	Bayhealth Hospital Kent Campus	Dover	Delaware	United States	19901
59	Beebe Medical Center	Lewes	Delaware	United States	19958
60	Helen F Graham Cancer Center	Newark	Delaware	United States	19713
61	Medical Oncology Hematology Consultants PA	Newark	Delaware	United States	19713
62	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
63	Beebe Health Campus	Rehoboth Beach	Delaware	United States	19971
64	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware	United States	19973
65	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware	United States	19801
66	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
67	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
68	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
69	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida	United States	33442
70	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
71	Baptist MD Anderson Cancer Center	Jacksonville	Florida	United States	32207
72	Lakeland Regional Health Hollis Cancer Center	Lakeland	Florida	United States	33805
73	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
74	UM Sylvester Comprehensive Cancer Center at Kendall	Miami	Florida	United States	33176
75	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida	United States	33324
76	Cleveland Clinic-Weston	Weston	Florida	United States	33331
77	Grady Health System	Atlanta	Georgia	United States	30303
78	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
79	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
80	Emory Saint Joseph's Hospital	Atlanta	Georgia	United States	30342
81	John B Amos Cancer Center	Columbus	Georgia	United States	31904
82	Medical Center of Central Georgia	Macon	Georgia	United States	31201
83	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
84	Pali Momi Medical Center	'Aiea	Hawaii	United States	96701
85	Queen's Cancer Center - Pearlridge	'Aiea	Hawaii	United States	96701
86	Hawaii Cancer Care Inc-POB II	Honolulu	Hawaii	United States	96813
87	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii	United States	96813
88	Queen's Medical Center	Honolulu	Hawaii	United States	96813
89	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
90	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
91	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii	United States	96817
92	Queen's Cancer Center - Kuakini	Honolulu	Hawaii	United States	96817
93	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
94	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
95	Kootenai Medical Center	Coeur d'Alene	Idaho	United States	83814
96	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho	United States	83619
97	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
98	Kootenai Cancer Clinic	Sandpoint	Idaho	United States	83864
99	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho	United States	83301
100	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
101	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
102	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
103	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
104	Memorial Hospital of Carbondale	Carbondale	Illinois	United States	62902
105	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
106	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
107	Northwestern University	Chicago	Illinois	United States	60611
108	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
109	Swedish Covenant Hospital	Chicago	Illinois	United States	60625
110	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
111	Weiss Memorial Hospital	Chicago	Illinois	United States	60640
112	Presence Saint Joseph Hospital-Chicago	Chicago	Illinois	United States	60657
113	Carle on Vermilion	Danville	Illinois	United States	61832
114	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois	United States	62526
115	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
116	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
117	Crossroads Cancer Center	Effingham	Illinois	United States	62401
118	AMITA Health Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
119	Elmhurst Memorial Hospital	Elmhurst	Illinois	United States	60126
120	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
121	Saint Francis Hospital	Evanston	Illinois	United States	60202
122	Freeport Memorial Hospital/Leonard C Ferguson Cancer Center	Freeport	Illinois	United States	61032
123	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
124	Western Illinois Cancer Treatment Center	Galesburg	Illinois	United States	61401
125	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois	United States	60134
126	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
127	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois	United States	60435
128	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
129	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
130	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
131	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
132	Loyola University Medical Center	Maywood	Illinois	United States	60153
133	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
134	Edward Hospital/Cancer Center	Naperville	Illinois	United States	60540
135	Community Cancer Center Foundation	Normal	Illinois	United States	61761
136	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453-2699
137	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
138	Radiation Oncology of Northern Illinois	Ottawa	Illinois	United States	61350
139	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
140	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
141	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
142	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois	United States	61615
143	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
144	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
145	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
146	Valley Radiation Oncology	Peru	Illinois	United States	61354
147	Edward Hospital/Cancer Center?Plainfield	Plainfield	Illinois	United States	60585
148	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
149	West Suburban Medical Center	River Forest	Illinois	United States	60305
150	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois	United States	61114
151	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
152	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
153	Springfield Clinic	Springfield	Illinois	United States	62702
154	Memorial Medical Center	Springfield	Illinois	United States	62781
155	Carle Cancer Center	Urbana	Illinois	United States	61801
156	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
157	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
158	Rush-Copley Healthcare Center	Yorkville	Illinois	United States	60560
159	IU Health North Hospital	Carmel	Indiana	United States	46032
160	IU Health Central Indiana Cancer Centers-Fishers	Fishers	Indiana	United States	46037
161	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
162	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
163	IU Health Methodist Hospital	Indianapolis	Indiana	United States	46202
164	Sidney and Lois Eskenazi Hospital	Indianapolis	Indiana	United States	46202
165	IU Health Central Indiana Cancer Centers-East	Indianapolis	Indiana	United States	46219
166	Franciscan Health Indianapolis	Indianapolis	Indiana	United States	46237
167	Springmill Medical Center	Indianapolis	Indiana	United States	46290
168	IU Health Arnett Cancer Care	Lafayette	Indiana	United States	47904
169	Woodland Cancer Care Center	Michigan City	Indiana	United States	46360
170	Franciscan Health Mooresville	Mooresville	Indiana	United States	46158
171	IU Health Ball Memorial Hospital	Muncie	Indiana	United States	47303
172	Reid Health	Richmond	Indiana	United States	47374
173	Union Hospital	Terre Haute	Indiana	United States	47804
174	Mary Greeley Medical Center	Ames	Iowa	United States	50010
175	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
176	University of Iowa Healthcare Cancer Services Quad Cities	Bettendorf	Iowa	United States	52722
177	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
178	Mercy Hospital	Cedar Rapids	Iowa	United States	52403
179	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
180	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
181	Mercy Cancer Center-West Lakes	Clive	Iowa	United States	50325
182	Alegent Health Mercy Hospital	Council Bluffs	Iowa	United States	51503
183	Genesis Medical Center - East Campus	Davenport	Iowa	United States	52803
184	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
185	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
186	Broadlawns Medical Center	Des Moines	Iowa	United States	50314
187	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
188	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
189	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa	United States	50501
190	Trinity Regional Medical Center	Fort Dodge	Iowa	United States	50501
191	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
192	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
193	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
194	Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
195	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
196	Mercy Medical Center-West Lakes	West Des Moines	Iowa	United States	50266
197	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
198	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
199	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
200	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
201	Saint Catherine Hospital	Garden City	Kansas	United States	67846
202	Central Care Cancer Center - Great Bend	Great Bend	Kansas	United States	67530
203	Saint Rose Ambulatory and Surgery Center	Great Bend	Kansas	United States	67530
204	HaysMed University of Kansas Health System	Hays	Kansas	United States	67601
205	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
206	University of Kansas Cancer Center-West	Kansas City	Kansas	United States	66112
207	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
208	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
209	Kansas Institute of Medicine Cancer and Blood Center	Lenexa	Kansas	United States	66219
210	Minimally Invasive Surgery Hospital	Lenexa	Kansas	United States	66219
211	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67905
212	Cancer Center of Kansas-Manhattan	Manhattan	Kansas	United States	66502
213	Cancer Center of Kansas - McPherson	McPherson	Kansas	United States	67460
214	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
215	Olathe Health Cancer Center	Olathe	Kansas	United States	66061
216	Menorah Medical Center	Overland Park	Kansas	United States	66209
217	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas	United States	66210
218	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
219	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
220	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
221	Salina Regional Health Center	Salina	Kansas	United States	67401
222	University of Kansas Health System Saint Francis Campus	Topeka	Kansas	United States	66606
223	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
224	Associates In Womens Health	Wichita	Kansas	United States	67208
225	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
226	Ascension Via Christi Hospitals Wichita	Wichita	Kansas	United States	67214
227	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
228	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
229	Flaget Memorial Hospital	Bardstown	Kentucky	United States	40004
230	Baptist Health Corbin	Corbin	Kentucky	United States	40701
231	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky	United States	41017
232	Saint Elizabeth Medical Center South	Edgewood	Kentucky	United States	41017
233	Hardin Memorial Hospital	Elizabethtown	Kentucky	United States	42701
234	Saint Elizabeth Fort Thomas	Fort Thomas	Kentucky	United States	41075
235	Baptist Health Lexington	Lexington	Kentucky	United States	40503
236	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky	United States	40504
237	Saint Joseph Hospital East	Lexington	Kentucky	United States	40509
238	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
239	Jewish Hospital	Louisville	Kentucky	United States	40202
240	Baptist Health Louisville	Louisville	Kentucky	United States	40207
241	Jewish Hospital Medical Center Northeast	Louisville	Kentucky	United States	40245
242	Baptist Health Madisonville/Merle Mahr Cancer Center	Madisonville	Kentucky	United States	42431
243	Baptist Health Paducah	Paducah	Kentucky	United States	42003
244	LSU Health Baton Rouge-North Clinic	Baton Rouge	Louisiana	United States	70805
245	Hematology/Oncology Clinic PLLC	Baton Rouge	Louisiana	United States	70809
246	Louisiana Hematology Oncology Associates LLC	Baton Rouge	Louisiana	United States	70809
247	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana	United States	70809
248	Ochsner Health Center-Summa	Baton Rouge	Louisiana	United States	70809
249	Our Lady of the Lake Physicians Group - Medical Oncology	Baton Rouge	Louisiana	United States	70809
250	Medical Center of Baton Rouge	Baton Rouge	Louisiana	United States	70816
251	Mary Bird Perkins Cancer Center - Covington	Covington	Louisiana	United States	70433
252	Northshore Oncology Associates-Covington	Covington	Louisiana	United States	70433
253	Mary Bird Perkins Cancer Center - Houma	Houma	Louisiana	United States	70360
254	Oncology Center of The South Incorporated	Houma	Louisiana	United States	70360
255	Louisiana State University Health Science Center	New Orleans	Louisiana	United States	70112
256	University Medical Center New Orleans	New Orleans	Louisiana	United States	70112
257	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
258	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
259	Eastern Maine Medical Center	Bangor	Maine	United States	04401
260	Lafayette Family Cancer Center-EMMC	Brewer	Maine	United States	04412
261	Penobscot Bay Medical Center	Rockport	Maine	United States	04856
262	York Hospital	York	Maine	United States	03909
263	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
264	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
265	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
266	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
267	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland	United States	21237
268	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
269	UM Upper Chesapeake Medical Center	Bel Air	Maryland	United States	21014
270	Western Maryland Regional Medical Center	Cumberland	Maryland	United States	21502
271	University of Maryland Shore Medical Center at Easton	Easton	Maryland	United States	21601
272	MedStar Montgomery Medical Center	Olney	Maryland	United States	20832
273	Northwest Hospital Center	Randallstown	Maryland	United States	21133
274	Beverly Hospital	Beverly	Massachusetts	United States	01915
275	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
276	Saint Anne's Hospital	Fall River	Massachusetts	United States	02721
277	Addison Gilbert Hospital	Gloucester	Massachusetts	United States	01930
278	Newton-Wellesley Hospital	Newton	Massachusetts	United States	02462
279	Berkshire Medical Center - Cancer Center	Pittsfield	Massachusetts	United States	01201
280	Winchester Hospital	Winchester	Massachusetts	United States	01890
281	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
282	Hickman Cancer Center	Adrian	Michigan	United States	49221
283	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
284	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan	United States	48183
285	IHA Hematology Oncology Consultants-Chelsea	Chelsea	Michigan	United States	48118
286	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan	United States	48038
287	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
288	Henry Ford Medical Center-Fairlane	Dearborn	Michigan	United States	48126
289	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
290	Henry Ford Hospital	Detroit	Michigan	United States	48202
291	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
292	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
293	Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
294	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
295	Hurley Medical Center	Flint	Michigan	United States	48503
296	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
297	William Beaumont Hospital-Grosse Pointe	Grosse Pointe	Michigan	United States	48230
298	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
299	Allegiance Health	Jackson	Michigan	United States	49201
300	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
301	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
302	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
303	Henry Ford Medical Center-Columbus	Novi	Michigan	United States	48377
304	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
305	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
306	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
307	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
308	William Beaumont Hospital - Troy	Troy	Michigan	United States	48085
309	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
310	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan	United States	48322
311	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota	United States	56601
312	Essentia Health Saint Joseph's Medical Center	Brainerd	Minnesota	United States	56401
313	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
314	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
315	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota	United States	56537
316	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
317	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
318	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
319	Health Partners Inc	Minneapolis	Minnesota	United States	55454
320	New Ulm Medical Center	New Ulm	Minnesota	United States	56073
321	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
322	Regions Hospital	Saint Paul	Minnesota	United States	55101
323	Lakeview Hospital	Stillwater	Minnesota	United States	55082
324	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
325	Baptist Memorial Hospital and Cancer Center-Golden Triangle	Columbus	Mississippi	United States	39705
326	Baptist Cancer Center-Grenada	Grenada	Mississippi	United States	38901
327	Hattiesburg Clinic - Hematology/Oncology Clinic	Hattiesburg	Mississippi	United States	39401
328	Forrest General Hospital / Cancer Center	Hattiesburg	Mississippi	United States	39404
329	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
330	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi	United States	38652
331	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi	United States	38655
332	Singing River Hospital	Pascagoula	Mississippi	United States	39581
333	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi	United States	38671
334	Saint Louis Cancer and Breast Institute-Ballwin	Ballwin	Missouri	United States	63011
335	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri	United States	63628
336	Cox Cancer Center Branson	Branson	Missouri	United States	65616
337	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
338	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
339	Saint Luke's Hospital	Chesterfield	Missouri	United States	63017
340	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
341	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri	United States	63141
342	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
343	Capital Region Southwest Campus	Jefferson City	Missouri	United States	65109
344	Truman Medical Centers	Kansas City	Missouri	United States	64108
345	The University of Kansas Cancer Center-South	Kansas City	Missouri	United States	64131
346	Research Medical Center	Kansas City	Missouri	United States	64132
347	University of Kansas Cancer Center - North	Kansas City	Missouri	United States	64154
348	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri	United States	64064
349	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
350	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
351	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
352	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
353	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri	United States	63376
354	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
355	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
356	CoxHealth South Hospital	Springfield	Missouri	United States	65807
357	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
358	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
359	Saint Vincent Healthcare	Billings	Montana	United States	59101
360	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
361	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
362	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
363	Saint Peter's Community Hospital	Helena	Montana	United States	59601
364	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
365	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
366	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
367	CHI Health Good Samaritan	Kearney	Nebraska	United States	68847
368	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
369	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
370	Alegent Health Lakeside Hospital	Omaha	Nebraska	United States	68130
371	Creighton University Medical Center	Omaha	Nebraska	United States	68131
372	Wentworth-Douglass Hospital	Dover	New Hampshire	United States	03820
373	Cheshire Medical Center-Dartmouth-Hitchcock Keene	Keene	New Hampshire	United States	03431
374	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
375	Norris Cotton Cancer Center-Manchester	Manchester	New Hampshire	United States	03102
376	Saint Joseph Hospital	Nashua	New Hampshire	United States	03060
377	Norris Cotton Cancer Center-Nashua	Nashua	New Hampshire	United States	03063
378	AtlantiCare Health Park-Cape May Court House	Cape May Court House	New Jersey	United States	08210
379	AtlantiCare Surgery Center	Egg Harbor Township	New Jersey	United States	08234
380	Englewood Hospital and Medical Center	Englewood	New Jersey	United States	07631
381	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
382	The Cancer Institute of New Jersey Hamilton	Hamilton	New Jersey	United States	08690
383	Monmouth Medical Center	Long Branch	New Jersey	United States	07740
384	Virtua Memorial	Mount Holly	New Jersey	United States	08060
385	Inspira Medical Center Mullica Hill	Mullica Hill	New Jersey	United States	08062
386	Jersey Shore Medical Center	Neptune	New Jersey	United States	07753
387	Robert Wood Johnson University Hospital Somerset	Somerville	New Jersey	United States	08876
388	Inspira Medical Center Vineland	Vineland	New Jersey	United States	08360
389	Virtua Voorhees	Voorhees	New Jersey	United States	08043
390	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
391	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico	United States	87109
392	Presbyterian Kaseman Hospital	Albuquerque	New Mexico	United States	87110
393	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico	United States	88011
394	Christus Saint Vincent Regional Cancer Center	Santa Fe	New Mexico	United States	87505
395	Hematology Oncology Associates of Central New York-Auburn	Auburn	New York	United States	13021
396	Montefiore Medical Center-Einstein Campus	Bronx	New York	United States	10461
397	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
398	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
399	Kings County Hospital	Brooklyn	New York	United States	11203
400	State University of New York Downstate Medical Center	Brooklyn	New York	United States	11203
401	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
402	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
403	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York	United States	14905
404	Mount Sinai Union Square	New York	New York	United States	10003
405	Mount Sinai West	New York	New York	United States	10019
406	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
407	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
408	University of Rochester	Rochester	New York	United States	14642
409	Staten Island University Hospital	Staten Island	New York	United States	10305
410	Hematology Oncology Associates of Central New York-Onondaga Hill	Syracuse	New York	United States	13215
411	Dickstein Cancer Treatment Center	White Plains	New York	United States	10601
412	Randolph Hospital	Asheboro	North Carolina	United States	27203
413	Mission Hospital	Asheville	North Carolina	United States	28801
414	Messino Cancer Centers	Asheville	North Carolina	United States	28806
415	Hope Women's Cancer Centers-Asheville	Asheville	North Carolina	United States	28816
416	Cone Health Cancer Center at Alamance Regional	Burlington	North Carolina	United States	27215
417	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
418	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina	United States	28328
419	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina	United States	27534
420	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
421	Cone Health Cancer Center	Greensboro	North Carolina	United States	27403
422	Hendersonville Hematology and Oncology at Pardee	Hendersonville	North Carolina	United States	28791
423	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
424	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina	United States	28546
425	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
426	Cone Heath Cancer Center at Mebane	Mebane	North Carolina	United States	27302
427	Annie Penn Memorial Hospital	Reidsville	North Carolina	United States	27320
428	Marion L Shepard Cancer Center at Vidant Beaufort Hospital	Washington	North Carolina	United States	27889
429	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
430	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
431	Essentia Health Cancer Center-South University Clinic	Fargo	North Dakota	United States	58103
432	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
433	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58122
434	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
435	Altru Cancer Center	Grand Forks	North Dakota	United States	58201
436	Trinity Cancer Care Center	Minot	North Dakota	United States	58701
437	Summa Health System - Akron Campus	Akron	Ohio	United States	44304
438	Cleveland Clinic Akron General	Akron	Ohio	United States	44307
439	Strecker Cancer Center-Belpre	Belpre	Ohio	United States	45714
440	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio	United States	43402
441	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
442	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio	United States	45202
443	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio	United States	45211
444	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio	United States	45220
445	Oncology Hematology Care Inc-Anderson	Cincinnati	Ohio	United States	45230
446	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio	United States	45236
447	Bethesda North Hospital	Cincinnati	Ohio	United States	45242
448	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio	United States	45242
449	TriHealth Cancer Institute-Westside	Cincinnati	Ohio	United States	45247
450	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio	United States	45255
451	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio	United States	44111
452	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
453	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
454	Mount Carmel East Hospital	Columbus	Ohio	United States	43213
455	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio	United States	43214
456	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
457	Grant Medical Center	Columbus	Ohio	United States	43215
458	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
459	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
460	Doctors Hospital	Columbus	Ohio	United States	43228
461	Delaware Health Center-Grady Cancer Center	Delaware	Ohio	United States	43015
462	Delaware Radiation Oncology	Delaware	Ohio	United States	43015
463	Grady Memorial Hospital	Delaware	Ohio	United States	43015
464	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio	United States	45014
465	Cleveland Clinic Cancer Center Independence	Independence	Ohio	United States	44131
466	Fairfield Medical Center	Lancaster	Ohio	United States	43130
467	Saint Rita's Medical Center	Lima	Ohio	United States	45801
468	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio	United States	44906
469	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
470	OhioHealth Marion General Hospital	Marion	Ohio	United States	43302
471	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio	United States	43537
472	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio	United States	44124
473	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
474	Licking Memorial Hospital	Newark	Ohio	United States	43055
475	Newark Radiation Oncology	Newark	Ohio	United States	43055
476	Saint Charles Hospital	Oregon	Ohio	United States	43616
477	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio	United States	43616
478	Mercy Health Perrysburg Cancer Center	Perrysburg	Ohio	United States	43551
479	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
480	North Coast Cancer Care	Sandusky	Ohio	United States	44870
481	Springfield Regional Cancer Center	Springfield	Ohio	United States	45504
482	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
483	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio	United States	44136
484	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
485	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio	United States	43617
486	Mercy Saint Anne Hospital	Toledo	Ohio	United States	43623
487	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
488	Upper Valley Medical Center	Troy	Ohio	United States	45373
489	South Pointe Hospital	Warrensville Heights	Ohio	United States	44122
490	Saint Ann's Hospital	Westerville	Ohio	United States	43081
491	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio	United States	44691
492	Wright-Patterson Medical Center	Wright-Patterson Air Force Base	Ohio	United States	45433
493	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
494	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma	United States	73505
495	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
496	Saint Charles Health System	Bend	Oregon	United States	97701
497	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon	United States	97015
498	Bay Area Hospital	Coos Bay	Oregon	United States	97420
499	Rogue Valley Medical Center	Medford	Oregon	United States	97504
500	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
501	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
502	Providence Portland Medical Center	Portland	Oregon	United States	97213
503	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
504	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
505	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania	United States	19317
506	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
507	Doylestown Hospital	Doylestown	Pennsylvania	United States	18901
508	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania	United States	17109
509	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
510	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
511	Jefferson Hospital	Jefferson Hills	Pennsylvania	United States	15025
512	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17602
513	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania	United States	17837
514	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
515	Riddle Memorial Hospital	Media	Pennsylvania	United States	19063
516	Forbes Hospital	Monroeville	Pennsylvania	United States	15146
517	Allegheny Valley Hospital	Natrona Heights	Pennsylvania	United States	15065
518	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
519	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
520	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
521	Einstein Medical Center Philadelphia	Philadelphia	Pennsylvania	United States	19141
522	Phoenixville Hospital	Phoenixville	Pennsylvania	United States	19460
523	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
524	West Penn Hospital	Pittsburgh	Pennsylvania	United States	15224
525	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232
526	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania	United States	17901
527	Penn State Health Saint Joseph Medical Center	Reading	Pennsylvania	United States	19605
528	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania	United States	18840
529	Geisinger Medical Group	State College	Pennsylvania	United States	16801
530	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
531	Chester County Hospital	West Chester	Pennsylvania	United States	19380
532	Reading Hospital	West Reading	Pennsylvania	United States	19611
533	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania	United States	15090
534	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
535	UPMC Susquehanna	Williamsport	Pennsylvania	United States	17701
536	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
537	Women and Infants Hospital	Providence	Rhode Island	United States	02905
538	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
539	Medical University of South Carolina	Charleston	South Carolina	United States	29425
540	Prisma Health Cancer Institute - Easley	Easley	South Carolina	United States	29640
541	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina	United States	29341
542	Saint Francis Hospital	Greenville	South Carolina	United States	29601
543	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina	United States	29605
544	Prisma Health Cancer Institute - Faris	Greenville	South Carolina	United States	29605
545	Saint Francis Cancer Center	Greenville	South Carolina	United States	29607
546	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina	United States	29615
547	Prisma Health Cancer Institute - Greer	Greer	South Carolina	United States	29650
548	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
549	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina	United States	29672
550	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
551	Prisma Health Cancer Institute - Spartanburg	Spartanburg	South Carolina	United States	29307
552	Avera Cancer Institute-Aberdeen	Aberdeen	South Dakota	United States	57401
553	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
554	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
555	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
556	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
557	Jackson-Madison County General Hospital	Jackson	Tennessee	United States	38301
558	Regional Cancer Center at Indian Path Community Hospital	Kingsport	Tennessee	United States	37660
559	Wellmont Holston Valley Hospital and Medical Center	Kingsport	Tennessee	United States	37660
560	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee	United States	38120
561	Baptist Memorial Hospital for Women	Memphis	Tennessee	United States	38120
562	Family Cancer Center-Memphis	Memphis	Tennessee	United States	38120
563	Meharry Medical College	Nashville	Tennessee	United States	37208
564	Hendrick Medical Center	Abilene	Texas	United States	79601
565	Parkland Memorial Hospital	Dallas	Texas	United States	75235
566	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
567	Texas Tech University Health Sciences Center-El Paso	El Paso	Texas	United States	79905
568	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas	United States	76104
569	University of Texas Health Science Center at Tyler	Tyler	Texas	United States	75708
570	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont	United States	05819
571	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
572	Hematology Oncology Associates of Fredericksburg Inc	Fredericksburg	Virginia	United States	22408
573	Centra Lynchburg Hematology-Oncology Clinic Inc	Lynchburg	Virginia	United States	24501
574	Sovah Health Martinsville	Martinsville	Virginia	United States	24115
575	Bon Secours Memorial Regional Medical Center	Mechanicsville	Virginia	United States	23116
576	Bon Secours Saint Francis Medical Center	Midlothian	Virginia	United States	23114
577	Southwest VA Regional Cancer Center	Norton	Virginia	United States	24273
578	Bon Secours Saint Mary's Hospital	Richmond	Virginia	United States	23226
579	Virginia Cancer Institute	Richmond	Virginia	United States	23230
580	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
581	VCU Community Memorial Health Center	South Hill	Virginia	United States	23970
582	Shenandoah Oncology PC	Winchester	Virginia	United States	22601
583	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
584	Harrison Medical Center	Bremerton	Washington	United States	98310
585	Highline Medical Center-Main Campus	Burien	Washington	United States	98166
586	Swedish Cancer Institute-Edmonds	Edmonds	Washington	United States	98026
587	Swedish Cancer Institute-Issaquah	Issaquah	Washington	United States	98029
588	Kadlec Clinic Hematology and Oncology	Kennewick	Washington	United States	99336
589	Seattle Cancer Care Alliance at EvergreenHealth	Kirkland	Washington	United States	98034
590	PeaceHealth Saint John Medical Center	Longview	Washington	United States	98632
591	Skagit Valley Hospital Regional Cancer Care Center	Mount Vernon	Washington	United States	98274
592	Skagit Valley Hospital	Mount Vernon	Washington	United States	98274
593	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington	United States	98370
594	Minor and James Medical PLLC	Seattle	Washington	United States	98104
595	Swedish Medical Center-Ballard Campus	Seattle	Washington	United States	98107
596	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
597	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
598	Kaiser Permanente Washington	Seattle	Washington	United States	98112
599	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
600	University of Washington Medical Center	Seattle	Washington	United States	98195
601	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington	United States	98405
602	Northwest Medical Specialties PLLC	Tacoma	Washington	United States	98405
603	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
604	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
605	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
606	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
607	Edwards Comprehensive Cancer Center	Huntington	West Virginia	United States	25701
608	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
609	Langlade Hospital and Cancer Center	Antigo	Wisconsin	United States	54409
610	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin	United States	53105
611	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
612	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
613	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin	United States	54937
614	Aurora Health Care Germantown Health Center	Germantown	Wisconsin	United States	53022
615	Aurora Cancer Care-Grafton	Grafton	Wisconsin	United States	53024
616	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
617	Bellin Memorial Hospital	Green Bay	Wisconsin	United States	54301
618	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
619	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
620	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
621	Aurora BayCare Medical Center	Green Bay	Wisconsin	United States	54311
622	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin	United States	53548
623	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
624	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin	United States	53142
625	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
626	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
627	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
628	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin	United States	54143
629	Saint Vincent Hospital Cancer Center at Marinette	Marinette	Wisconsin	United States	54143
630	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
631	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin	United States	53209
632	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
633	Aurora Sinai Medical Center	Milwaukee	Wisconsin	United States	53233
634	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
635	ProHealth D N Greenwald Center	Mukwonago	Wisconsin	United States	53149
636	Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
637	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
638	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
639	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin	United States	54904
640	Ascension All Saints Hospital	Racine	Wisconsin	United States	53405
641	Aurora Cancer Care-Racine	Racine	Wisconsin	United States	53406
642	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
643	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin	United States	54868
644	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
645	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin	United States	53081
646	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
647	Marshfield Clinic Stevens Point Center	Stevens Point	Wisconsin	United States	54482
648	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235-1495
649	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
650	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
651	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin	United States	54241
652	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin	United States	53188
653	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
654	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin	United States	53188
655	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401
656	Marshfield Clinic-Wausau Center	Wausau	Wisconsin	United States	54401
657	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin	United States	53226
658	Aurora West Allis Medical Center	West Allis	Wisconsin	United States	53227
659	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
660	Aspirus UW Cancer Center	Wisconsin Rapids	Wisconsin	United States	54494
661	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
662	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming	United States	82001
663	University Of Pretoria	Pretoria		South Africa	0002

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Roisin M Connolly, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 22, 2019

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02115282
• Other Study ID Numbers: NCI-2014-00746; NCI-2014-00746; E2112; E2112; U10CA180820; U10CA021115; U24CA196172
• First Posted: Apr 16, 2014
• Last Update Posted: Nov 16, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Cancer Institute (NCI): Entinostat; Hormone-receptor positive breast cancer; Recurrent breast cancer; Histone deacetylase
• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Recurrence; Exemestane; Goserelin; Entinostat; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Recruitment Details	This study was activated on March 19, 2014 and terminated on October 17, 2018 with a total accrual of 608 patients.

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Period Title: Overall Study
STARTED	305	303
Eligible	265	257
Treated	296	293
COMPLETED	0	0
NOT COMPLETED	305	303

Baseline Characteristics

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)	Total
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO	Total of all reporting groups
Overall Participants	305	303	608
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	63	63
Sex: Female, Male (Count of Participants)
Female	302 99%	300 99%	602 99%
Male	3 1%	3 1%	6 1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	18 5.9%	18 5.9%	36 5.9%
Not Hispanic or Latino	284 93.1%	278 91.7%	562 92.4%
Unknown or Not Reported	3 1%	7 2.3%	10 1.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1%	0 0%	3 0.5%
Asian	5 1.6%	2 0.7%	7 1.2%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	1 0.2%
Black or African American	42 13.8%	49 16.2%	91 15%
White	246 80.7%	244 80.5%	490 80.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	8 2.6%	8 2.6%	16 2.6%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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.
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

Outcome Measure Data

Analysis Population Description

The first 360 patients randomized to the trial (primary analysis population for the PFS endpoint)

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	180	180
Median (95% Confidence Interval) [months]	3.3	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Exemestane, Entinostat), Arm B (Exemestane, Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments	The p value was based on stratified log rank test, the threshold for significance was two-sided p value of 0.2%.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Overall Survival (OS)
Description	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.
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

Outcome Measure Data

Analysis Population Description

All randomized patients (ie, intent-to-treat patients, primary analysis population for the OS endpoint)

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	305	303
Median (95% Confidence Interval) [months]	23.4	21.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Exemestane, Entinostat), Arm B (Exemestane, Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments	The p value was based on stratified log rank test, stratified on the four randomization factors. The threshold for statistical significance was two-sided p value of 3.7% after taking into account the five interim analyses of OS into account.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	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).
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

Outcome Measure Data

Analysis Population Description

All randomized patients (ie, the intent-to-treat population)

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	305	303
Number (95% Confidence Interval) [percentage of participants]	4.6 1.5%	4.3 1.4%

4. Secondary Outcome

Title	Time-to-treatment Deterioration (TTD)
Description	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.
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

Outcome Measure Data

Analysis Population Description

The first 360 patients randomized to the trial who received at least one dose of protocol therapy

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	175	176
Median (95% Confidence Interval) [months]	2.9	2.9

5. Secondary Outcome

Title	Lysine Acetylation Change in CD45 Blood Mononuclear Cells Between C1D1 and C1D15 and PFS in Patients on Arm A
Description	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.
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

Outcome Measure Data

Analysis Population Description

All patients who were randomized to arm A (exemestane +entinostat) and had lysine acetylation test results at both C1D1 and C1D15

Arm/Group Title	Arm A (Exemestane, Entinostat)- Lysine Acetylation Change>=1.5 Fold	Arm A (Exemestane, Entinostat)- Lysine Acetylation Change<1.5 Fold
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC
Measure Participants	43	146
Median (95% Confidence Interval) [months]	2.8	2.7

6. Secondary Outcome

Title	Patient-reported Health-related Quality of Life
Description	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.
Time Frame	Assessed at baseline and end of cycle 3

Outcome Measure Data

Analysis Population Description

All randomized patients who reported health-related quality of life data at end of cycle 3 assessment

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	203	205
Mean (Standard Deviation) [units on a scale]	20.5 (5.0)	20.9 (4.7)

7. Secondary Outcome

Title	Patient-reported Diarrhea
Description	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.
Time Frame	Assessed at baseline and end of cycle 3

Outcome Measure Data

Analysis Population Description

All randomized patients who reported FACIT-Diarrhea data at end of cycle 3 assessment

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	208	209
Mean (Standard Deviation) [units on a scale]	38.8 (7.2)	41.5 (4.3)

8. Secondary Outcome

Title	Patient-reported Fatigue
Description	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.
Time Frame	Assessed at baseline and end of cycle 3

Outcome Measure Data

Analysis Population Description

All randomized patients who reported PROMIS fatigue data at end of cycle 3 assessment

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	201	207
Mean (Standard Deviation) [T-score]	55.5 (8.2)	54.1 (8.9)

9. Secondary Outcome

Title	Patient-reported Nausea and Anorexia
Description	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.
Time Frame	Assessed at baseline and end of cycle 3

Outcome Measure Data

Analysis Population Description

All randomized patients who reported FAACT nausea and anorexia data at end of cycle 3 assessment

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	208	203
Mean (Standard Deviation) [units on a scale]	35.8 (7.8)	37.0 (7.9)

10. Secondary Outcome

Title	Proportion of High Adherence Score at End of Cycle 3
Description	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.
Time Frame	Assessed at end of cycle 3

Outcome Measure Data

Analysis Population Description

All randomized patients who received treatment and reported Morisky adherence data for entinostat/placebo at end of cycle 3

Arm/Group Title	Arm A (Exemestane, Entinostat)	Arm B (Exemestane, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Measure Participants	193	189
Number (95% Confidence Interval) [percentage of participants]	43.5 14.3%	43.4 14.3%

Adverse Events

Time Frame	Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry
Adverse Event Reporting Description	Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Arm/Group Title	Arm A (Exemestance, Entinostat)		Arm A (Exemestance, Placebo)
Arm/Group Description	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. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC		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. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
All Cause Mortality
	Arm A (Exemestance, Entinostat)		Arm A (Exemestance, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	209/305 (68.5%)		203/303 (67%)
Serious Adverse Events
	Arm A (Exemestance, Entinostat)		Arm A (Exemestance, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	151/296 (51%)		47/293 (16%)
Blood and lymphatic system disorders
Anemia	22/296 (7.4%)		5/293 (1.7%)
Febrile neutropenia	2/296 (0.7%)		0/293 (0%)
Cardiac disorders
Atrial fibrillation	2/296 (0.7%)		0/293 (0%)
Heart failure	2/296 (0.7%)		1/293 (0.3%)
Myocardial infarction	0/296 (0%)		1/293 (0.3%)
Pericardial effusion	1/296 (0.3%)		0/293 (0%)
Right ventricular dysfunction	1/296 (0.3%)		0/293 (0%)
Endocrine disorders
Endocrine disorders - Other, specify	1/296 (0.3%)		0/293 (0%)
Gastrointestinal disorders
Abdominal pain	1/296 (0.3%)		0/293 (0%)
Colitis	2/296 (0.7%)		0/293 (0%)
Colonic perforation	0/296 (0%)		2/293 (0.7%)
Diarrhea	12/296 (4.1%)		1/293 (0.3%)
Enterocolitis	1/296 (0.3%)		0/293 (0%)
Gastric ulcer	0/296 (0%)		1/293 (0.3%)
Gastroesophageal reflux disease	1/296 (0.3%)		0/293 (0%)
Nausea	5/296 (1.7%)		1/293 (0.3%)
Vomiting	2/296 (0.7%)		3/293 (1%)
General disorders
Edema limbs	3/296 (1%)		1/293 (0.3%)
Edema trunk	1/296 (0.3%)		0/293 (0%)
Fatigue	12/296 (4.1%)		3/293 (1%)
Non-cardiac chest pain	3/296 (1%)		0/293 (0%)
Hepatobiliary disorders
Hepatic failure	1/296 (0.3%)		0/293 (0%)
Immune system disorders
Anaphylaxis	1/296 (0.3%)		0/293 (0%)
Infections and infestations
Abdominal infection	0/296 (0%)		1/293 (0.3%)
Bone infection	1/296 (0.3%)		0/293 (0%)
Lung infection	0/296 (0%)		1/293 (0.3%)
Sepsis	1/296 (0.3%)		2/293 (0.7%)
Urinary tract infection	1/296 (0.3%)		1/293 (0.3%)
Investigations
Alanine aminotransferase increased	2/296 (0.7%)		2/293 (0.7%)
Alkaline phosphatase increased	2/296 (0.7%)		2/293 (0.7%)
Aspartate aminotransferase increased	2/296 (0.7%)		5/293 (1.7%)
Blood bilirubin increased	3/296 (1%)		1/293 (0.3%)
GGT increased	1/296 (0.3%)		0/293 (0%)
INR increased	1/296 (0.3%)		0/293 (0%)
Lymphocyte count decreased	10/296 (3.4%)		3/293 (1%)
Neutrophil count decreased	58/296 (19.6%)		1/293 (0.3%)
Platelet count decreased	10/296 (3.4%)		2/293 (0.7%)
Weight loss	1/296 (0.3%)		1/293 (0.3%)
White blood cell decreased	18/296 (6.1%)		2/293 (0.7%)
Metabolism and nutrition disorders
Anorexia	5/296 (1.7%)		0/293 (0%)
Dehydration	3/296 (1%)		0/293 (0%)
Hypercalcemia	0/296 (0%)		1/293 (0.3%)
Hyperglycemia	4/296 (1.4%)		2/293 (0.7%)
Hypoalbuminemia	3/296 (1%)		0/293 (0%)
Hypocalcemia	5/296 (1.7%)		0/293 (0%)
Hypokalemia	7/296 (2.4%)		2/293 (0.7%)
Hyponatremia	8/296 (2.7%)		1/293 (0.3%)
Hypophosphatemia	39/296 (13.2%)		4/293 (1.4%)
Metabolism and nutrition disorders - Other, specify	1/296 (0.3%)		0/293 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/296 (0.3%)		3/293 (1%)
Back pain	1/296 (0.3%)		0/293 (0%)
Bone pain	0/296 (0%)		1/293 (0.3%)
Generalized muscle weakness	3/296 (1%)		0/293 (0%)
Muscle weakness lower limb	1/296 (0.3%)		0/293 (0%)
Muscle weakness right-sided	0/296 (0%)		1/293 (0.3%)
Nervous system disorders
Encephalopathy	0/296 (0%)		1/293 (0.3%)
Headache	1/296 (0.3%)		0/293 (0%)
Stroke	0/296 (0%)		1/293 (0.3%)
Syncope	2/296 (0.7%)		1/293 (0.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/296 (2%)		1/293 (0.3%)
Hypoxia	1/296 (0.3%)		1/293 (0.3%)
Pleural effusion	2/296 (0.7%)		0/293 (0%)
Pneumonitis	2/296 (0.7%)		0/293 (0%)
Pulmonary edema	1/296 (0.3%)		0/293 (0%)
Respiratory failure	0/296 (0%)		1/293 (0.3%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/296 (0%)		1/293 (0.3%)
Rash maculo-papular	2/296 (0.7%)		1/293 (0.3%)
Urticaria	1/296 (0.3%)		0/293 (0%)
Vascular disorders
Hypertension	0/296 (0%)		5/293 (1.7%)
Thromboembolic event	4/296 (1.4%)		0/293 (0%)
Other (Not Including Serious) Adverse Events
	Arm A (Exemestance, Entinostat)		Arm A (Exemestance, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	280/296 (94.6%)		228/293 (77.8%)
Blood and lymphatic system disorders
Anemia	110/296 (37.2%)		55/293 (18.8%)
Gastrointestinal disorders
Abdominal pain	37/296 (12.5%)		21/293 (7.2%)
Constipation	36/296 (12.2%)		36/293 (12.3%)
Diarrhea	106/296 (35.8%)		47/293 (16%)
Dyspepsia	41/296 (13.9%)		15/293 (5.1%)
Nausea	120/296 (40.5%)		76/293 (25.9%)
Vomiting	56/296 (18.9%)		33/293 (11.3%)
General disorders
Edema limbs	54/296 (18.2%)		16/293 (5.5%)
Fatigue	167/296 (56.4%)		108/293 (36.9%)
Injury, poisoning and procedural complications
Bruising	18/296 (6.1%)		3/293 (1%)
Investigations
Alanine aminotransferase increased	38/296 (12.8%)		35/293 (11.9%)
Alkaline phosphatase increased	85/296 (28.7%)		47/293 (16%)
Aspartate aminotransferase increased	56/296 (18.9%)		54/293 (18.4%)
Creatinine increased	33/296 (11.1%)		19/293 (6.5%)
Lymphocyte count decreased	52/296 (17.6%)		23/293 (7.8%)
Neutrophil count decreased	138/296 (46.6%)		12/293 (4.1%)
Platelet count decreased	188/296 (63.5%)		19/293 (6.5%)
Weight loss	29/296 (9.8%)		12/293 (4.1%)
White blood cell decreased	163/296 (55.1%)		39/293 (13.3%)
Metabolism and nutrition disorders
Anorexia	62/296 (20.9%)		30/293 (10.2%)
Hyperglycemia	29/296 (9.8%)		12/293 (4.1%)
Hypoalbuminemia	66/296 (22.3%)		10/293 (3.4%)
Hypocalcemia	81/296 (27.4%)		14/293 (4.8%)
Hypokalemia	22/296 (7.4%)		11/293 (3.8%)
Hyponatremia	37/296 (12.5%)		15/293 (5.1%)
Hypophosphatemia	67/296 (22.6%)		12/293 (4.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	26/296 (8.8%)		26/293 (8.9%)
Myalgia	18/296 (6.1%)		24/293 (8.2%)
Nervous system disorders
Dizziness	21/296 (7.1%)		14/293 (4.8%)
Dysgeusia	20/296 (6.8%)		8/293 (2.7%)
Headache	39/296 (13.2%)		16/293 (5.5%)
Psychiatric disorders
Insomnia	18/296 (6.1%)		10/293 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough	15/296 (5.1%)		8/293 (2.7%)
Dyspnea	33/296 (11.1%)		19/293 (6.5%)
Vascular disorders
Hot flashes	23/296 (7.8%)		36/293 (12.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.