A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo in Patients With Hormone Receptor-Positive Advanced Breast Cancer
Phase: PHASE3
Conditions: Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Breast Adenocarcinoma, HER2/Neu Negative, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Recurrent Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
 
 
May 22, 2019 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD 20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #7 to E2112, A Randomized Phase III Trial of Endocrine Therapy plus 
Entinostat/Placebo in Patients with Hormone Receptor-Positive Advanced Breast Cancer. 
Please note that this study is under the Special Protocol Assessment which will require FDA 
review. 
There are revised case report forms as a result of this amendment. Case Report Forms in 
Medidata Rave will be amended to reflect changes in data collection related to this amendment. 
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions. 
IRB Review Requirements: 
An expedited review by the IRB can be considered for this amendment. However, please consult 
your local IRB’s standard operating procedures, since their requirements may differ and require 
a full board review.  
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the CIRB 
posting of this notice. 
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed 
consent changes must be approved by local IRBs within 90 days of distribution of this notice. If 
your local IRB has different SOPs, they must be available at future E-A audit. 
The following revisions to E2112 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated version date 
Inserted study champions 
2. 
5.2.3 
Updated NCI fax number  
3. 
5.6.1 
Renamed Medication Adherence Scale  
4. 
5.6.3.3 
Renamed Medication Adherence Scale 
5. 
5.6.3.5 
Renamed Medication Adherence Scale 
6. 
6.2.4 
Renamed Medication Adherence Scale 

ii 
 
Section 
Change 
7. 
7 
Renamed Medication Adherence Scale in footnote 7 
8. 
8.2.10 
Removed note regarding site participation from Korea and Peru  
9. 
8.3.10 
Removed note regarding site participation from Korea and Peru  
10. 9.6 
Renamed Medication Adherence Scale 
11. 9.7 
Renamed Medication Adherence Scale 
12. 9.7.2 
Renamed Medication Adherence Scale 
13. Appendix VIII 
Updated CTEP fax number  
14. Appendix X 
Included Sarcopenia imaging substudy  
The following revisions to E2112 Informed Consent Document have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page  
Updated Version Date 
If you have any questions regarding this addendum, please contact csamuel@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to E2112 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development  
Enclosure 
 
CC: Roisin Connolly, MB, BCh 
Kathy Miller, MD 
Joseph Sparano, MD 
Antonio Wolff, MD 
Angela DeMichele, MD 
Min-Jung Lee, PhD 
Fengmin Zhao, PhD 
Lynne Wagner, PhD 
Amye Tevaarwerk, MD 
Tarah Ballinger, MD 
Judy Murray, CCRC 
Matthew Shimizu 
Sarah Archambault 
Bruce Giantonio, MD 
Donna Marinucci 
Carol Chami, RN 
Melinda Flood 
Peter J. O’Dwyer, MD 
Alison Bricker 
Kerry Higgins 
Michelle Azaroff 
Gayle Ipock 
Jean MacDonald 
Christiana Samuel 
Lauren Lambert 
Michael Balco 
 

E2112 
 
1 
This is an FDA Registration Trial 
A Randomized Phase III Trial of Endocrine Therapy plus 
Entinostat/Placebo in Patients with Hormone Receptor-
Positive Advanced Breast Cancer 
STUDY CHAIR: 
Roisin Connolly, MB, BCh 
STUDY STATISTICIAN: 
Fengmin Zhao, Ph.D. 
STUDY CO-CHAIR: 
Kathy D. Miller, M.D. 
LABORATORY CO-CHAIR: 
Min-Jung Lee, Ph.D. 
QUALITY OF LIFE CO-CHAIRS: 
Lynne Wagner, Ph.D. 
 
Amye Tevaarwerk, M.D. 
BREAST CANCER COMMITTEE CHAIR: 
Joseph Sparano, M.D. 
Version Date:  May 22, 2019 
NCI Update Date: October 4, 2017 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
 
March 19, 2014 
NRG / NRG Oncology Foundation, Inc 
 
Update #1 – Incorporated Prior to Activation 
SWOG / SWOG 
 
Addendum #1 – 7/14 
 
 
Addendum #2 – 4/15 
Study Champions 
 
Addendum #3 – 10/15 
ALLIANCE: Peter A. Kaufman, MD 
 
Addendum #4 – 10/16 
NRG ONCOLOGY: Alexandra Thomas, MD 
 
Update #2 – 9/17 
 
 
Update #3 – 10/17 
 
 
Addendum #5 
 
 
Addendum #6 
 
 
Addendum #7 
 
Agents 
IND# 
NSC# 
Supply 
Exemestane 
 
NSC 713563 NCI-Supplied (for U.S. sites only) 
Goserelin Acetate 
 
NSC 606864 Commercially Available 
Entinostat/Placebo 
118068 
IND Sponsor: DCTD, NCI 
NSC 706995 Syndax Pharmaceuticals  
(NCI-Supplied) 
 
Rev.7/14,  
4/15 
Rev.10/15 
Rev. Add7 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 Metastatic Breast Cancer .......................................................................... 8 
1.2 Targeting the ER Pathway ......................................................................... 8 
1.3 Resistance to Hormonal Therapy ............................................................ 10 
1.4 Study Rationale ....................................................................................... 14 
1.5 Patient Reported Outcomes ................................................................... 15 
2. Objectives ......................................................................................................... 18 
2.1 Primary Objective .................................................................................... 18 
2.2 Secondary Objectives .............................................................................. 18 
2.3 Exploratory Objectives ............................................................................ 18 
3. Selection of Patients ......................................................................................... 19 
3.1 Eligibility Criteria ..................................................................................... 19 
4. Randomization Procedures ............................................................................... 24 
4.1 Randomization ........................................................................................ 27 
4.2 Eligibility Verification .............................................................................. 28 
4.3 Stratification Factors ............................................................................... 28 
4.4 Additional Requirements ........................................................................ 28 
4.5 Additional Registration Training Requirement ....................................... 29 
4.6 Instructions for Patients who Do Not Start Assigned Protocol Treatment30 
4.7 Emergency Unblinding ............................................................................ 30 
5. Treatment Plan ................................................................................................. 31 
5.1 Administration Schedule ......................................................................... 31 
5.2 Adverse Event Reporting Requirements ................................................. 31 
5.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Entinostat ................................................................................................ 41 
5.4 Dose Modifications ................................................................................. 44 
5.5 Supportive Care ....................................................................................... 46 
5.6 Patient-Reported Outcomes Administration .......................................... 47 
5.7 Duration of Therapy ................................................................................ 51 
5.8 Duration of Follow-up ............................................................................. 51 
6. Measurement of Effect ..................................................................................... 52 
6.1 Antitumor Effect – Solid Tumors ............................................................. 52 
6.2 Patient-Reported Outcomes Endpoints .................................................. 59 
7. Study Parameters .............................................................................................. 61 
8. Drug Formulation and Procurement ................................................................. 65 
8.1 Entinostat/Placebo (NSC 706995) (IND# 118068) .................................. 68 
8.2 Exemestane ............................................................................................. 70 
8.3 Goserelin ................................................................................................. 71 

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9. Statistical Considerations .................................................................................. 73 
9.1 Study Objectives ...................................................................................... 73 
9.2 Study Design ............................................................................................ 73 
9.3 Statistical Consideration for Objective Response, Toxicity and Time to 
Treatment Deterioration ......................................................................... 79 
9.4 Analysis Plan for Primary Endpoints, Objective Response, Toxicity and 
Time to Treatment Deterioration ........................................................... 82 
9.5 Integrated Pharmacodynamic Biomarker Study of Acute Change in 
Protein Lysine Acetylation ...................................................................... 83 
9.6 Patient-Reported Outcomes Assessment ............................................... 85 
9.7 Adherence to Protocol Therapy .............................................................. 88 
9.8 Gender and Ethnicity .............................................................................. 91 
9.9 Study Monitoring .................................................................................... 91 
10. Imaging Study ................................................................................................... 92 
10.1 Imaging Recommended Parameters and Time Points ............................ 92 
10.2 Independent Imaging Review ................................................................. 95 
10.3 Images Submission .................................................................................. 96 
11. Biological Sample Submissions ......................................................................... 98 
11.1 Sample Collection and Submission Schedule .......................................... 98 
11.2 Submissions to Trepel Laboratory........................................................... 98 
11.3 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) ........................................................................................ 100 
11.4 Submissions to Covance Central Laboratory Services for Population 
Pharmacokinetics [OPTIONAL] .............................................................. 102 
11.5 ECOG-ACRIN Sample Tracking System .................................................. 102 
11.6 Reimbursements for Population Pharmacokinetic Plasma Sample 
Submissions ........................................................................................... 103 
11.7 Use of Specimens in Research .............................................................. 104 
11.8 Sample Inventory Submission Guidelines ............................................. 104 
12. Correlative Studies .......................................................................................... 105 
12.1 Acute Change in Protein Lysine Acetylation as a Predictor of Benefit 
from Entinostat ..................................................................................... 105 
12.2 Population Pharmacokinetics ............................................................... 105 
12.3 Future Research Studies ....................................................................... 105 
12.4 Lab Data Transfer Guidelines ................................................................ 106 
13. Electronic Data Capture .................................................................................. 107 
13.1 Records Retention ................................................................................. 107 

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NCI Update Date: October 4, 2017 
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14. Patient Consent and Peer Judgment .............................................................. 107 
15. References ...................................................................................................... 107 
Appendix I  Pathology Submission Guidelines ...................................................... 113 
Appendix II  Patient Thank You Letter ................................................................... 117 
Appendix III  Patient Pill Calendar ......................................................................... 118 
Appendix IV  CRADA/CTA ...................................................................................... 121 
Appendix V  ECOG Performance Status ................................................................ 123 
Appendix VI  E2112 Collection and Shipping Kit Order Instructions ..................... 124 
Appendix VII  E2112 Mandatory Participating Site Training Form ........................ 125 
Appendix VIII  Instructions for Reporting Pregnancies on a Clinical Trial ............. 126 
Appendix IX  E2112 Covance Site Information/Initial Kit Order Form .................. 128 
 
 
 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
5 
 
STUDY CHAIR 
Roisin Connolly, M.B., B.Ch. 
Sidney Kimmel Comprehensive Cancer Center 
at Johns Hopkins 
1650 Orleans Street, CRB1 153 
Baltimore, MD 21287 
Phone: (410) 614-9217 
Fax: (410) 614-4073 
Email: rconnol2@jhmi.edu  
 
STUDY CO-CHAIR 
Kathy D. Miller, M.D. 
Indiana University Melvin and Bren Simon 
Cancer Center  
535 Barnhill Drive, RT-473 
Indianapolis, IN 46202 
Phone: (317) 948-3855 
Fax: (317) 944-3646 
Email: kathmill@iu.edu  
 
STUDY CHAIR LIAISON (SCL) 
Judy Murray, CCRC 
JHU Cooperative Groups Program Manager 
Johns Hopkins University School of Medicine 
550 North Broadway, Suite 412 
Baltimore, MD 21205 
410-955-4044 (ph) 
410-614-7344 (fax) 
jmurra33@jhmi.edu 
 

ECOG-ACRIN 
E2112 
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Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation can be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
through Medidata Rave. 
Please see the data 
submission section of 
the protocol for further 
instructions.  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev.7/14 
Rev. Add5 
Rev.10/16 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
7 
Schema 
Accrual Goal = 600 patients
Cycle = 28 days
R
A
N
D
O
M
I
Z
E
Exemestane 25 mg
po, days 1-28
Entinostat 5 mg po, days 1, 
8, 15, and 22
Stratify:
• Setting in which patient 
developed resistance to prior 
non steroidal AI treatment 
(adjuvant vs. metastatic)
• Geographic region 
(USA vs. other)
• Visceral disease (yes vs. no)
• Prior fulvestrant use (yes vs. no)
Exemestane 25 mg
po, days 1-28
Placebo 5 mg po, days 1, 8, 
15, and 22
Treatment continued 
until progressive 
disease or 
unacceptable toxicity
Treatment continued 
until progressive 
disease or 
unacceptable toxicity
Arm A1, 2
Arm B1, 2
1. Treatment is blinded. Confirmation of randomization will indicate that patient is on Arm X.
2. Male participants and pre/perimenopausal women will receive Goserelin 3.6 mg SubQ injection on day 1.
 
Rev.10/15 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
8 
1. 
Introduction 
1.1 
Metastatic Breast Cancer 
Breast cancer is the most common malignancy in women in Western societies. It 
is estimated that more than 200,000 women will be diagnosed with breast cancer 
in the US in 2012.1 Advances in the early detection and optimal adjuvant 
treatment of breast cancer have led to a significant reduction in disease relapse 
and death. Nevertheless, approximately 40,000 women per year continue to die 
from this disease. New therapeutic agents, or combinations of agents, are 
therefore urgently required in an effort to improve both the efficacy of adjuvant 
therapy and management of metastatic disease. 
1.2 
Targeting the ER Pathway 
Hormone therapy is an important component of the treatment paradigm for the 
majority of women with hormone receptor-positive breast cancers. Estrogen 
signaling is a key driver of breast cancer cell growth and targeting this pathway is 
an effective method of treating this subtype of breast cancer. There are two 
isoforms of the estrogen receptor (ER), ERα and ERβ, with ERα mediating the 
growth properties of breast cancer cells. Several therapeutic options exist for 
blocking estrogen signaling including selective estrogen receptor modulators 
(SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down-
regulators (SERDs) such as faslodex. SERMs such as tamoxifen bind to the ER 
and selectively inhibit transcriptional activity in breast cancer cells, while 
functioning to activate the receptor in other tissues. 
For patients with metastatic disease, the response rate to first-line hormonal 
therapy with anti-estrogens or AIs ranges from 21% to 33%.2-4 The objective 
response rates of second-line hormonal therapies, such as exemestane or 
fulvestrant, measured by Response Evaluation Criteria in Solid Tumours 
(RECIST) criteria were approximately 7%.4 A study of low dose estradiol as 
second- or third-line therapy documented stable disease, but no objective 
responses.5 Thus, novel approaches to improve the efficacy of currently available 
strategies for hormone receptor-positive breast cancer are urgently needed.  
1.2.1 
Aromatase Inhibitors 
Anti-estrogen or endocrine therapy remains the mainstay of treatment 
for patients with hormone-sensitive metastatic breast cancer. Due to 
both the clinical activity and the benign side effect profile of endocrine 
agents, the standard of care typically involves sequencing of these 
agents until either the development of resistance and/or visceral 
crises necessitates switching to chemotherapy. For patients with 
metastatic disease, the response rate to first-line endocrine therapy 
with anti-estrogens such as tamoxifen, or AIs ranges from 21% to 
33%.2-4 The AIs function by inhibiting the aromatase (CYP19A1) 
enzyme, a protein that plays a critical role in estrogen biosynthesis 
and is encoded by the aromatase gene. Aromatase catalyzes 
conversion of androgens to aromatic estrogens in the adrenal gland 
and adipose tissue, which results in profound estrogen deprivation in 
post-menopausal women whose ovaries no longer produce estrogen. 
Anastrozole and letrozole are non-steroidal AIs that bind reversibly to 

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Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
9 
aromatase while exemestane is a steroidal AI that functions through 
irreversible binding and inactivation of the enzyme.  
The AIs have been studied extensively in a variety of breast cancer 
settings. In terms of breast cancer prevention, the only published data 
we have related to use of the AIs is with the steroidal AI, exemestane. 
Exemestane was found to significantly reduce invasive breast cancers 
in postmenopausal women who were at moderately increased risk for 
breast cancer when compared to placebo.6 During a median follow- 
up period of 3 years, exemestane was associated with no serious 
toxic effects and only minimal changes in health-related quality of life. 
The AIs are the agent of choice in treating postmenopausal women 
with hormone receptor-positive early breast cancer, with over a dozen 
large randomized trials comparing adjuvant AIs with tamoxifen in 
several sequences demonstrating significant improvement in disease-
free survival and reduction in breast cancer events.7 These trials have 
investigated the use of both nonsteroidal and steroidal AIs.  In 
addition, a meta-analysis of randomized trials of AIs compared with 
tamoxifen in the adjuvant setting revealed that AIs produce 
significantly lower recurrence rates compared with tamoxifen, either 
as initial monotherapy or after 2 to 3 years of tamoxifen.8 It is 
generally believed that the efficacy of the non-steroidal and steroidal 
AIs is equivalent, although no head to head comparisons in the 
adjuvant setting have been published to date. The MA.27 trial 
randomly assigned postmenopausal women with hormone receptor-
positive breast cancer in the adjuvant setting to receive exemestane 
25 mg/daily or anastrozole 1 mg/daily for 5 years. The aim of the trial 
was to determine which of the nonsteroidal AI anastrozole and the 
steroidal AI exemestane was superior in terms of preventing 
recurrence and/or death from breast cancer, and whether either had a 
superior toxicity profile. Data reported to date found no differences in 
efficacy or toxicity between the agents9.  
In addition to the benefits observed with the AIs in the breast cancer 
prevention and early breast cancer settings, the AIs are generally the 
agent of choice in treating post-menopausal patients with advanced 
breast cancer. A Cochrane review was performed to evaluate the 
available randomized controlled trials in postmenopausal women 
comparing the effects of any AI versus another endocrine therapy, no 
endocrine therapy or another AI in advanced breast cancer. This 
review demonstrated a survival benefit of 10% with the use of AIs for 
the treatment of advanced breast cancer. Notably, the greatest benefit 
(a survival benefit of 12%) was associated with use of the 3rd 
generation AIs in current clinical use, namely anastrozole, 
exemestane and letrozole. No significant differences were observed 
between the different 3rd generation AIs.10 As in the adjuvant setting, 
it is generally believed that the efficacy of the non-steroidal and 
steroidal AIs is equivalent and these may be used essentially 
interchangeably based on physician preference. Depending on the 
agent used for first line therapy, an AI from a different class may be 
used as second line therapy or other endocrine therapies such as 
tamoxifen or faslodex. However, the objective response rates of 

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NCI Update Date: October 4, 2017 
10 
second-line hormonal therapies, such as exemestane or fulvestrant, 
measured by RECIST criteria has been shown to be approximately 
7%.4 Thus, novel approaches to improve the efficacy of currently 
available strategies for hormone receptor-positive breast cancer are 
urgently needed.  
1.2.2 
Exemestane 
Exemestane is an irreversible, steroidal AI, structurally related to the 
natural substrate androstenedione. It acts as a false substrate for the 
aromatase enzyme, and is processed to an intermediate that binds 
irreversibly to the active site of the enzyme causing its inactivation, an 
effect also known as “suicide inhibition”. Exemestane significantly 
lowers circulating estrogen concentrations in postmenopausal women, 
but has no detectable effect on adrenal biosynthesis of corticosteroids 
or aldosterone. Exemestane has no effect on other enzymes involved 
in the steroidogenic pathway up to a concentration at least 600 times 
higher than that inhibiting the aromatase enzyme.11 We propose to 
use exemestane as a backbone for this proposal in order to parallel 
the ENCORE phase 2 trial described in Section 1.3.4.12 As discussed 
in Section 1.2.1, data from trials in the metastatic and adjuvant setting 
suggest that the efficacy of the non-steroidal and steroidal AIs is 
equivalent. 
1.3 
Resistance to Hormonal Therapy 
Although pharmacologic therapies that reduce or block estrogen signaling are 
effective in the treatment of ER-positive breast cancer, acquired resistance to 
individual drugs can develop. Furthermore, these therapies may be ineffective as 
initial therapy for a subgroup of receptor-positive patients (de novo resistance). 
The mechanisms of drug resistance are not completely understood, but the 
presence of alternative signaling pathways for activating ER response appears to 
play a significant role. Cross-talk between signaling pathways can activate ERs 
when conventional ER pathways are blocked or inactivated. For example, 
signaling via epidermal growth factor or HER-2 receptors, mitogen-activated 
protein kinases, phosphatidylinositol 3' kinase (PI3K)/protein kinase B, and 
vascular endothelial growth factor receptor can lead to estrogen-independent 
stimulation of ERs and tumor growth. The discovery that alternative pathways are 
involved in estrogen signaling has prompted development of newer endocrine 
therapies, such as AIs and pure estrogen antagonists, with distinct mechanisms 
for interrupting signal transduction. The existence of multiple pathways may 
explain the effectiveness of follow-up therapy with a different class of endocrine 
agents after failure of prior endocrine treatment. Although optimal sequencing of 
these agents has not been determined and is continuing to evolve, current 
evidence allows rational recommendations to be made. The multiple pathways 
involved in activating ERs also provide a rationale for combining endocrine and 
non-endocrine therapies that block different signaling pathways, which may have 
synergistic and overlapping interactions.13  
Whether strategies combining endocrine therapies with novel agents are more 
efficacious than endocrine therapy alone has been investigated recently. An 
emerging mechanism of endocrine resistance is aberrant signaling via the 
PI3K/Akt/mTOR intracellular signaling pathway. mTOR has been identified as a 

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NCI Update Date: October 4, 2017 
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rational target to enhance the efficacy of hormonal therapy. The BOLERO-2 trial 
was a randomized Phase III study evaluating exemestane in combination with 
everolimus (mTOR inhibitor)/placebo in post-menopausal women with ER-
positive refractory metastatic breast cancer (with recurrence or progression 
following prior therapy with letrozole or anastrozole).14 Patients could have 
received any prior number of endocrine treatments and a single prior 
chemotherapy. The trial met its primary endpoint of improvement in progression-
free survival (PFS) by local review with the combination therapy (7.8 months) vs 
the placebo arm (3.2 months). These results were confirmed with the use of an 
independent, blinded radiologic assessment (10.6 months vs 4.1 months). 
Overall survival (OS) data remains immature at this time. The most common 
grade 1-4 adverse reactions (incidence greater than or equal to 30%) in patients 
receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, 
diarrhea, and decreased appetite.  The most common grade 3-4 adverse 
reactions (greater than or equal to 2%) were stomatitis, infections, 
hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Fatal adverse 
reactions occurred in 2% of patients on the everolimus arm compared to 0.4% of 
patients on the placebo arm.  Adverse reactions resulting in permanent 
discontinuation occurred in 24% and 5% of patients in the everolimus and 
placebo arms, respectively.  Dose interruptions or reductions were necessary in 
63% of patients on the everolimus arm compared to 14% on the placebo arm. 
Based on the PFS benefit observed, this regimen has been approved for use in 
patients with metastatic breast cancer who have experienced disease 
progression on anastrozole or letrozole. Everolimus is, therefore, the first agent 
to be approved for use in addition to endocrine therapy in patients with HER2-
negative disease. However, other strategies to improve outcomes with endocrine 
therapy in patients with hormone receptor-positive metastatic breast cancer are 
needed. Ideally, agents that prolong OS and are associated with less toxicity 
than that observed with everolimus would be welcome. A promising potential 
mechanism of overcoming resistance and which we anticipate will lead to 
improved clinical outcomes for patients with a manageable toxicity profile may lie 
in the use of epigenetic modifiers such as the histone deacetylase (HDAC) 
inhibitors. 
1.3.1 
Targeting Epigenetic Changes 
The development and progression of cancer is now recognized as 
being not only secondary to inherited or sporadic genetic mutations, 
but also epigenetic changes in the genome.15 Epigenetics is a term 
which refers to changes in gene expression that are not secondary to 
alterations in the primary nucleotide sequence of a gene, such as is 
the case with a genetic mutation. Epigenetic changes include both 
histone hypoacetylation and abnormal methylation of DNA in the 
promoter region of important genes. These changes may result in 
alterations in chromatin structure leading to a repressive chromatin 
state and silencing of both gene expression and transcription of DNA 
into RNA. Importantly, epigenetic changes contribute to drug 
resistance, are generally considered to be reversible and thus 
represent an active and attractive area of new drug investigation. 
Histone acetylation is controlled by a balance in activity between 
histone acetyltransferase (HAT) and HDAC. The HDACs exert their 

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NCI Update Date: October 4, 2017 
12 
targeted action during post-translational acetylation of core 
nucleosomal histones, which affects chromatin structure, thereby 
regulating gene expression. DNA that is wrapped around condensed, 
non-acetylated histones is transcriptionally inactive, whereas 
acetylation of N-terminal histone lysine residues exposes DNA to 
important transcription factors that promote transcriptional activity.16,17 
The dynamic equilibrium between histone acetylation and 
deacetylation is regulated by HATs and HDACs. The action of HDACs 
on nucleosomal histones leads to tight coiling of chromatin and 
silencing of expression of various genes, including those implicated in 
the regulation of cell survival, proliferation, differentiation, and 
apoptosis.18 The effects of HDACs are not limited to histone 
deacetylation. HDACs also act as members of a protein complex to 
recruit transcription factors to the promoter region of genes, including 
those of tumor suppressors, and they affect the acetylation status of 
specific cell cycle regulatory proteins.17 Because aberrant HDAC 
activity has been implicated in a variety of cancers, development of 
HDAC inhibitors is a rational approach to the design of targeted 
anticancer therapeutics. 
1.3.2 
HDAC Inhibitors 
Because of the frequency of detection of epigenetic alterations in 
breast cancers, agents that target these changes are of great interest. 
Several strategies have been initiated to relieve transcriptional 
repression and include the use of HDAC inhibitors. Examples of 
HDAC inhibitors include entinostat (SNDX-275, previously MS-275), 
trichostatin (TSA), vorinostat (SAHA), LAQ824 and LBH589. 
Vorinostat was found to induce differentiation or arrest growth of a 
wide variety of human carcinoma cells including breast cancer.19-21 
The antitumor activity of vorinostat was also demonstrated in several 
in vivo models of cancer, including in the carcinogen-induced 
mammary tumor model. It reduced tumor incidence in NMU-induced 
rat mammary tumorigenesis by 40%.22 In vitro studies demonstrated 
that vorinostat inhibits clonogenic growth of the breast cancer cell 
lines MCF-7, MDA-231, and MDA-435 by inducing G1 and G2/M cell 
cycle arrest and subsequent apoptosis.19 Further analysis 
demonstrated that exposure to low concentrations of vorinostat was 
associated with accumulation of cells mainly in G1, while higher 
vorinostat concentrations caused cell cycle arrest predominantly in 
G2/M.20 This agent also induced a dose-dependent increase in H3 
acetylation in MCF-7 cells and its’ effects are reversible upon drug 
discontinuation.  
The ability of the HDAC inhibitors to relieve transcriptional repression 
in preclinical breast cancer models has also been investigated. The 
accumulation of acetylated H3 and H4 histone tails in conjunction with 
re-expression of a functional ER in ER-negative breast cancer cell 
lines has been observed with a novel HDAC inhibitor, scriptaid.23 
Treatment of ER-negative breast cancer cell lines with vorinostat was 
also found to result in reactivation of silenced ER, as well as 
downregulation of DNMT1 and EGFR protein expression.24 The 

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significance of an epigenetically reactivated ER was demonstrated 
when the formerly unresponsive ER-negative MDA-MB-231 breast 
cancer cells became responsive to tamoxifen after treatment with both 
HDAC (trichostatin A) and DNA methyltransferase inhibitors.25 
Entinostat has been shown to induce not only re-expression of ERα 
but also the androgen receptor, and the aromatase enzyme (CYP19) 
in both in vitro and triple-negative breast cancer xenografts.26 In 
addition, the combination of entinostat and letrozole resulted in a 
significant and durable reduction in the xenograft tumor volume when 
compared to treatment with either agent alone. These experiments 
have provided the strong rationale for combining epigenetic modifiers 
with hormonal therapy in breast cancer clinical trials. 
1.3.3 
Entinostat 
Several HDAC inhibitors have been studied in phase I and II trials in 
hematological malignancies and solid tumors.27-30 Entinostat belongs 
to the class of HDAC inhibitors which are critically important in the 
regulation of gene expression and in the field of target-specific 
anticancer drug development.31 It is a synthetic benzamide derivative 
that appears to be a potent inhibitor of histone deacetylases that has 
shown anti-tumor activity against multiple human tumors.28 Vorinostat 
has been approved by the Food and Drug Administration (FDA) for 
those with heavily pretreated T-cell lymphoma.32 In a phase II trial in 
the advanced breast cancer setting, administration of single agent oral 
vorinostat resulted in stable disease in four out of fourteen patients.33 
Accumulating evidence has demonstrated the effectiveness of HDAC 
inhibitors in combination with several other agents in vitro including 
hypomethylating agents, 34,35 anti-metabolites,36,37 retinoids,38 and 
many novel agents. Combination strategies with hormonal treatments 
for breast cancer will now be described. 
1.3.4 
Combination Strategies: HDAC Inhibitors and Hormonal Therapy 
Whether the addition of a HDAC inhibitor to hormonal strategies for 
breast cancer can reverse resistance to hormonal therapy and 
therefore improve breast cancer outcomes has been investigated. 
Preclinical models which suggested that the efficacy of tamoxifen can 
be enhanced by vorinostat39 prompted the development of a phase II 
trial in advanced breast cancer patients. Oral vorinostat 400mg daily 
(21 days of a 28 day cycle) and tamoxifen 20 mg daily administered to 
women with hormone-resistant breast cancer yielded an objective 
response rate of 19% and a clinical benefit rate of 40% (n=43).40 The 
combination of agents was well tolerated with no unexpected adverse 
events.  Prior tamoxifen had been received in the adjuvant setting in 
approximately 60% of patients and 54% had received two prior lines 
of therapy with AIs. Histone hyperacetylation and higher baseline 
HDAC2 levels were found to correlate with response. These findings 
suggest that vorinostat may indeed restore responsiveness to 
tamoxifen in patients with hormone-resistant disease, and support the 
development of a randomized trial for further delineation of the clinical 
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The ENCORE 301 randomized phase 2 study evaluated the role of 
entinostat, a class 1 selective HDAC inhibitor, in combination with 
exemestane (steroidal AI) in the advanced breast cancer setting. 
Postmenopausal women who had received ≤ 1 prior chemotherapy 
and were progressing on a non-steroidal AI were randomized to 
exemestane 25 mg daily plus entinostat 5 mg weekly versus 
exemestane plus placebo weekly.12 A significant improvement in PFS 
was noted in the entinostat arm versus placebo (median 4.3 versus 
2.3 months, respectively). In an exploratory analysis of patients who 
were deemed resistant to prior AI, patients randomized to the 
entinostat arm had a greater PFS than those in the placebo arm. OS, 
an exploratory endpoint, was also significantly longer in the entinostat 
arm versus the placebo arm (28.1 versus 19.8 months, respectively). 
Interestingly, in a subset analysis examining protein acetylation in 
entinostat patients (n=27), the median PFS increased to 8.5 months in 
those exhibiting protein lysine hyperacetylation, and this was apparent 
after just 2 weeks of therapy.41 The addition of entinostat to AI therapy 
may delay the initiation of subsequent therapies such as 
chemotherapy by prolonging PFS on exemestane. We propose to 
evaluate the addition of entinostat or placebo to exemestane in 
patients who have progressed on a non-steroidal AI. In addition, we 
will explore whether benefit varies with changes in lysine acetylation. 
Table 1.1: Select Clinical Trials of Novel Combinations with Endocrine Therapy in 
Metastatic Breast Cancer 
 
Clinical Trial 
Treatment Arms 
Patient Population 
Results 
 
ENCORE 
Phase 2 Trial12 
Exemestane + 
Entinostat/Placebo 
5mg po weekly  
Postmenopausal women 
Prior progression on a non-steroidal AI and 
≤ 1 prior chemotherapy  
Median PFS 4.3 
(entinostat) versus 2.3 
months (placebo); HR 
0.73 
Median OS 28.1 
(entinostat) versus 
19.8 months (placebo); 
HR 0.59 
Rev. 4/15 
ECOG-ACRIN 
Phase 3 Trial 
(Connolly) 
Exemestane + 
Entinostat/Placebo  
5 mg po weekly 
Pre/perimenopausal and post-menopausal 
women and men 
HR-positive advanced breast cancer 
Prior progression on a non-steroidal AI 
(adjuvant/metastatic) and  
≤ 1 prior chemotherapy for metastatic 
disease 
Pending 
 
BOLERO-2 
Phase 3 Trial14 
Exemestane + 
Everolimus/Placebo 
Postmenopausal women 
Prior progression on a non-steroidal AI and 
≤ 1 prior chemotherapy 
Median PFS 7.8 
(everolimus) vs 3.2 
(placebo) months 
1.4 
Study Rationale 
Despite advances in the treatment of patients with ER-positive breast cancer, 
many women fail to respond to an AI or suffer recurrence of disease 
notwithstanding optimal adjuvant therapy. Patients with advanced stage ER-
positive breast cancer have a median survival of approximately 18-24 months 
and in this setting hormonal therapy provided a 20-30% response rate and a 9-11 
month PFS. Tumors may be intrinsically (de novo) resistant to hormonal therapy 
and will therefore never respond to an AI, or they may acquire resistance at a 
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later time-point through various host or tumor-mediated mechanisms.42 Women 
with hormone receptor-positive metastatic breast cancer receiving hormonal 
therapy are also subject to drug resistance. Clearly strategies to overcome 
resistance to hormonal agents are urgently required in an effort to improve 
outcomes for breast cancer patients and delay the time to chemotherapy use. 
A variety of resistance mechanisms have been shown to occur in tumor cells 
resistant to AIs, including loss of ER expression, activated growth factor signaling 
pathways, estrogen independent tumor growth, hypersensitivity of tumor cells to 
low estrogen concentrations and cyclin D1 over-expression. Targeting these 
mechanisms would be expected to restore sensitivity to AIs and increase both 
the number of patients that respond as well as prevent or delay the time to 
progression on AI therapy. HDAC inhibitors are one class of compounds that 
have been shown to inhibit many of the AI resistance pathways pre-clinically.  
Pre-clinically, entinostat has been shown to induce protein lysine acetylation, 
resulting in down-regulation of estrogen-independent growth factor signaling 
pathways and normalization of ER levels. In addition, there is a suggestion that 
entinostat may have longer term effects on cancer phenotypes, cancer stem cell 
or progenitor cell pool and potentially sensitization to subsequent post-study 
treatments.43 In a recently reported randomized phase II trial, the addition of 
entinostat to exemestane improved PFS and OS in patients with previously 
treated hormone-sensitive metastatic breast cancer. Pharmacodynamic analysis 
in a subset of patients links HDAC inhibitor activity to breast cancer clinical 
outcome. A phase II biomarker validation study is being planned to further 
delineate the role of entinostat and the potential biomarker of lysine acetylation in 
this setting (refractory to non-steroidal AI). 
We propose to simultaneously evaluate the addition of entinostat to exemestane 
in patients who have experienced disease progression on a non-steroidal AI. 
Observing a positive treatment effect for entinostat in this ECOG-ACRIN trial 
would be practice changing and if successful would lead to FDA approval of this 
agent for use in the metastatic setting. This clinical trial will, therefore, serve to 
validate the preclinical and clinical findings supporting the role of HDAC inhibitors 
in overcoming resistance to hormonal therapy in breast cancer patients. We 
anticipate that it will provide a novel treatment approach which will both improve 
and extend the benefits of hormone therapy in breast cancer patients. Finally, if 
successful this trial may provide impetus to study entinostat in the 1st line 
metastatic and adjuvant settings. 
1.5 
Patient Reported Outcomes 
Patient-reported outcomes (PROs) capture unique data on treatment toxicities 
and disease symptoms that complements clinician-rated toxicities. In addition, it 
is important to understand from the patient perspective how the addition of this 
novel agent, entinostat, will impact overall health-related quality of life (HRQL). 
Collecting PROs to document treatment toxicities from the patient’s perspective 
will provide invaluable data to inform patient-centered counseling regarding the 
risks and benefits of endocrine therapy plus entinostat if the combination should 
prove to prolong PFS or OS. This lesson has been re-capitulated in the 
experience with exemestane and everolimus, where concerns over increased 
toxicity limit the use of everolimus in the hormone-refractory setting.  
Prior studies have generally indicated entinostat is well tolerated, so we expect 
that overall HRQL will be comparable between treatment arms. However, we 

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recognize the use of this novel agent in a novel treatment regimen may be 
associated with unanticipated side effects. We have designed the PRO endpoints 
for this trial to detect the most common treatment side effects and to also detect 
decrements to HRQL related to unanticipated side effects. We anticipate the 
most common side effect associated with entinostat combination will be 
fatigue,12,44,45 which is common in metastatic breast cancer due to disease. 
However, entinostat has also been associated with nausea, anorexia and 
diarrhea12,44,45 and these symptoms may also be more common in the 
exemestane and entinostat arm. Therefore, we propose to administer PRO 
measures to assess overall HRQL as well as specific treatment-related 
symptoms to detect differences between the two treatment arms.  
Given that PFS is a primary endpoint for this trial, we will also evaluate whether 
improvement in PFS is associated with improved HRQL. To answer this 
question, we will assess whether the addition of entinostat to exemestane 
improves time to treatment deterioration (TTD) compared to exemestane + 
placebo. TTD is a composite endpoint consisting of time to death, disease 
progression, or worsening of symptoms. TTD has been used as an endpoint in a 
phase III study of renal cell cancer comparing two similar oral agents (axitinib vs 
sorafenib)62,63. As the primary endpoint, Rini et al were able to demonstrate that 
axitinib extended PFS compared with sorafenib (6.7 mos vs 4.7 mos, p<0.0001). 
Because of the valuable addition of TTD as an endpoint, they were also able to 
demonstrate that axitinib accomplished this without negatively affecting HRQL, 
and in fact was associated with less deterioration in HRQL (axitinib was 
associated with a 17% reduction in risk for TTD, HR 0.83,p=0.01). This is 
invaluable data for clinicians and patients when making treatment decisions that 
balance PFS benefit with possible treatment toxicities. 
Because we believe that the benefits from improving PFS (and thus symptoms 
from disease) will outweigh any increase in toxicity from the addition of entinostat 
to exemestane, we hypothesize that the combination arm (EE) will have a 
significantly longer TTD than the EP arm. 
The National Cancer Institute’s Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a library of 
78 items developed to obtain patient reporting of Adverse Events (AEs) in clinical 
trials. The NCI is seeking partnerships with clinical trials investigators by 
embedding PRO-CTCAE into therapeutic trials. The PRO-CTCAE data collected 
will be used to provide descriptive and parallel information about using this new 
measurement system to gather information directly from patients about the 
symptomatic adverse effects of their treatment. Content validity of PRO-CTCAE 
items has been established through cognitive interviews with 127 adults with 
different cancer types and undergoing chemotherapy or radiation therapy. 
Interviews and review of PRO-CTCAE items established the content validity of 
PRO-CTCAE items for patient-reporting of AEs71. Interviews demonstrated that 
most AE terms were comprehended, and the attribute terms and response 
options required no modifications. The next step in establishing the validity of 
PRO-CTCAE items includes administering select items in the context of a cancer 
clinical trial. Given the phase III, double-blind placebo-controlled randomized 
design of this trial, E2112 offers the opportunity to validate PRO-CTCAE items to 
measure six symptoms: decreased appetite, diarrhea, nausea, vomiting, joint 
aches, and muscle aches. These toxicities were selected because we anticipate 
these to be the most common toxicities associated with entinostat or 

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exemestane. In addition, we anticipate that PRO-CTCAE items may identify 
toxicities earlier than would be identified using the clinician-rated CTCAE system. 
This will provide the opportunity to intervene earlier to manage symptoms that 
may interfere with treatment adherence. 

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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate whether the addition of entinostat to endocrine therapy 
(exemestane) improves progression-free survival (PFS) and/or overall 
survival (OS) in patients with HR-positive, HER2-negative locally 
advanced or metastatic breast cancer who have previously 
progressed on a non-steroidal aromatase inhibitor (Al). 
2.2 
Secondary Objectives 
2.2.1 
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. 
2.2.2 
To evaluate the objective response rate of exemestane in combination 
with entinostat or placebo. 
2.2.3 
To evaluate whether the efficacy of exemestane with entinostat varies 
with changes in acetylation status in peripheral blood mononuclear 
cells (PBMCs). 
2.2.4 
To evaluate the time to treatment deterioration (as defined by 
decrease in HRQL, progression, death) of exemestane + entinostat 
versus exemestane + placebo arms. 
2.2.5 
To evaluate the differences in overall health-related quality of life 
(HRQL) between the exemestane + entinostat versus exemestane + 
placebo arms. 
2.2.6 
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. 
2.2.7 
To measure adherence to protocol therapy. 
2.2.8 
To evaluate the pharmacokinetics of entinostat in patients with 
advanced breast cancer. 
2.2.9 
To evaluate what, if any, patient variables alter the pharmacokinetic 
profile of entinostat in patients with advanced breast cancer. 
2.3 
Exploratory Objectives 
2.3.1 
To collect archival tumor samples and germline DNA to explore other 
potential biomarkers of therapeutic efficacy. 
2.3.2 
To collect patient ratings of AEs using select PRO-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. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Estrogen receptor (ER) and/or progesterone receptor (PR) positive 
histologically confirmed adenocarcinoma of the breast with staining of 
≥ 1% cells will be considered positive. Receptor status may be based 
on any time during treatment prior to study randomization, and from 
any site (i.e. primary, recurrent, or metastatic). 
3.1.2 
Patients whose tumors have HER2 IHC 3+, ISH ≥ 2.0, or average 
HER2 copy number ≥ 6.0 signals per cell are not eligible.74 Receptor 
status may be based on any time during treatment prior to study 
randomization, and from any site (i.e. primary, recurrent, or 
metastatic). 
3.1.3 
Patients must have measurable or non-measurable Stage III/locally 
advanced or metastatic carcinoma of the breast, as defined in Section 
6.1.2, where local therapy with curative intent is not possible. Lesions 
must be evaluated ≤ 4 weeks prior to study randomization. 
Diagnostic-quality CT scans with both oral and IV contrast are the 
expected radiologic method, unless an alternative is approved per 
Section 6.1.3. 
NOTE: 
Where baseline imaging has already been performed ≤ 6 
weeks prior to study randomization, repeat imaging may 
not be required. Please refer to footnotes 5 and 6 of Study 
Calendar (Section 7). 
NOTE: 
As of October 16, 2016, accrual of new patients having 
non-measureable disease has stopped. Per Section 9.2, 
the planned accrual for this target population has been 
reached. 
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3.1.4 
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 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. 
3.1.5 
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. 
3.1.6 
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). 
Female? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.7 
Patients must not have known central nervous system metastasis or a 
history of CNS metastases. Patients with leptomeningeal disease are 
not eligible.  
3.1.8 
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. 
3.1.9 
Patients must meet at least one of the following criteria: 
3.1.9.1 
Disease progression any time after non-steroidal AI use in 
the advanced disease setting. 
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3.1.9.2 
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 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 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. 
3.1.10 
Patients may have received only one prior chemotherapy regimen for 
metastatic disease provided treatment was completed ≥ 3 weeks prior 
to randomization. 
3.1.11 
Patients may be treated with bone modifying agents such as 
bisphosphonates or RANK-ligand agents (e.g. denosumab) per 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. 
3.1.12 
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. 
3.1.13 
Patients must NOT receive concurrent anti-cancer therapy or 
investigational agent unless specified in protocol. 
3.1.14 
Patients must NOT be receiving valproic acid, an 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. 
3.1.15 
Patients must have no known allergies to exemestane, entinostat, or 
medications that have a benzamide structure (e.g., tiapride, 
remoxipride, clebropride). 
3.1.16 
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.  
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3.1.17 
Patients must have recovered from all clinically relevant adverse 
events to grade 1 or baseline due to previous agents administered 
(except alopecia) and the criteria outlined in Section 3.1.18.  
3.1.18 
Patients must have adequate hematologic, liver and renal function as 
defined below ≤ 28 days prior to randomization:  
3.1.18.1 
Hemoglobin (HgB) ≥ 9.0 g/dL 
Hemoglobin:  ____________  
Date of Test:  ____________ 
3.1.18.2 
Platelet count ≥ 100,000/ mcL 
Platelets:  ____________  
Date of Test:  ____________ 
3.1.18.3 
Absolute neutrophil count ≥ 1,500/mcL  
Neutrophil count:_______  
Date of Test:________ 
3.1.18.4 
Creatinine ≤ 2.0 mg/dL  
Creatinine:  ____________  
Date of Test:  ____________ 
3.1.18.5 
Total bilirubin < 1.5 x institutional upper limit of normal (≤ 3 
mg/dL in case of Gilbert’s syndrome) 
Total bilirubin:  ____________ ULN:_____________ 
Date of Test:  ____________ 
3.1.18.6 
Transaminases (ALT, AST) ≤ 2.5 x institutional upper limit 
normal 
ALT:  ____________ ULN:_____________ 
Date of Test:  ____________ 
AST:  ____________ ULN:_____________ 
Date of Test:  ____________ 
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. 
3.1.19 
Known HIV-positive patients should have a CD4 count > 250/mm3. 
3.1.20 
Patients must have ECOG Performance Status 0-1. See Appendix V. 
3.1.21 
Patients must have a life expectancy ≥ 12 weeks. 
3.1.22 
Patients must be ≥ 18 years of age. 

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3.1.23 
Patients must be able to swallow tablets. 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions 
wishing to use the eligibility checklist as source 
documentation. 

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4. 
Randomization Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. 
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
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• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied 
to the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their intent 
to open the study locally. The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E2112 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E2112 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements for E2112 site registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab  
→ Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
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Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks 
or alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved 
by the IRB. 
2. 
A.  
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: The above submissions must include the following details: 
• Indicate all sites approved for the protocol under an assurance 
number. 
• OHRP assurance number of reviewing IRB 
• Full protocol title and number 
• Version Date 
• Type of review (full board vs. expedited) 
• Date of review. 
• Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website. (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Treatment must start within ten working days of randomization. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at <https://eapps-
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ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
randomization and treatment information. Please print this confirmation for 
your records.  
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-
888-823-5923 or ctsucontact@westat.com. 
4.1 
Randomization 
Please note that no blinded starter supplies will be available for this study. 
Blinded, patient-specific clinical supplies will be shipped from the Pharmaceutical 
Management Branch (PMB) of the NCI to the registering investigator at the time 
of patient randomization and should arrive within five working days (see Section 
8.0). 
For sites within the United States, the Pharmaceutical Management Branch will 
ship patient-specific open label exemestane with the initial blinded, patient 
specific supplies of entinostat or placebo. 
Please note that when a patient has been successfully randomized, the 
confirmation of randomization will indicate that the patient is on arm X. The 
patient will actually be randomized to arm A or B, but as this is a double-
blind trial, that information cannot be displayed. 
At time of randomization, the following information will be requested:  
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
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• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.3 
Stratification Factors 
• 
Setting in which patient developed resistance to prior non steroidal AI 
treatment (adjuvant vs. metastatic) 
• 
Geographic region (USA vs. other) 
• 
Visceral disease (yes vs. no)  
NOTE: 
Visceral disease for this protocol refers to liver and/or lung 
involvement. 
• 
Prior fulvestrant use (yes vs. no) 
4.4 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.4.2 
Clinical data collection for this study will be done through the 
Medidata Rave clinical data management system. Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must have an 
active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) 
and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave CRA role or 
CRA Lab Admin role, the user must hold a minimum of an AP 
registration type. To hold the Rave Site Investigator role, the individual 
must be registered as an NPIVR or IVR. Associates can hold read-
only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
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Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
ECOG-ACRIN has contracted with Alpha Oncology, a contract 
research organization (CRO) to conduct on-site and remote 
monitoring activities. The goal of these monitoring activities is to 
provide source document verification (SDV). Alpha Oncology will be in 
contact with sites as patients reach the pre-defined milestones for 
initiation of monitoring activities. 
Alpha Oncology will also be conducting data sweeps. The goal of 
these data sweeps is to assist institutions with timely data entry and 
query resolution. Alpha Oncology will utilize phone requests and email 
notifications to request entry of outstanding data and/or completion of 
open queries. The objective of these sweeps is to collect data; they 
are not designed as an audit, nor are they intended to generate 
corrections to previously submitted data. 
4.4.3 
Pathological materials are to be submitted for future undefined 
research as indicated in Section 11. 
4.4.4 
Blood samples are to be submitted for laboratory research studies 
and future undefined research as outlined in Section 11.  
4.4.5 
Plasma samples are to be submitted for population pharmacokinetic 
studies as outlined in Section 11 per patient consent. 
NOTE: 
To obtain starter kits and the Site Laboratory Instruction 
Manual please Email or Fax Appendix IX E2112 Covance 
Site Information/Initial Kit Order Form to Syndax. Please 
note Covance requires ten (10) days to process the form 
and ship the initial kits. 
4.5 
Additional Registration Training Requirement 
Mandatory Participating Site Training Course 
ECOG-ACRIN has developed a training course to provide an overview of the 
E2112 trial to site research staff and investigators. This training includes 
information regarding the general protocol overview, data collection and data 
management, and the imaging component of the trial which will require 
submission of scans for routine tumor assessments. ECOG-ACRIN recommends 
all research staff (CRAs, Data Managers, Imaging Staff, Investigators, Pharmacy 
Staff, etc) involved in E2112 complete the training. 
Prior to the first patient enrollment at a participating site, one person from the 
research staff (i.e. a research coordinator or an investigator) must review and 
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complete the training course. The course is available 24/7 via the following URL: 
http://coccg.mindflash.com/PublicCoursePage.aspx?c=832897692 
Upon completion of training, please complete the form titled E2112 Mandatory 
Participating Site Training Form, available in Appendix VII, and submit directly to 
the CTSU Regulatory Office via Fax: 215-569-0206 or email: 
CTSURegulatory@ctsu.coccg.org. Patient enrollments will be blocked via the 
OPEN system until one individual at your site completes the required protocol 
training. 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the E2112 Forms Completion Guidelines. 
4.7 
Emergency Unblinding  
The information provided below is for the use by a physician, nurse, CRA or 
pharmacist treating the patient. These contact numbers should not be used by 
patients. Patients should be instructed to call their doctor’s office in the event of 
an emergency or adverse event that may result in the need to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating 
identification of the medication for the welfare of the patient, please contact the 
Study Chair, Dr. Roisin Connolly, at (410) 614-9217, or email: 
rconnol2@jhmi.edu first to ensure the reason for unblinding is valid. Then call a 
member of the ECOG-ACRIN Operations Office – Boston drug team at (857) 
504-2900, Monday through Friday between 9:00 AM and 5:00 PM Eastern Time. 
For unblinding outside of these hours, contact AnswerConnect at 1-866-296-
8940. This service will request the reason for unblinding and then page the on-
call ECOG-ACRIN staff who will return your call and provide the unblinded 
treatment assignment if applicable. Remember, AnswerConnect should only be 
contacted outside of normal business hours and only in the event of an 
emergency. The ECOG-ACRIN Operations Office – Boston or AnswerConnect 
will require the protocol number (i.e., “E2112”), the patient ID number (e.g., 
“44444”), and the patient initials (e.g., “FL”) to unblind the patient. Note that if a 
patient is unblinded, he/she must discontinue protocol treatment. 
NCI CTEP should also be notified of a request for unblinding. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Cycle = 4 weeks (28 days)  
A complete cycle of treatment is defined as 28 days (± 3 days) of once daily 
continuous treatment of exemestane in combination with entinostat/placebo. A 
new cycle start is defined as the first planned date of entinostat/placebo for the 
cycle. 
Entinostat/placebo should be taken on an empty stomach, at least 1 hour before 
and 2 hours after a meal/snack. Missed doses should not be made up later. 
5.1.1 
Arm X (Arms A and B)  
Exemestane 25mg po (single dose), days 1-28 
Entinostat/placebo 5mg po (single dose), days 1, 8, 15, and 22 
Goserelin (Pre/perimenopausal female and all male participants only): 
3.6 mg SubQ injection day 1 
Repeat cycles every 28 days until development of disease 
progression per Section 6 or unacceptable toxicity.  
NOTE: 
The patient will be randomized to Arm A (Entinostat) or 
Arm B (placebo), but as this is a double-blind trial, all 
patients will be identified as on Arm X.  
The schedule should be followed as closely as is realistically possible; 
however, the schedule may be modified due to problems such as 
scheduling delays or conflicts (e.g., clinic closure, poor weather 
conditions, vacations, etc.) with the guidance of the protocol 
chair/designee, as appropriate, and will not be reportable as a 
deviation unless the endpoints of the study are affected. 
5.2 
Adverse Event Reporting Requirements 
NOTE: 
Effective April 1, 2018 expedited adverse event reporting done 
via CTEP-AERS will use CTCAE version 5.0 terminology and 
grading. Routine adverse event reporting and dose modifications 
guidelines on this study will continue to be based on CTCAE 
version 4.0 terminology and grading. 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave. 
• 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner via 
CTEP-AERS for timelier monitoring of patient safety and care. The 
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following sections provide information and instructions regarding 
expedited adverse event reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List): An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND. Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization): For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours. 
• 
Life Threatening Adverse Event: Any AE that places the subject 
at immediate risk of death from the AE as it occurred. 
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
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may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in 
this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting): A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use the 
CTEP Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301-897-7404) in the same 
timeframe. 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
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• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E2112 and outline the 
specific expedited adverse event reporting requirements for study 
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5.2.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arm X (Arms A and B)  
5.2.5.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
Determine if the event meets the 
definition of a Serious Adverse Event 
(SAE) as outlined by the six criteria in 
the top portion of the table below in 
Section 5.2.6. 
Yes 
No 
Identify the type and 
grade of the event using 
CTCAE v5.0. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
With this information, review 
the chart in Section 5.2.6 to 
determine if event is 
reportable via CTEP-AERS. 
Refer to Section 5.2.7 to 
determine if the event meets the 
protocol specific reporting 
requirements for this study. If 
so, report the event via  
CTEP-AERS. 
Refer to Section 5.2.7 to 
determine if the event meets the 
protocol specific reporting 
requirements for this study. If so, 
report the event via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.2.7 to 
determine if the event meets 
the criteria as an exception 
to reporting on this protocol. 
If it does not, report the 
event via CTEP-AERS.
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5.2.5.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.6, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported via CTEP-AERS even if the patient 
is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events   
5.2.6 
Expedited Reporting Requirements for Arm X (Arms A and B) on 
protocol E2112 
Investigational Agents: Entinostat/Placebo 
Commercial Agents: Exemestane 
When an investigational agent is used in combination with a 
commercial agent, the combination is considered to be investigational 
and expedited reporting of adverse events follows the guidelines for 
investigational agents.   
Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration of 
the Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
Effective Date: May 5, 2011 
 

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5.2.7 
Additional instructions, requirements and exceptions for protocol 
E2112 
Additional Instructions: 
• 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital 
anomaly, or birth defect events via CTEP-AERS, please contact 
the AEMD Help Desk at aemd@tech-res.com or 301-897-7497. 
This will need to be discussed on a case-by-case basis. 
• 
Reporting a death on study:  A death occurring while on study 
or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality.  
Attribution to treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder 
and administration site conditions”.  Evidence that 
the death was a manifestation of underlying disease 
(e.g. radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with 
a disease process) should be submitted. 
 
E2112 specific expedited reporting requirements: 
• 
Thrombocytopenia 
Any ≥ grade 4 platelet count must be reported via CTEP-AERS 
within 24 hours of learning of the event followed by a complete 
expedited report within 5 calendar days of the initial 24-hour 
report. 
Any grade 3 platelet count with significant bleeding, regardless 
of whether or not the patient was hospitalized, must be reported 
via CTEP-AERS within 10 calendar days of learning of the 
event. 
• 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive 
pregnancy test regardless of age or disease state) occurring 
with a female patient while the subject is on Entinostat/Placebo, 
or within 3 months of the subject’s last dose of 
Entinostat/Placebo, are considered immediately reportable 
events. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported via CTEP-AERS within 24 
hours of the Investigator’s knowledge.  Please refer to 
Appendix VIII for detailed instructions on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
E2112 specific expedited reporting exceptions: 
Rev. 10/15 
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The adverse events listed below do not require expedited reporting 
via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in 
the parentheses next to the event. The only exception is that 
platelet count decrease (thrombocytopenia) must be reported 
via CTEP-AERS as outlined above. 
5.2.8 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.9 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting as 
follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
• 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
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3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
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5.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Entinostat 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 221 patients. 
Below is the CAEPR for entinostat (SNDX-275, MS-275). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. The only exception is that platelet 
count decrease (thrombocytopenia) must be reported via CTEP-
AERS as outlined above in Section 5.2.7 
Version 2.5, September 10, 20181 
Adverse Events with Possible 
Relationship to MS-275 (SNDX-275, entinostat) 
(CTCAE 5.0 Term) 
[n= 221] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr 3) 
INVESTIGATIONS 
  
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased  
(Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased 
(Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count 
decreased 
 
 
 Platelet count decreased (Gr 4) 
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Adverse Events with Possible 
Relationship to MS-275 (SNDX-275, entinostat) 
(CTCAE 5.0 Term) 
[n= 221] 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 
3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
Hypoalbuminemia 
 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
Hypophosphatemia 
 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
Headache 
 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema 
multiforme 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATION SOC. 
3 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, 
Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
Adverse events reported on MS-275 (SNDX-275, entinostat) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MS-275 
(SNDX-275, entinostat) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis; 
Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac disorders - 
Other (transient right-side heart failure with worsening tricuspid regurgitation); Chest pain - 
cardiac; Conduction disorder; Heart failure; Left ventricular systolic dysfunction; Palpitations; 
Pericardial effusion; Pericarditis; Sinus tachycardia; Supraventricular tachycardia; Ventricular 
fibrillation 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Blurred vision 

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GASTROINTESTINAL DISORDERS - Anal mucositis; Colitis; Dysphagia; Enterocolitis; 
Esophageal pain; Esophagitis; Flatulence; Gastrointestinal disorders - Other (hyperdefecation); 
Gastrointestinal hemorrhage3; Hemorrhoids; Mucositis oral; Pancreatitis; Periodontal disease; 
Rectal mucositis; Rectal pain; Small intestinal mucositis; Typhlitis; Visceral arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Generalized edema; Injection site reaction; Multi-organ failure; Non-cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; 
Creatinine increased; GGT increased; INR increased; Investigations - Other (coagulopathy); 
Investigations - Other (vitamin D deficiency); Lipase increased; Serum amylase increased; Weight 
loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hyperuricemia; 
Hypoglycemia; 
Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone 
pain; Chest wall pain; Generalized muscle weakness; Muscle cramp; Musculoskeletal and 
connective tissue disorder - Other (thorax pain); Myositis; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dizziness; 
Dysphasia; Intracranial hemorrhage; Neuralgia; Olfactory nerve disorder; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Libido decreased 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary 
disorders - Other (bladder distension); Renal calculi; Renal hemorrhage; Urinary frequency; 
Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Atelectasis; 
Epistaxis; Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; Pleural effusion; Pleuritic pain; 
Pulmonary edema; Respiratory failure; Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; 
Photosensitivity; Pruritus; Purpura; Rash maculo-papular; Skin and subcutaneous tissue 
disorders - Other (hyperkeratotic lesions/squamous cell carcinoma); Urticaria 
SURGICAL AND MEDICAL PROCEDURES - Surgical and medical procedures - Other (packed 
RBC transfusion) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event 
NOTE: 
MS-275 (SNDX-275, entinostat) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
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5.4 
Dose Modifications  
Although entinostat and exemestane have distinct toxicity profiles, they do share 
some adverse events such as fatigue, nausea, and diarrhea. There is the 
theoretical possibility that one agent may potentiate the other and hence drug 
causality will not always be clear. In the event of uncertainty, dose reductions 
and/or delays will follow the most conservative approach. 
Treatment will be modified based on treatment-related toxicity as described 
below for all patients receiving entinostat/placebo. Dose omits due to toxicity will 
not be made-up; patients may resume treatment once toxicity resolves as per the 
regular schedule. Dose reductions due to toxicity are permanent. Dose 
escalation is not allowed. 
 If more than two doses of entinostat/placebo are omitted in a single cycle due to 
entinostat/placebo-related toxicity, the patient will be permanently discontinued 
from protocol therapy, followed until event resolution, and managed at the 
investigator’s discretion. Exemestane may continue in this case.  
Regular dosing and compliance with medication is strongly encouraged. If ≥ 2 
doses of entinostat/placebo per cycle are omitted for reasons other than toxicity 
in > 2 cycles, the patient will discontinue protocol therapy. However, if the 
treating investigator believes the subject is benefitting from treatment and feels it 
is in the best interest of the participant to continue on study, exceptions may be 
considered after discussion with the Study Chair.  
Prior to administration of first dose of entinostat/placebo in each cycle, patient’s 
organ function must have recovered to the following values:  
Minimum Values for Dose Administration 
Absolute Neutrophil Count 
≥ 1 x 109/L 
Platelets 
≥ 50 x 109/L 
Creatinine 
≤ 2 x institutional upper limit of normal (ULN) 
NOTE: 
The dose modifications noted below refer to administration of 
entinostat/placebo. Exemestane dose reductions are not allowed. If 
exemestane administration is held for any reason, patient can remain 
on study for up to 7 days. If exemestane administration is held for > 7 
days, patient will be considered off protocol treatment. 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.4.1 
Entinostat/Placebo Dose Modifications 
5.4.1.1 
Special Considerations 
For any grade 4 toxicity that recurs despite prophylaxis or 
dose reduction, protocol treatment should be permanently 
discontinued. 
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Any consideration of changes to these dose modification 
guidelines must be discussed with the Study Chair for 
approval in advance.  
NOTE: 
If a patient experiences a grade 3 or 4 event 
that requires a dose modification after dose has 
previously been reduced, entinostat/placebo 
should be omitted for 2 weeks and continued at 
the reduced dose of 3mg. 
Table 5.4.1: Dose Reductions for Entinostat/Placebo-Related Toxicity1,2, 
Hematologic Toxicity 
CTCAE 
System Organ 
Class (SOC) 
Adverse Event 
Grade 
Entinostat/Placebo Dose Change 
Investigations 
Neutrophil count decreased 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
Platelet count decreased 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
White blood cell decreased 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
Non-Hematologic Toxicity 
CTCAE 
System Organ 
Class (SOC) 
Adverse Event 
Grade 
Entinostat/Placebo Dose Change 
Gastrointestin
al disorders 
Diarrhea 
(Reduce dose only after 
optimal use of loperamide) 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
Nausea / Vomiting 
(Reduce dose only after 
optimal use of anti-emetics) 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
Metabolism 
and nutrition 
disorders 
-Hyperglycemia 
-Hypoglycemia 
-Hypophosphatemia 
-Hypernatremia 
-Hyponatremia 
-Hypercalcemia 
-Hypocalcemia 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit for 2 weeks and reduce to 3mg 
Other non-hematologic adverse events not 
mentioned above 
Grade 1 or 2 
No change 
Grade 3 or 4 
Omit treatment until toxicity resolves to 
Grade 1 then dose reduce to 3mg 
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2If more than two doses of entinostat/placebo are omitted in a single cycle due to entinostat/placebo-
related toxicity, the patient will be permanently discontinued from protocol therapy 
5.5 
Supportive Care  
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
Bone-modifying agents 
Patients may be treated with bone modifying agents such as 
bisphosphonates or RANK-ligand agents (e.g. denosumab) per 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. 
5.5.3 
Hypersensitivity Reactions 
Hypersensitivity reactions to exemestane or entinostat/placebo should 
be managed as per standard of care at the treating institution. Severe 
reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema or generalized urticaria require 
immediate discontinuation of study drug administration and 
aggressive symptomatic therapy. Subjects who experience a severe 
hypersensitivity reaction to treatment should not be re-challenged. 
5.5.4 
GI Medications 
Drugs used to reduce the acidity (increase pH) of the stomach, i.e. H2 
antagonists, proton-pump inhibitors, antacids, etc., could potentially 
interfere with entinostat absorption. Delay administration of H2-
antagonists, antacids, or proton pump inhibitors, or other drugs 
that lower acidity for at least 2 hours after dosing 
entinostat/placebo. 
5.5.5 
Nausea and Vomiting 
Nausea and vomiting after entinostat/placebo administration are 
expected. Prophylactic 5-HT3 serotonin receptor antagonist will be 
administered prior to ingestion of entinostat/placebo as well as on an 
as needed basis. Other anti-emetic medications (prochloroperazine, 
lorazepam, etc.) may also be taken for delayed nausea as needed. 
5.5.6 
Diarrhea 
If diarrhea occurs during dosing, an antidiarrheal agent(s) may be 
used. Loperamide may be taken in the following manner: 4 mg at the 
first onset of diarrhea, then 2 mg every two hours (4 mg every 4 hours 
while asleep) around the clock until diarrhea-free for at least 12 hours. 
Additional or institutional standard antidiarrheal measures may be 
used at the discretion of the treating physician. 
5.5.7 
Neutropenia without fever 
The clinical situation should be closely followed for fever, focal signs 
of infection, and neutrophil nadir. Growth factor support should be 
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5.5.8 
Neutropenia with fever  
Hospitalization and urgent broad-spectrum antibiotics are required for 
this potentially life-threatening complication. The occurrence of a 
temperature higher than 38.3°C (100.9°F) demands prompt 
evaluation of blood counts and examination for source of infection. 
Growth factor support should be administered in accordance with 
ASCO guidelines. 
5.5.9 
Anemia 
Red blood cell support should be given for any patient with 
symptomatic anemia and is recommended for patients with 
asymptomatic anemia when hemoglobin is below 8 g/dL. 
5.5.10 
Platelet Count Decrease 
Platelet transfusion should be given for a platelet count below 
10,000/mm3 in the absence of bleeding. If bleeding develops or 
invasive procedures are planned, platelet transfusion should be 
administered in accordance with standard practice. 
5.6 
Patient-Reported Outcomes Administration 
A detailed description of the PRO measures to be administered has been 
included in Section 6.2. 
5.6.1 
PRO Instruments to be administered: 
1) The Functional Assessment of Cancer Therapy–General (FACT-
G); 27 items 
2) The PROMIS Fatigue 7-item Short Form 
3) The Functional Assessment of Anorexia/Cachexia Treatment 
(FAACT; 12 items)  
4) Functional Assessment of Chronic Illness Therapy-Diarrhea 
(FACIT-D; 11 items) 
5) FACT-Breast Symptom Index (FBSI; 8 items) – taken from 8-item 
FBSI outlined by Yost et al that has event-based anchor points 
6) Medication Adherence Scale 
5.6.2 
PRO-CTCAE items to be administered: 
Select PRO-CTCAE items (16 items) will be administered to measure 
patient reporting of AEs. 
5.6.3 
Patient-Reported Outcomes Assessment Schedule 
5.6.3.1 
Brief symptom index to evaluate TTD: we plan to use 6 
items from the FBSI -- FACT Breast Symptom Index to 
detect symptom deterioration. These 6 items have been 
selected to focus on proximal change in symptoms. 
However, we will collect all 8 of the items from the FBSI 8 
outlined by Yost et al.73 These items will be administered at 
the following times: 
1) Baseline (before Cycle 1 Day 1) 
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2) End of Every Cycle for Cycles 1-6 
3) End of Cycles 8, 10, and 12 
4) Then administered on the same schedule as tumor 
assessments until disease progression (Note, for FBSI 
there are not assessments planned at or post 
progression). 
5.6.3.2 
PRO measures of treatment toxicities (PROMIS Fatigue, 
FAACT, FACIT-D) will be administered at the following 
time points: 
1) Baseline (before Cycle 1 Day 1)  
2) End of Cycle 3 
3) End of Cycle 6 
4) End of Cycle 12 
5) At end of protocol treatment, including treatment 
discontinuation for any reason (i.e. toxicity, 
progression, completion of protocol therapy) 
6) 4-weeks after end of protocol treatment, including 
treatment discontinuation for any reason (i.e. toxicity, 
progression, completion of protocol therapy). 
5.6.3.3 
The ECOG-ACRIN Medication Adherence Scale Modified 
from the Morisky Index will be administered: 
1) End of Cycle 3 
2) End of Cycle 6 
3) End of Cycle 12 
4) At end of protocol treatment, including treatment 
discontinuation for any reason (i.e. toxicity, 
progression, completion of protocol therapy) 
5.6.3.4 
Patient-reported HRQL will be assessed using the FACT-G 
and will be administered:  
1) Baseline (before Cycle 1 Day 1) 
2) End of Cycle 3 
3) End of Cycle 6 
4) End of Cycle 12 
5) At end of protocol treatment, including treatment 
discontinuation for any reason (i.e. toxicity, 
progression, completion of protocol therapy) 
5.6.3.5 
PRO-CTCAE: PRO-CTCAE items will be administered 
1) Baseline and prior to every cycle, following the same 
schedule as trial symptom/toxicity assessments.  
2) End of each Cycle during treatment 
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3) At end of protocol treatment, including treatment 
discontinuation for any reason (i.e. toxicity, 
progression, completion of protocol therapy) 
NOTE: 
The PRO-CTCAE should be completed 
each time a Symptom/Toxicity Assessments 
is completed. 
The total length of this assessment is dependent on the 
assessment time point. One of the lengthiest assessments 
will occur at Baseline (FACT-G, PROMIS-fatigue, FAACT-
subscale, FACIT-diarrhea subscale, FBSI, PRO-CTCAE) is 
80 multiple choice items. The anticipated time to complete 
all items is roughly 15-20 minutes. Assessments prior to 
cycles 4, 7 and 13 will also include the ECOG-ACRIN 
Medication Adherence Scale Modified from the Morisky 
Index that will include 8 multiple choice or yes/no items 
and will take roughly 2-3 minutes. This assessment 
schedule corresponds to the first, second, and fourth 
disease assessments. We have scheduled PRO 
assessments with standard clinic office visits to minimize 
participant and site burden, thus minimizing the risk of 
missing PRO data. Assessments to be administered at 
every cycle (FBSI, PRO-CTCAE) will include 21 multiple 
choice items and will take 4-5 minutes to complete. 
PRO assessments at treatment discontinuation and 4 
weeks post-treatment discontinuation for all participants 
regardless of the reason for treatment discontinuation 
(toxicity, progression) will provide valuable information on 
HRQL and symptom burden. As noted by Rini et al.72 
HRQL can appear to improve overall as the trial 
progresses due to participant selection bias. Participants 
with poorer performance status, more aggressive disease, 
and greater treatment toxicities come off treatment earlier. 
We may observe a high rate of attrition due to progression 
of illness. Patients on EE are expected to remain on 
treatment longer than patients on EP due to anticipated 
benefit in PFS. To obtain an unbiased assessment of 
HRQL and treatment toxicities, PRO assessment at the 
end of treatment and a short period of time following end of 
treatment (4 weeks) for all participants is needed. 
Otherwise, PRO assessments only capture data on 
participants who remain on treatment and are likely to be 
healthier, therefore, presenting a biased source of data 
that will likely indicate that HRQL improves over time. In 
addition, the assessment 4 weeks post-end of treatment 
will evaluate whether entinostat-related symptoms resolve 
within 4 weeks. This design (retaining participants who 
discontinue treatment) has been employed with other 
PROs studies such as the side effect sub-study of MA.27. 
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A PRO measure of breast cancer-specific symptoms will 
be administered at baseline, and every 28-day cycle for the 
first six months after randomization, and then every two 
cycles between 6 months and 1 year. After 1 year, the 
FBSI will be administered on the same schedule as tumor 
assessments until disease progression. The FBSI will be 
administered more frequently to allow for an assessment of 
time to treatment deterioration (TTD), a critical secondary 
endpoint. 
The PRO measure of adherence to therapy, the 
Medication Adherence Scale - , will be administered as 
outlined in Section 5.6.3 (before Cycle 4, 7, 13, and end of 
protocol therapy). With the exception of baseline, these 
assessment time points correspond with other study PRO. 
The FBSI and Medication Adherence Scale include 8 and 
8 items each and the anticipated time to complete the 16 
items is roughly 5-6 minutes. Please note there will be one 
Medication Adherence Scale form completed for each 
agent (entinostat/placebo and exemestane). 
5.6.4 
PRO Administration Instructions 
All PRO questionnaires will be administered as a paper survey. 
Ideally, participants will complete questionnaires at the time of 
scheduled study visits. For the first assessment (Cycle 1), PRO 
should be administered prior to the administration of study drug. With 
the exception of the 8-item FBSI, PRO time points overlap with 
protocol-specified clinic visits. If the 8-item FBSI does not overlap with 
protocol-specified clinic visits and/or if PRO assessments are not 
administered in clinic, the study questionnaires will be mailed to 
participants who will be asked to complete questionnaires and return 
by mail to clinic. After 7 days, clinic or research staff may contact 
participants by telephone and ask participants to complete the 
questionnaire on paper and then read their answers over the 
telephone to the staff person. 
In the event that the 8-item FBSI for TTD endpoint is being assessed 
at a protocol-specified clinic visit that includes an evaluation for 
progression, questionnaires will be completed before participants 
discuss disease status with health-care professionals. This will 
minimize potential bias, and is modeled after the study by Rini et al.72 
For the post-end of treatment PRO, we propose to administer to 
participants who return to clinic via paper. In the event that a 
participant does not return to clinic for a visit after end of treatment, 
we will collect the PROs via telephone. This will compensate for 
potential responder bias, wherein healthier patients are more likely to 
return to clinic and thus, to complete the post-treatment surveys. In 
collecting PRO data via phone, the survey will be mailed to the 
participant, who will complete it and then read their responses to the 
interviewer. This procedure will minimize mode effect, whereby 
participants report less symptoms burden during phone or in-person 
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interviews than with written surveys. This approach will approximate 
the completion of PROs in clinic as closely as possible. 
PRO-CTCAE items will be administered on paper along with study 
PRO measures following procedures for PRO administration as 
described above. PRO-CTCAE items will be administered prior to 
clinic visits, or prior to participant’s discussion of disease status and 
treatment side effects with health-care professionals. This is modeled 
after NCI PRO-CTCAE study procedures employed in other clinical 
trial validation studies. Clinicians will be instructed to complete 
clinician-rated treatment toxicities (CTCAE) prior to reviewing PRO-
CTCAE ratings. This will minimize the extent to which PRO-CTCAE 
responses introduce a bias to clinician CTCAE ratings. PRO-CTCAE 
are currently undergoing validation and thus exploratory in nature, 
therefore, at this point should not be used to inform clinician CTCAE 
ratings. Clinicians will be instructed to review PRO-CTCAE items after 
clinician toxicity ratings have been completed to identify any patient-
reported symptoms and toxicities that warrant clinical attention. 
Supportive care measures to manage treatment toxicities are 
described in Section 5.5. 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Progressive disease by RECIST criteria. See Section 6.1. 
• 
Severe toxicity at discretion of treating physician or unresolved Grade 3 or 4 
toxicity.  
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event, submit forms according to the instructions in the 
E2112 Forms Packet. 
• 
Patient withdraws consent. 
• 
Exemestane or entinostat/placebo is held for longer than permitted per 
Section 5.4.  
• 
Patient receives non-protocol therapy, including chemotherapeutic or 
investigational anti-neoplastic drugs or radiation therapy to only lesion 
available to monitor response. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression even if non-protocol therapy 
is initiated. Upon discontinuation of treatment, patients will be followed for 
survival per the standard ECOG-ACRIN follow-up schedule: Every 3 months if 
patient is < 2 years from study entry, every 6 months if patient is 2-5 years from 
study entry, and every 12 months if patient is > 5 years from study entry for up to 
10 years, including patients removed from study for unacceptable adverse 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be evaluated for response 
according to the schedule in Section 7.  
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1).46 Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in RECIST 1.1. 
For purposes of comparability to the phase 3 study of exemestane in advanced 
breast cancer patients by Chia et al,4 enrollment in this study will attempt to 
achieve a target patient population that consists of approximately 80% of patients 
having measurable disease (with at least 1 measurable lesion at study entry) and 
approximately 20% of patients having non-measurable disease only. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before 
randomization. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
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6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area may only be considered measurable if there is 
evidence of post-radiation progression. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
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A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before randomization. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
Conventional CT and MRI  
This RECIST 1.1 guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or 
less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body 
scans).   
Diagnostic quality CT is preferred (with oral and IV contrast); any 
deviations from this must be approved by the Study Chair in advance. 
See note below regarding contrast allergy.  

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Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
NOTE: 
If prior to enrollment it is known a patient is not able to 
undergo CT scans with IV contrast due to allergy or renal 
insufficiency, the decision as to whether a non-contrast CT 
or MRI (with or without IV contrast) should be used to 
evaluate the subject at baseline and follow-up should be 
guided by the anatomic location(s) of the disease. For 
patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether 
non-contrast CT or MRI (enhanced or non-enhanced) 
should be performed should also be based on the 
anatomic location of the disease and should be optimized 
to allow for comparison to the prior studies if possible. 
Each case should be discussed with the radiologist and 
Protocol Chair/designee to determine if substitution of 
these other approaches is possible and, if not, the patient 
may be considered not evaluable from that point forward. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
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ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression. See Section 
6.1.4.3. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
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more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 12 weeks.  
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesions. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel. 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
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at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it: a) increases in size to  
≥ 15 mm in the short axis, or b) there is new pathological 
confirmation that it is disease (regardless of size). 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded 
since the treatment started). The patient’s best response 
assignment will depend on the achievement of both 
measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 12 wks. from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 guidelines for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 

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Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 12 weeks. 
6.2 
Patient-Reported Outcomes Endpoints 
The patient-reported outcomes assessment for this protocol will measure overall 
HRQL, treatment-related toxicities, breast cancer-specific symptoms, and 
adherence to protocol therapy. 
6.2.1 
Overall HRQL 
Overall HRQL will be measured using the Functional Assessment of 
Cancer Therapy – General (FACT-G).57 The FACT-G includes 27 
items that assess physical, functional, social and emotional well-
being. We will select individual items a priori from the FACT-G to 
assess nausea, diarrhea, other side effects and overall bother by 
treatment side effects based on differences in the side effects noted 
with arm A vs. arm B. This a priori approach has also been employed 
for ATAC59 and E1Z0360 data analysis. Use of the FACT-G will allow 
us to assess for overall HRQL, while performing a relatively broad 
screen for other, potentially unanticipated symptoms related to the 
Exemestane + Entinostat combination. All items are rated on a 5-point 
Likert scale, from 0 to 4. 
6.2.2 
Treatment-related toxicities 
PROs to assess fatigue and GI distress will be administered to 
measure treatment-related side effects. 
6.2.2.1 
PROMIS Fatigue: The PROMIS Fatigue is a 7-item short-
form. Minimally important difference (MIDs) scores have 
been empirically derived for the PROMIS Fatigue short 
form56 and use of the PROMIS fatigue short form will also 
allow us to compare this metastatic breast cancer sample 
to other cancers, non-cancer chronic illnesses, and general 
population norms. All items are rated on a 6-point Likert 
scale, from 0 to 5. 
6.2.2.2 
FAACT: The Functional Assessment of Anorexia/Cachexia 
Treatment (FAACT) subscale consists of 12 items focused 
on appetite and nausea61. We will use the 12-item FAACT-
additional concerns subscale to assess differences in 
nausea and anorexia. All items are rated on a 5-point 
Likert scale, from 0 to 4. 
6.2.2.3 
FACIT-Diarrhea: The 11-item Functional Assessment of 
Chronic Illness Therapy (FACIT)-Diarrhea subscale will be 
used to assess diarrhea. All items are rated on a 5-point 
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6.2.2.4 
PRO-CTCAE: The NCI PRO-CTCAE library includes 78 
items to quantify patient reports of AEs. We have selected 
6 common treatment-related symptoms which will be 
measured using 13 PRO-CTCAE items: decreased 
appetite, diarrhea, nausea, vomiting, joint aches, and 
muscle aches. We have selected 2 additional symptoms 
(bruising, hiccups) that we anticipate to be similar between 
treatment arms for validation purposes. Hiccups will be 
measured using 2 PRO-CTCAE items. 
6.2.3 
Breast cancer-specific symptoms 
8-items of the FACT-Breast Symptom Index were assessed by Yost et 
al among patients with metastatic breast cancer being treated on 
E1193.73 The 8-items includes items assessing fatigue, pain (general 
and pain in specific bodily areas), nausea, shortness of breath, worry 
about condition worsening, trouble meeting needs of family and 
content with QOL. We will use six of the eight items that we believe 
will focus on the most proximal changes to assess TTD (an important 
secondary endpoint). We will NOT use the following questions: “I 
worry that my condition will get worse” and “Because of my physical 
condition, I have trouble meeting the needs of my family” in assessing 
TTD but will collect these items for additional exploratory work. All 
items are rated on a 5-point Likert scale, from 0 to 4. 
According to Yost et al, using distribution-based criteria, the 
minimally important differences for the 8-items above ranged from 
1.5 to 2.5 points with a median of 2.2 points.73 Cross-sectional 
anchor-based criteria yielded similar estimates, with score 
differences between adjacent categories of performance status 
ratings of 2.8 and 3.2 points. 
6.2.4 
Adherence 
The ECOG-ACRIN Medication Adherence Scale Modified from the 
Morisky Index will be administered to understand the reasons for non-
adherence to protocol therapy. There will be one Medication 
Adherence Scaleform completed for each agent (entinostat /placebo 
and exemestane). The Medication Adherence Scale measures the 
likelihood that a patient will take prescribed medications. The 
Medication Adherence Scale has been validated against medication 
pill count methods of assessing compliance and used in a variety of 
settings. It is an 8-item measure with a Likert response scale69. The 
minimal detectable change has been defined as 1.98 points 
(Muntner). 
Patient’s adherence to protocol therapy will be quantified using the pill 
count (entinostat/placebo) and diary (exemestane) methods. Patients 
will be instructed to bring their medication bottles and diaries to clinic 
visits. Clinic or pharmacy staff will count the number of remaining 
entinostat/placebo pills or note the number of exemestane pills as 
taken on the pill diary, and will calculate the number of pills taken 
using a treatment form.69,70 
Rev. Add5 
Rev. Add7 

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7. 
Study Parameters 
1. Baseline evaluations within 4 weeks prior to randomization unless specified. 
2. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done ≤ 4 weeks 
prior to randomization. 
3. Prestudy CBC (with differential and platelet count) and all required prestudy chemistries must be done ≤ 4 weeks before 
randomization, as outlined in Section 3. 
 
Baseline 
Cycle 1 
Day 15 
End of 
Cycles 1 
and 2 
End of 
Cycle 3 
End of each 
cycle (cycle 3-
forward) 10 
Every 3 
cycles (cycle 
3, 6 etc) 
At discontinuation 
of treatment10 
Post treatment11 
History, Physical Exam, ECOG PS, 
Vital signs, Height, Weight 
 X1 
 
X 
X 
X 
 
X 
X 
Symptom/Toxicity assessments 
 X1 
 
X 
X 
X 
 
X 
 
CBC2 
X 
X 
X 
X 
X 
 
X 
 
Chemistries3 
X 
X 
X 
X 
 
X 
X 
 
Serum estradiol4 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Bone scan5 
X 
 
 
X 
 
X 
 
  X12 
Tumor assessment by CT or MRI6 
X 
 
 
X 
 
X 
X 
  X12 
Serum or Urine Pregnancy Test20 
X 
 
 
 
 
 
 
 
PRO Assessments7 
X 
 
 
X 
 
X 
X 
X 
PRO Assessment: FBSI8 
X 
 
X 
X 
X 
 
 
 
PRO-CTCAE16 
X 
 
X 
X 
X 
 
X 
 
Exemestane18 
 
X (daily) 
 
 
Entinostat/placebo18 
 
X (weekly) 
 
 
LHRH agonist (pre/perimenopausal 
female and all male participants 
only)19 
 
X (monthly) 
 
 
Pill Count/Diary9 
 
 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
 
X 
X 
X 
 
X 
X17 
Biological Sample Submissions [See Sections 11 and 12] 
Whole blood, one (1) 8mL CPT citrate 
tube13,14,15 
X 
X 
 
 
 
 
 
 
Rev.4/15 
Rev.10/15 
Rev. 10/16 
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Baseline 
Cycle 1 
Day 15 
End of 
Cycles 1 
and 2 
End of 
Cycle 3 
End of each 
cycle (cycle 3-
forward) 10 
Every 3 
cycles (cycle 
3, 6 etc) 
At discontinuation 
of treatment10 
Post treatment11 
FFPE tumor tissue (primary & 
metastatic)13,14 
X 
 
 
 
 
 
 
 
Whole blood, one (1) 8mL ACD yellow 
top13,14,15 
X 
 
 
 
 
 
 
 
 
 
Cycle 1, Day 1 [2 samples drawn at 
least 2 hours apart, 2-5 hours after 
dosing] 
Cycle 1, Day 15 [1 sample drawn 1 
hour after dosing] 
Within 72 hours prior to the start of 
Cycle 2 
Population Pharmacokinetics 
[OPTIONAL PER PATIENT 
CONSENT]: Plasma, one (1) 6mL 
K2EDTA lavender top tube per time 
point 14, 21 
X 
X 
X 
1. Physical exam, ECOG PS, vital signs, and symptom/toxicity assessment must be performed ≤ 2 weeks before randomization.  
NOTE: Height measurements may have been taken > 4 weeks from baseline. 
2. CBCs, which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done ≤ 72 hours prior to Cycle 2 and every 
cycle thereafter. Baseline CBCs do not need to be repeated prior to Cycle 1 Day 1. 
3. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, magnesium, phosphorus, potassium, 
total protein, SGOT (AST), SGPT (ALT), sodium must be done ≤ 72 hours prior to Cycles 2-4 and every 3 cycles thereafter. Baseline 
chemistries do not need to be repeated prior to Cycle 1 Day 1.  
4. Only required for women age < 55 years and with intact ovaries as described in Section 3.1. 
5. Baseline bone scan required in all patients. 
NOTE: If bone scan done ≤ 6 weeks prior to registration showed no evidence suggesting bone metastases and no clinical indication of 
skeletal pain or other evidence suggesting bone metastases, a repeat baseline bone scan is not required.  
6. CT of the chest and CT or MRI of abdomen/pelvis are required at baseline. Subsequent imaging for the subject should be conducted on the 
same scanner using the same acquisition and reconstruction parameters. Those tests required to follow known site(s) of disease must be 
repeated at the end of 12 weeks from randomization and then every 12 weeks (3 cycles) during treatment and according to the follow up 
schedule if off treatment, until first progression of disease. NOTE: All tumor assessment should be scheduled based on calendar time (every 
12 weeks) and not cycle length. Image thickness (reconstructed) should be 5 mm or less for CT and MRI, and contiguous slices are 
preferred to those with intervening gaps. Consistent use of contrast agent, dose, and injection parameters (including time of image collection 
after contrast) are recommended. See Section 10 for additional details and submission instructions. 
NOTE: If the CT of the chest and CT or MRI of abdomen/pelvis done ≤ 6 weeks prior to randomization showed no evidence of disease in 
the area(s) and no clinical indication suggesting new metastases, full re-staging including all areas is not required; however, ensure 
that disease is evaluable per RECIST 1.1 requirements (Section 6). 
7. Patient-Reported Outcomes to be assessed at the following time (see Section 5.6 for detailed instructions): 

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PROMIS Fatigue, FAACT, FACIT-D: Baseline (before Cycle 1 Day 1), end of Cycle 3, end of Cycle 6, end of Cycle 12, at end of protocol 
treatment, including treatment discontinuation for any reason (i.e., toxicity, progression, completion of protocol therapy) and 4 weeks after 
end of protocol treatment, including treatment discontinuation for any reason (i.e., toxicity, progression, completion of protocol therapy). 
The ECOG-ACRIN Medication Adherence Scale Modified from the Morisky Index: end of Cycle 3, end of Cycle 6, end of Cycle 12, and at 
end of protocol treatment, including treatment discontinuation for any reason (i.e. toxicity, progression, completion of protocol therapy). 
Please note there will be one Medication Adherence Scale form completed for each agent (entinostat/placebo and exemestane). 
FACT-G: Baseline (before Cycle 1 Day 1), end of Cycle 3, end of Cycle 6, end of Cycle 12, and at end of protocol treatment, including 
treatment discontinuation for any reason (i.e. toxicity, progression, completion of protocol therapy). 
8. The FBSI will be administered at baseline, end of each cycle for the first six months after randomization, and then at the end of Cycles 8, 10, 
and 12. After Cycle 12, the FBSI will be administered on the same schedule as Tumor assessments until disease progression. 
9. Pill counts for entinostat/placebo and diaries for exemestane should be collected at the end of each cycle until discontinuation of study 
treatment. 
10. Repeat any test not done ≤ the prior 28 days. 
11. Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, and annually if patient is >5 
years from study entry. No specific requirements if patient is more than 10 years from study entry.  
12. Tumor assessments are to be done up to (and including) the assessment which shows first progression of disease. If patient discontinues 
treatment due to reasons other than disease progression, concomitant medication and tumor assessments should be performed until 
disease progression on the following schedule: Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years 
from study entry, and annually if patient is >5 years from study entry. No specific requirements if patient is more than 10 years from study 
entry. 
13. Submit blood samples to the Trepel Laboratory from patients who answer “Yes” to “I agree to participate in the laboratory research studies 
that are being done as part of this clinical trial.” Baseline blood samples should be collected after randomization, prior to start of treatment on 
Day 1 (preferably within 2 days of Day 1). Day 15 blood samples should be collected prior to entinostat/placebo dose on that day. 
NOTE: 
Do not start treatment on Fridays as the baseline and day 15 blood collections cannot be shipped on Fridays. 
Submit optional blood and tissue samples for future research to the ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF) from 
patients who answer “Yes” to “I agree to provide additional specimens for research.” 
14. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). The exact date and time 
of entinostat/placebo administration and of PK plasma sample collection must be entered into the STS. 
15. Kits are available for blood collection and shipment. Kit order instructions are provided in Appendix VI. Kit orders will, on average, be 
delivered within 3 business days from time of order placement. 
16. PRO-CTCAE items will be administered at Baseline, end of each Cycle, and at end of protocol treatment, including treatment discontinuation 
following the same schedule as trial Symptom/Toxicity assessments. 
17. Concomitant Medications will be collected up to 90 days from the end of study treatment. 
18. A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous treatment of exemestane in combination with 
entinostat/placebo.  A new cycle start is defined as the first planned date of entinostat/placebo for the cycle. 
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19. Pre/perimenopausal females must have commenced treatment with LHRH agonist at least 4 weeks prior to randomization. If patients have 
received alternative LHRHR agonist prior to study entry, they must switch to goserelin for the duration of the trial. 
20. For all women of child bearing potential, must be done ≤ 2 weeks prior to randomization. 
21. Kits are being provided for the collection and shipment of the  plasma samples for the population pharmacokinetic studies. Process and 
submit the plasma samples to Covance Central Laboratory Services. See Section 11.4 for instructions. To obtain starter kits and the Site 
Laboratory Instruction Manual please Email or Fax Appendix IX E2112 Covance Site Information/Initial Kit Order Form to Syndax. Please 
note Covance requires ten (10) days to process the form and ship the initial kits. 
 
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8. 
Drug Formulation and Procurement 
Agent Accountability and Availability 
Entinostat and matching Placebo (IND# 118068) will be provided free of charge by 
Syndax Pharmaceuticals and distributed by the Pharmaceutical Management Branch 
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD), National Cancer Institute (NCI). 
Entinostat is supplied by the Syndax Pharmaceuticals, Inc. and distributed by DCTD, 
NCI as 1 mg (pink to light red, in bottles of 15 tablets), or 5 mg (yellow, in bottles of 5 
tablet) film-coated tablets (round-biconvex). Each tablet also contains mannitol, sodium 
starch glycolate, hydroxypropyl cellulose, potassium bicarbonate, and magnesium 
stearate.  The film coating consists of hypromellose, talc, titanium dioxide, and ferric 
oxide pigments (red and yellow) as colorants. 
Matching placebo for entinostat has the same appearance as the corresponding active 
tablets and contains the same inactive ingredients and film coating. 
NOTE: 
Under no circumstances can commercially supplied Entinostat be used or 
substituted for the NCI-supplied Entinostat/Placebo. 
Commercial exemestane will be provided free of charge by Syndax Pharmaceuticals. In 
the United States it will be distributed by the Pharmaceutical Management Branch 
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and 
Diagnosis (DCTD), National Cancer Institute (NCI). Outside of the United States, 
distribution will be arranged by Syndax Pharmaceuticals. 
Each tablet is round, biconvex, and off-white to slightly gray. Exemestane is packaged in 
HDPE bottles with a child-resistant screw cap, 30 tablets per bottle. Exemestane tablets 
contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, 
hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch 
glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, 
magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol. [Pfizer, 
Package Insert] 
NCI Supplied Agents – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling (240) 276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. You may also contact PMB via e-mail at 
PMBAfterHours@mail.nih.gov. 
Drug Orders, Transfers, Returns, Accountability and Emergency Unblinding  
No blinded starter supplies will be available for this study. 
Once a patient has been randomized, blinded, patient specific supplies will be sent 
automatically to the registering investigator and should arrive within 10 days. Study drug 
requests are transmitted by the ECOG-ACRIN Operations Office – Boston the day the 
patient is randomized and will be processed by PMB the next business day and shipped 
the following business day. Shipments within the United States are sent by FedEx 
ground (generally three to five day delivery) and shipments to Canada are sent by 
FedEx (generally one to two day delivery) Thus, if a patient is registered on Monday, 
ECOG-ACRIN would enter a clinical drug request for that patient on Monday and PMB 
would process that request on Tuesday and ship the drug on Wednesday. United States 
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sites could expect to receive their order approximately Wednesday. Shipments to United 
States sites can be expedited (i.e., receipt on Thursday in example above) by the 
provision of an express courier account name and number to the ECOG-ACRIN 
Operations Office – Boston at the time the patient is randomized. 
The initial request will be for 3 bottles of Entinostat or matching placebo. Ten (10) weeks 
after the initial electronic request [i.e., two (2) weeks before needed], sites may reorder 
an additional 3 bottles of Entinostat or matching placebo by using the PMB Online Agent 
Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the establishment of 
a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” 
password. The assigned patient ID number (e.g., "999999") and the patient initials (e.g., 
"L,FM") must be entered in the "Patient or Special Code" field. A separate order is 
required for each patient ID number (e.g., "999999") being ordered. All drug orders will 
be shipped directly to the physician responsible for treating the patient. 
Each blinded, patient -specific bottle will be labeled with: 
• 
The protocol number (i.e., “E2112”) 
• 
The bottle number (i.e., “Bottle 1 of 3, 2 of 3, 3 of 3”) 
• 
The number of tablets (i.e., “5 tablets” or “15 tablets”) 
• 
The patient ID number (e.g.,"44444", where “44444” represents a unique patient 
identifier assigned at randomization) 
• 
The patient initials (i.e., first initial, last initial [e.g., "FL"]) 
• 
The agent identification (i.e., “Entinostat 5 mg or placebo”) 
• 
A blank line for the pharmacist to enter the patient’s name 
• 
Administration instructions  
• 
Storage instructions (i.e., Store at 25°C (77°F), excursions permitted from 15°C to 
30° C (59-86 °F) ) 
• 
Emergency contact instructions 
• 
A Julian date 
The Julian date indicates the day the bottles were labeled and shipped and is composed 
of the last two digits of the calendar year (e.g., 2013 = 13, 2014 = 14) and a day count 
(e.g., January 1 = 001, December 31 = 365). For example, a bottle labeled and shipped 
on January 1, 2013 would have a Julian date of ‘13001’ and a bottle labeled and shipped 
on December 31, 2013 would have a Julian date of ‘13365’. The Julian date will be used 
by PMB for recalls. When a lot expires, PMB will determine the last date the expired lot 
was shipped and will recall all bottles shipped on or before that date thus eliminating any 
chance of breaking the blind.  
Sites within the United States 
No exemestane starter supplies will be available for this study. 
Once a patient has been randomized, patient specific supplies will be sent automatically 
to the registering investigator and should arrive within 10 days. Exemestane requests 
are transmitted by the ECOG-ACRIN Operations Office – Boston the day the patient is 
randomized and will be processed by PMB the next business day and shipped the 
following business day. Shipments within the United States are sent by FedEx ground 
(generally three to five day delivery). Thus, if a patient is registered on Monday, ECOG-

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ACRIN would enter a clinical drug request for that patient on Monday and PMB would 
process that request on Tuesday and ship the drug on Wednesday. United States sites 
could expect to receive their order approximately Wednesday. Shipments to United 
States sites can be expedited (i.e., receipt on Thursday in example above) by the 
provision of an express courier account name and number to the ECOG-ACRIN 
Operations Office – Boston at the time the patient is randomized. 
The initial request will be for 3 bottles of Exemestane. Ten (10) weeks after the initial 
electronic request [i.e., two (2) weeks before needed], sites may reorder an additional 3 
bottles of Exemestane by using the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status 
and a “current” password. The assigned patient ID number (e.g., "999999") and the 
patient initials (e.g., "L,FM") must be entered in the "Patient or Special Code" field. A 
separate order is required for each patient ID number (e.g., "999999") being ordered. All 
drug orders will be shipped directly to the physician responsible for treating the patient. 
Each open label, patient-specific bottle will be labeled with: 
• 
The protocol number (i.e., “E2112”) 
• 
The bottle number (i.e., “Bottle 1 of 3, 2 of 3, 3 of 3”) 
• 
The number of tablets (i.e., “30 tablets”) 
• 
The patient ID number (e.g.,"44444", where “44444” represents a unique patient 
identifier assigned at randomization) 
• 
The patient initials (i.e., first initial, last initial [e.g., "FL"]) 
• 
The agent identification (i.e., “Exemestane 25 mg”) 
• 
A blank line for the pharmacist to enter the patient’s name 
• 
Administration instructions 
• 
Storage instructions (i.e., Store at 25°C (77°F), excursions permitted from 15°C to 
30° C (59-86 °F) ) 
• 
Emergency contact instructions 
• 
A Julian date 
The Julian date indicates the day the bottles were labeled and shipped and is composed 
of the last two digits of the calendar year (e.g., 2016 = 16, 2017 = 17) and a day count 
(e.g., January 1 = 001, December 31 = 365). For example, a bottle labeled and shipped 
on January 1, 2016 would have a Julian date of ‘16001’ and a bottle labeled and shipped 
on December 31, 2016 would have a Julian date of ‘16365’. The Julian date will be used 
by PMB for recalls. When a lot expires, PMB will determine the last date the expired lot 
was shipped and will recall all bottles shipped on or before that date. 
Special Ordering Procedures for Patients Requiring a Dose Reduction: If the 
patient is dose reduced from entinostat/placebo 5 mg once a week TO 
entinostat/placebo 3 mg once a week (see Section 5.4.1), a request must be placed by 
using the PMB Online Agent Order Processing (OAOP) application to obtain the 
entinostat 1 mg and matched placebo tablets. 
Drug Transfers: Patient specific study drug supplies MAY NOT be transferred from one 
patient to another patient or from one protocol to another protocol. All other transfers 
(e.g., a patient moves from one participating clinical site to another participating clinical 
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site, the principal investigator at a given clinical site changes) must be approved in 
advance by the PMB. To obtain an approval for transfer, investigators should complete 
and submit to the PMB (fax number 240-276-7893) a Transfer Investigational Agent 
Form available on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 
301-496-5725. The patient ID number (e.g., "44444"') and the patient initials (e.g., "FL”) 
should be entered in the "Received on NCI Protocol No." and the "Transferred to NCI 
Protocol No." fields in addition to the protocol number (i.e., "E2112"). 
Drug Returns: Only undispensed clinical supplies should be returned to the PMB. 
When it is necessary to return study drug investigators should return the study drug to 
the PMB using the NCI Return Drug List available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. The patient ID number 
(e.g., "44444") and the patient initials (e.g., "FL") should be entered in the "Lot Number" 
field. A separate line item is required for each patient ID number (e.g., "44444") that is 
being returned. Bottles with remaining tablets should be documented in the patient-
specific NCI Investigational Agent Accountability Record (i.e., logged is as “returned by 
patient” and logged out as “destroyed on site”) and destroyed on site in accordance with 
institutional policy. 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
for Oral Agents available on the CTEP home page (http://ctep.cancer.gov) or by calling 
the PMB at 240-276-6575. A separate NCI Investigational Agent Accountability Record 
must be maintained for each patient ID number (e.g., "44444") on this protocol. 
Emergency Unblinding  
The information provided below is for the use by a physician, nurse, CRA or pharmacist 
treating the patient. These contact numbers should not be used by patients. Patients 
should be instructed to call their doctor’s office in the event of an emergency or adverse 
event that may result in the need to unblind the patient. 
In the event of an emergency or severe adverse reaction necessitating identification of 
the medication for the welfare of the patient, please contact the Study Chair, Dr. Roisin 
Connolly, at (410) 614-9217, or email: rconnol2@jhmi.edu first to ensure the reason for 
unblinding is valid. Then call a member of the ECOG-ACRIN Operations Office – Boston 
drug team at (857) 504-2900 Monday through Friday between 9:00 AM and 5:00 PM 
Eastern Time. For unblinding outside of these hours, contact AnswerConnect at 1-866-
296-8940. This service will request the reason for unblinding and then page the on-call 
ECOG-ACRIN staff who will return your call and provide the unblinded treatment 
assignment if applicable. Remember, AnswerConnect should only be contacted outside 
of normal business hours and only in the event of an emergency. The ECOG-ACRIN 
Operations Office – Boston or AnswerConnect will require the protocol number (i.e., 
“E2112”), the patient ID number (e.g., “44444”), and the patient initials (e.g., “FL”) to 
unblind the patient. Note that if a patient is unblinded, he/she must discontinue protocol 
treatment. 
NCI CTEP should also be notified of a request for unblinding 
8.1 
Entinostat/Placebo (NSC 706995) (IND# 118068) 
8.1.1 
Other Names  
MS-27-275, MS-275, SNDX-275 
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8.1.2 
Chemical Name 
3-Pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate 
8.1.3 
Classification 
Histone deacetylase inhibitor (HDACi) 
8.1.4 
Molecular Formula  
C21H20N4O3 
M.W.: 376.41 
8.1.5 
Mode of Action 
Histone deacetylases (HDACs) are a family of enzymes that regulate 
chromatin remodeling and gene transcription via the dynamic process 
of acetylation and deacetylation of core histones. Entinostat inhibits 
histone deacetylases, changes chromatin configuration, and induces 
differentiation and apoptosis of cancer cells through an epigenetic 
mechanism. 
8.1.6 
Storage and Stability 
Store the bottles at controlled room temperature (15-25oC), and 
protect from light. Entinostat is not to be exposed to extremes of 
temperature (greater than 30ºC or less than 5ºC). Shelf life stability 
studies of the intact bottles are on-going. 
8.1.7 
Dose Specifics 
Entinostat/Placebo 5mg once every week (days 1, 8, 15, and 22) of a 
28 day cycle. See Section 5.4 for information regarding dose 
reductions. Entinostat/Placebo 1mg tablets are also available in case 
of dose reduction. 
8.1.8 
Route of Administration  
Oral, on an empty stomach, at least 1 hour before and 2 hours after a 
meal. Entinostat tablets should not be split, crushed, or chewed. 
8.1.9 
Incompatibilities  
Metabolism: Data from in vitro metabolism experiments in human 
tissues demonstrated that entinostat is not metabolized by CYP 
enzymes (Acharya 2006), but UGT 1A4 did metabolize entinostat to 
its M2 glucuronide metabolite. No metabolites could be detected after 
incubation of entinostat in human liver microsomes (Acharya 2006). 
While inhibition of CYP enzymes 2B6 and 3A4 was seen, the data 
show that the degree of the inhibition makes it unlikely that any in vivo 
systemic interactions would occur. Intestinal CYP 3A4 may be 
inhibited by entinostat. However, entinostat did not inhibit any UGT 
enzymes tested. Entinostat was found to induce CYP 1A2, CYP 2C6, 
and CYP 2B8 as well as UGT 1A4. Finally, entinostat was found to be 
a substrate for P-gp and BCRP transporters, but did not inhibit either 
of these transport proteins. 
8.1.10 
Availability  
See Section 8.0 above for complete details.  
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8.1.11 
Side Effects 
See Section 5.3 for CAEPR. 
8.1.12 
Nursing/Patient Implications  
Entinostat should be taken on an empty stomach, at least 1 hour 
before and 2 hours after a meal/snack. If the patient’s dose requires 
more than one tablet, the tablets should be taken one at a time. Delay 
administration of H2-antagonists, antacids, or proton pump inhibitors, 
or other drugs that lower acidity for at least 2 hours after dosing 
entinostat. 
Entinostat may cause fatigue or malaise; advise patient to exercise 
caution while driving a vehicle or operating machinery. 
Administration of entinostat is contraindicated in patients with a history 
of allergy to entinostat or other medications that have a benzamide 
structure (eg, tiapride, remoxipride, clebropride). 
Careful monitoring of patients for signs of infection or reactivation of 
past infections is recommended, as reactivation of infection has been 
reported in patients treated with entinostat, in some cases without 
evidence of neutropenia. The clinical significance of this finding and 
the potential association with entinostat is unknown. 
Entinostat must not be used during pregnancy or while breast-feeding. 
Women and men participating in entinostat clinical studies must agree 
to use acceptable contraceptive methods, as indicated in the clinical 
study protocol, during treatment and for 3 months thereafter. 
8.2 
Exemestane 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information.  
8.2.1 
Other names 
Aromasin 
8.2.2 
Chemical name 
6-methylenandrosta-1,4-diene-3,17-dione 
8.2.3 
Classification 
Exemestane is a steroidal aromatase inhibitor (inhibitor of estrogen 
synthesis). 
8.2.4 
Molecular Formula 
C20H24O2 
8.2.5 
Mode of Action 
Exemestane is an irreversible, steroidal aromatase inactivator, 
structurally related to the natural substrate androstenedione. It acts as 
a false substrate for the aromatase enzyme, and is processed to an 
intermediate that binds irreversibly to the active site of the enzyme 
causing its inactivation, an effect also known as “suicide inhibition”. 
Exemestane significantly lowers circulating estrogen concentrations in 
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postmenopausal women, but has no detectable effect on adrenal 
biosynthesis of corticosteroids or aldosterone. Exemestane has no 
effect on other enzymes involved in the steroidogenic pathway up to a 
concentration at least 600 times higher than that inhibiting the 
aromatase enzyme. [Pfizer, Package Insert]. 
8.2.6 
Storage and Stability 
Store at 25°C (77ºF); excursions permitted to 15°–30°C (59°–86°F). 
Exemestane tablets should remain in their original container. 
8.2.7 
Dose Specifics 
Exemestane 25 mg once daily after a meal, days 1-28 of each cycle. 
8.2.8 
Route of Administration 
Oral 
8.2.9 
Incompatibilities 
CYP3A4 inducers: Caution, may significantly decrease exposure to 
exemestane. CYP 3A4 inhibitors: Significant pharmacokinetic 
interactions appear unlikely. [Pfizer, Package Insert] 
8.2.10 
Availability 
Sites within the United States should refer to Section 8.0 above for 
complete details. Information for sites outside of the United States will 
be included once available. 
8.2.11 
Nursing/Patient Care Implications 
Exemestane should be taken with food. 
8.2.12 
Adverse Effects 
Advanced breast cancer: Most common adverse events were mild to 
moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 
5%),fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and 
increased appetite (3% vs. 6%) for exemestane and megestrol 
acetate,respectively. [Pfizer, Package Insert] Please see the 
Exemestane Package Insert for more details on the known 
precautions, warnings, and adverse reactions. 
8.2.13 
References 
Pfizer Package Insert 
(http://labeling.pfizer.com/showlabeling.aspx?id=523) 
8.3 
Goserelin 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. This will be used in pre/perimenopausal female and all 
male participants only in this clinical trial. 
8.3.1 
Other names 
Zoladex 
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8.3.2 
Chemical name 
Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate  
8.3.3 
Classification 
Goserelin is a GnRH agonist. 
8.3.4 
Molecular Formula 
C59H84N18O14 
8.3.5 
Mode of Action 
Goserelin is a synthetic decapeptide analogue of GnRH.  It acts as an 
inhibitor of pituitary gonadotropin secretion when administered in the 
biodegradable formulation.  In animal and in vitro studies, 
administration of goserelin resulted in the regression or inhibition of 
growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-
induced rat mammary tumor and Dunning R3327 prostate tumor. 
[AstraZeneca, Package Insert]. 
8.3.6 
Storage and Stability 
Goserelin will be handled per routine pharmaceutical standards. 
8.3.7 
Dose Specifics 
Goserelin is available commercially as 3.6 mg doses in disposable 
syringe devices. 
8.3.8 
Preparation 
Not applicable, dose is ready for administration. 
8.3.9 
Route of Administration 
Subcutaneous injection 
8.3.10 
Availability 
Goserelin is commercially available and will be prescribed by the 
treating physician and covered by the patients insurance.  
8.3.11 
Adverse Effects 
Most common adverse events occurring in >10% of men: hot flashes, 
sexual dysfunction, decreased erections and lower urinary tract 
symptoms. 
8.3.12 
References 
AstraZeneca Package Insert 
(http://www1.astrazeneca-us.com/pi/zoladex3_6.pdf) 
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9. 
Statistical Considerations 
9.1 
Study Objectives 
The primary objective of this randomized, placebo-controlled, double-blinded, 
phase III study is to determine whether Exemestane + Entinostat (Arm A) 
improves progression-free survival (PFS) and/or overall survival (OS) compared 
to the Exemestane + Placebo (Arm B) in patients with hormone receptor-positive, 
human epidermal growth factor receptor 2 (HER2)-negative locally advanced or 
metastatic breast cancer (MBC) who have experienced disease progression after 
non-steroidal AI use in the adjuvant setting (within 12 months prior to enrollment) 
or in the metastatic setting. 
Both PFS and OS are primary endpoints, and the study is designed to show an 
improvement in either PFS or OS. PFS is defined to be time from randomization 
to the earliest of documented disease progression as defined by the Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, new primary breast 
cancer, or death without progression. Disease assessment will continue until 
disease progression, even after non-protocol anti-cancer therapy is started. 
Cases with incomplete follow up or without adequate disease evaluations will be 
censored at the date last documented to be free of progression, regardless of 
whether non-protocol anti-cancer therapy is started or not. Tumor response and 
progression will be defined by central review, including time point-by-time point 
radiologist reader review at the ACR Imaging Core Lab for patients with 
radiographically measurable/evaluable disease, and/or an independent review 
committee for patients with measurable/non-measurable disease that is not 
radiographically evident (i.e., skin lesions). OS is defined to be time from 
randomization to death from any cause, censoring cases who had not died at the 
date last known alive. 
This study is aimed to give adequate power for both PFS and OS comparisons. 
The one-sided type I error of 0.025 is split between two hypotheses tests to 
control the overall type I error rate for the whole trial. Specifically, type I error rate 
is 0.001 for PFS test and 0.024 for OS test. 
9.2 
Study Design  
Patients with histologic confirmation of invasive adenocarcinoma of the breast 
will be randomized according to the permuted block algorithm with a 1:1 
randomization ratio to arms A and B. Stratification factors include: 
• 
Setting in which patient developed resistance to prior non steroidal AI 
treatment (adjuvant vs. metastatic) 
• 
Geographic region (USA vs. other) 
• 
Visceral disease (yes vs. no) 
• 
Prior fulvestrant use (yes vs. no) 
NOTE: Visceral disease is defined as lung and/or liver involvement. 
Taking into consideration the accrual rates of the BOLERO-2 study (40 
patients/month, 700 patients over 18 months with 24 international sites), the 
ENCORE 301 study (5 patients/month, 130 patients over 2 years at 38 sites US 
and international) and the CONFIRM study (24 patients/month at 128 sites), all of 
which have been conducted in the AI refractory setting, and the 1st line SWOG 
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S0226 study (10 patients/month,700 patients over 6 years), we anticipate an 
accrual rate of approximately 15 patients per month in our study.  
Enrollment of 600 patients will be required to provide adequate power for the OS 
endpoint (see Section 9.2.2). The first 360 patients will be used for the primary 
evaluation of PFS (see Section 9.2.1), objective response rate (ORR), toxicity, 
time to treatment deterioration and patient-reported outcomes. If the PFS 
analysis is positive, the data for first 360 patients would be used for a submission 
to the FDA. At the time of final analysis for the OS endpoint, secondary analyses 
of PFS, objective response and toxicity will be conducted in all 600 patients, 
along with the primary analyses for the pharmacodynamic acetylation marker 
data and adherence to protocol therapy data. Imaging studies for all 600 
participants will be collected and archived at the ACR Imaging Core Laboratory. 
For purposes of comparability to the phase 3 study of exemestane in advanced 
breast cancer patients by Chia et al.,4 enrollment in this study will attempt to 
achieve a target patient population that consists of approximately 80% of patients 
having measurable disease (with at least 1 measurable lesion at baseline 
assessment and identification of up to 5 total target lesions [maximum of 2 
lesions per organ] and 5 total non-target lesions) and approximately 20% of 
patients having non-measurable disease only. 
No early stopping for efficacy based on PFS will be considered in the study so 
that there will be sufficient death events for OS comparison in the final analysis. 
Hence, for PFS, the study will only be monitored for early stopping for futility. 
Interim analyses of OS will start at about 30 months (24 months of accrual + 6 
months of data collection and cleaning) after study activation. Details about 
interim analysis for PFS and OS are described in Section 9.2.3. 
9.2.1 
Sample size and accrual for PFS 
For patients with HR-positive, HER2-negative MBC, the median PFS 
on the Exemestane + Placebo arm will be about 4.1 months in AI 
refractory setting based on BOLERO-2 central assessment results14. 
The null hypothesis is hazard ratio (HR)=1 for comparison of PFS in 
the two treatment arms, and the alternative hypothesis is HR=0.58 for 
arms A/B. The primary analysis of PFS will be performed using a 
stratified log-rank test, with one-sided type I error of 0.1%, stratifying 
on randomization stratification factors. The primary comparisons will 
be intention-to-treat analysis (defining groups by assigned treatment 
regardless of treatment received) among all refractory patients 
regardless of eligibility status. A total accrual of 360 patients and total 
information of 247 PFS failures is planned, to give 88.5% power to 
detect a 42% reduction in the PFS failure hazard rate with no interim 
efficacy analysis. This difference corresponds to an improvement in 
median PFS from 4.1 to 7.1 months (i.e., 3.0 months of benefit), under 
the assumption of exponential distribution of PFS. Assuming an 
accrual rate of 15 patients per month, about 24 months of accrual will 
be needed without additional follow up to reach the expected number 
of PFS events. 
The data for the primary analysis for the PFS comparison is expected 
to be available at about 30 months (24 months of accrual + 6 months 
of data collection and cleaning) after study activation, when the first 

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interim analysis for OS will be conducted. When to release the PFS 
data, however, depends on the result for the first interim analysis of 
OS. If the OS interim analysis is positive (ie, crossing the efficacy 
boundary listed in Table 9.2, see Section 9.2.3) at the final PFS 
analysis time, the whole study will be stopped early for efficacy and 
the results for both PFS and OS will be released to Syndax and the 
public. If OS does not cross the efficacy boundary, in order to 
minimize the potential effect of releasing PFS result on the OS 
endpoint, the results of primary analysis for PFS will be held by the 
ECOG-ACRIN study statistician and the ECOG-ACRIN Data Safety 
Monitoring Committee (DSMC) members and not released to Syndax, 
CTEP, the principal investigators, anyone at ECOG-ACRIN involved 
in the day-to-day running of the trial or publically until all 600 patients 
required for the OS endpoint have been accrued for the whole trial 
(expected to occur at about 40 months after study activation, see 
Section 9.2.2). In this case, the primary analysis of PFS will use 
follow-up through the calendar time of the 247th PFS event among the 
first 360 patients enrolled, even though more follow-up is expected to 
be available at that time (ie, completion of accrual). After completion 
of overall study accrual, the PFS results will be released to Syndax 
and may be released publically if allowed by the ECOG-ACRIN 
DSMC. 
9.2.2 
Sample size and accrual for OS  
Taking into consideration the median OS in the ENCORE 301 trial (20 
months in the Exemestane + Placebo arm and 28 months in the 
entinostat arm) and the CONFIRM 2 trial (25.1 months in the high 
dose fulvestrant arm and 22.8 months in the low dose arm), it is 
expected that the median OS for patients on the Exemestane + 
Placebo arm will be about 22 months in the AI refractory patients. The 
null hypothesis for the OS comparison is HR=1, and the alternative 
hypothesis is HR=0.75 for arms A/B. The primary analysis of OS will 
be performed using a stratified log-rank test, with one-sided type I 
error of 2.4%, stratifying on randomization stratification factors. The 
primary comparisons will be intention-to-treat analysis among all 
refractory patients regardless of eligibility status. A total accrual of 600 
patients and total information of 410 OS failures is planned to give 
80% power to detect a 25% reduction in the OS failure hazard rate 
with interim analysis plan described in Section 9.2.3 (Table 9.2).This 
difference corresponds to an improvement in median OS from 22 to 
29.3 months (i.e., 7.3 months of benefit), under the assumption of 
exponential distribution of OS. Assuming an accrual rate of 15 
patients per month, about 40 months of accrual will be needed with 
additional 24 months of follow up to reach the expected number of OS 
events. The final analysis for the OS comparison is expected to occur 
at about 70 months (40 months of accrual + 24 months of follow up + 
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9.2.3 
Interim analysis 
Interim futility analysis for PFS tests 
As mentioned above, in order to ensure sufficient sample size for OS 
comparison, no early stopping for efficacy based on PFS is 
considered in the study, and the study will only be monitored for early 
stopping in favor of the null hypothesis for PFS tests (i.e., futility) by 
the ECOG-ACRIN DSMC via its semi-annual DSMC meetings.  
We adopt the general inefficacy interim monitoring method (described 
in the paper by Freidlin, Korn and Gray, Clinical Trials, 2010, which is 
called Linear 20% Inefficacy Boundary method)49 for futility monitoring 
in the study. This method generally results in less than 1% loss of 
power, there will be no sample size increase to account for the futility 
monitoring in the study. 
Before interim analysis using the Linear 20% Inefficacy Boundary 
method, we will first perform a “harm” look at 25% information (about 
9.5 months after study activation), using the rule that stops the trial for 
harm if the one-sided lower 95% unadjusted confidence bound for the 
observed hazard ratio (HR) is above 1 (i.e., HR > 1.52). This is the 
same as one-sided 0.05 level test of the null hypothesis in the 
direction of harm. If the trial does not stop at the “harm” look, the 
study will be monitored by formal interim analysis via Linear 20% 
Inefficacy Boundary method as described below. If the study stops at 
the “harm” look, the whole trial stops for lack of efficacy. 
The one-sided type I error is 0.1% and the power is 88.5% for the 
PFS test, the first interim analysis could take place at as early as 21% 
information time per the Linear 20% Inefficacy Boundary method, at 
which the observed hazard ratio > 1 would imply that the two-sided 
95% confidence interval for log hazard ratio would not contain the 
log(0.58). Since the “harm” look will take place at 25% information 
time, and a 10% increment in information time is suggested for interim 
futility analysis by the method, the first interim analysis will be 
performed at the first DSMC meeting when at least 35% of the total 
information has been reported. Since 247 PFS events are required as 
the total information under the alternative hypothesis, the first interim 
analysis for futility is estimated to take place after 87 PFS events have 
occurred, which corresponds to 11.5 months after activation of the 
study in calendar time, under the accrual and failure rate assumptions 
mentioned above. Interim analysis will be performed for each 
subsequent DSMC meeting until either the criteria for early stopping 
(described below) are met or the total planned number of PFS events 
has been reported. In total, this design is expected to incorporate 2 
interim analyses and one final analysis for PFS comparisons. The cut-
off values for HRs and lower two-sided 95% confidence interval bound 
(unadjusted) are given in Table 9.1. If at any time point, the observed 
hazard ratio (arms A/B) is larger than the cut off values, the trial will 
stop in refractory setting for lack of efficacy. 
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In each interim analysis, the observed hazard ratio will be calculated 
using stratified Cox proportional-hazards model, stratified on 
randomization stratification factors, without any other covariates.  
Because interim analyses are timed to coincide with the semi-annual 
ECOG-ACRIN DSMC meetings, the boundaries for HRs may change 
depending on the number of observed PFS events at that time. Also, 
because of delays in data submission and processing, it is likely that 
actual analysis times will be 6-12 months later. 
Table 9.1: Inefficacy stopping boundaries for PFS endpoint 
(Alternative HR=0.58, Full information=247 PFS events, Type I 
error=0.1%, Power=88.5%) 
Repeated interim futility analysis 
1 
2 
Information time 
35% 
65% 
Calendar time (months after study activation) 
11.5 
17.5 
Hazard ratio (stopping boundaries) 
0.981 
0.941 
Lower two-sided 95% confidence bound 
(unadjusted, Z=1.96 at all interim looks) 
0.643 
0.691 
Interim analysis for OS tests 
Regardless of PFS results, the first interim analysis of OS will be 
performed at the final PFS analysis time (expected to be 24 months 
after study activation-see Section 9.2.1). Interim analysis for OS will 
then be performed biannually until either the criteria for early stopping 
(described below) are met or the total planned number of OS events 
has been reported. Of note, interim analyses will be skipped if the 
change in the information since the previous interim analysis is less 
than 10%. In addition, when the information time reaches 90% or 
more, interim analysis will not be conducted, and the final analysis of 
OS will be performed when full information is reached. These interim 
analyses will be monitored by ECOG-ACRIN DSMC. Table 9.2 shows 
the operating characteristics for OS endpoint. 
At each interim analysis, the stratified log rank test statistic will be 
computed. To preserve the overall one-sided type I error rate at 2.4% 
for the OS endpoint, critical values for rejecting null hypothesis at the 
interim analyses will be determined using a truncated version of the 
Lan-DeMets spending function50 corresponding to the O'Brien-
Fleming boundary (1979)51. If the boundary is crossed at an interim 
analysis or at the final analysis, then the null hypothesis will be 
rejected, and the Exemestane + Entinostat therapy is superior to the 
exemestane monotherapy in terms of OS. If the criteria for rejecting 
the null hypothesis are not met, then it will be concluded that this trial 
fails to show superiority of Exemestane + Entinostat therapy over the 
exemestane monotherapy on OS. 
Because interim analyses are timed to coincide with the ECOG-
ACRIN DSMC meetings, these boundaries may change depending on 
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delays in data submission and processing, it is likely that actual 
analysis times will be 6-12 months later. 
Table 9.2: Operating Characteristics for OS Endpoint 
Repeated 
Analysis 
Real time 
(months) 
Information 
time 
Failures under 
alternative 
hypothesis 
Nominal 
significance 
(one-sided) 
Upper 
boundary 
1 
24 
0.24 
101 
0.00048 
3.3020 
2 
30 
0.36 
149 
0.00048 
3.3020 
3 
36 
0.49 
203 
0.00068 
3.2036 
4 
42 
0.64 
261 
0.00400 
2.6518 
5 
48 
0.76 
313 
0.00805 
2.4065 
6 
54 
0.87 
355 
0.01193 
2.2593 
Final 
64 
1.00 
410 
0.01872 
2.0808 
If PFS test is negative in the primary analysis, this study will also be 
monitored for early stopping in favor of the null hypothesis (i.e., futility) 
for the OS test using the Jennison-Turnbull repeated confidence 
interval (RCI) method. At each interim OS analysis, the RCI on the 
observed hazard ratio will be computed using the critical values from 
the above error spending rate function. If the RCI does not include the 
alternative hazard ratio of 1.33 (arms B/A), then the OS comparison 
would be stopped early for lack of benefit. The observed hazard ratio 
will be calculated using stratified Cox proportional-hazards model, 
stratified on randomization stratification factors, without any other 
covariates. If the PFS test is positive in the primary analysis, no 
interim futility analysis for OS will be conducted. 
As mentioned in Section 9.2.1, if the first interim analysis of OS is 
positive, the interim OS data will be released to Syndax and the public 
and the study will be stopped early for efficacy. If the first interim 
analysis of OS does not cross the efficacy boundary, then at the time 
study accrual is completed, if (1) the primary PFS test is positive at 
the 0.001 level, and (2) the estimated PFS hazard ratio for 
Exemestane + Entinostat vs. Exemestane + Placebo is < 0.675, the 
interim OS data will also be confidentially released to Syndax. The 
DSMC will also be asked to allow use of interim OS data from the first 
360 patients enrolled in an application to the FDA, with the 
understanding that the data not be made public unless required as 
part of the FDA review process. 
Interim analysis for toxicity  
For safety considerations, an interim analysis for toxicity data will be 
conducted when 30 patients have been assigned to arm A and have 
received at least one dose (expected to occur at about 4 months after 
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events (at a rate of 20%) are observed in the first 30 patients in this 
arm, the study will be terminated. Table 9.3 shows the probability that 
the trial will be terminated early due to excessive toxicity. This 
probability is provided under different assumptions about the true 
proportion of Grade 4 non-hematologic toxicity in this arm. 
Table 9.3: Probability that the trial will be terminated early due to 
excessive toxicity on arm A 
True proportion of the toxicity 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
Probability of early termination 
0.026 
0.15 
0.39 
0.65 
0.84 
0.94 
9.3 
Statistical Consideration for Objective Response, Toxicity and Time to Treatment 
Deterioration 
9.3.1 
Objective response 
Objective response in the two arms will be evaluated by comparing 
objective response rate (ORR, PR+CR) using a Fisher's exact test on 
the intention-to-treat patients with one-sided type I error of 2.5%. The 
primary analysis of ORR will be evaluated on the first 360 patients 
enrolled for the PFS analysis, a secondary analysis of ORR will be 
conducted on all patients. Patients who are unevaluable for response 
and patients never starting protocol therapy will be included as non-
responders in this analysis. Based on the BOLERO-2 results, the 
ORR will be about 0.4% on arm B. For the primary analysis of 
objective response, with 180 refractory patients on each arm, the 
study will have 86% power to detect an increase to a 6% objective 
response rate on arm A. 
9.3.2 
Toxicity 
Another secondary endpoint of the study is to evaluate toxicities. 
Toxicity will be evaluated on the first 360 patients for the PFS analysis 
and on all patients for the OS analysis.  All patients who start protocol 
therapy (i.e., receive at least one dose of protocol treatment) will be 
included in toxicity analysis. For the 360 patients for the PFS analysis, 
assuming 9 patients (9/180=5%) will not start protocol therapy in each 
arm, with 171 evaluable patients per arm, there is 92% power to 
detect a difference in grades 3-4 toxicity rate of 24% vs. 10% between 
arms A and B, assuming an one-sided type I error rate of 2.5%, based 
on the Fisher’s exact test. For each arm, with 171 patients, the 
binomial exact 95% confidence interval for toxicity rate would be no 
wider than 0.16. 
9.3.3 
Time to Treatment Deterioration (TTD) 
Another secondary endpoint of the study is to evaluate time to 
treatment deterioration (TTD) of arm A vs. B. TTD is a composite 
endpoint and it captures toxicity (measured by symptom worsening), 
symptom worsening due to disease progression between radiological 
tumor assessments (provided symptoms are being assessed more 
frequently than the radiological disease assessments), radiological 
confirmed disease progression and death. TTD is defined as time 

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from randomization to radiological confirmed disease progression or 
death or worsening of symptoms, whichever occurs first. Disease 
progression is assessed per RECIST v1.1. Symptoms deterioration 
will be measured by 6 items from the 8-item FACT-Breast Symptom 
Index (FBSI). The 6 items (GP1, GP2, GP4, GF7, B1, P2, scored 0-
24) were selected as being most clinically relative and most 
responsive to “proximal” change based from clinical deterioration. In 
addition, the other two items (GP3 or GE6) in the 8-item FBSI will be 
collected as well for explanatory analysis. 
The selected 6 items capture both symptoms related to progressive 
breast cancer (fatigue, malaise, pain, shortness of breath, overall 
change in QOL) as well as symptoms related to entinostat (fatigue, 
nausea, overall change in QOL). According to Yost et al, the minimally 
important difference (median 2.2, range 1.5-2.5) and anchor-based 
criteria overlapped (PSR 2.8 and 3.2), 73 and based on these criteria, 
2-3 point changes in this 8-item FBSI survey can be interpreted as a 
MID. To be conservative, symptom deterioration is defined as two 
consecutive available decreases of at least 3 points from baseline 
using the 6-item FBSI57 in this trial, and the second visit time will be 
used as the time of symptom deterioration in this case, unless it is the 
final score, for which one decrease is sufficient. 
In order to fully capture the impact of toxicity and disease progression 
before radiological assessment on patient’s QOL, symptoms will be 
assessed every cycle for the first six months after randomization, 
every two cycles between 6 months and 1 year. It then will be 
assessed based on the same schedule for tumor assessments until 
disease progression. Since symptom change cannot be associated 
with protocol therapy if the patient never receives any treatment on 
protocol, the primary population for the TTD analysis will be the 
enrolled 360 patients for the PFS analysis who receive at least one 
dose of protocol therapy (i.e., all treated patients in the first 360 
enrolled patients). TTD will not be evaluated on the additional 240 
patients primarily enrolled for the OS endpoint. 
Because we expect that the benefits from improving PFS (and thus 
less symptoms from disease) on arm A will outweigh any increase in 
toxicity from the addition of entinostat to exemestane (more symptoms 
from the treatment), we hypothesize that the combination arm (A) will 
have a significantly longer TTD than arm B. It is expected that 
symptom deterioration will occur before radiological confirmed 
disease progression or death for some patients. Hence, the median 
TTD should be shorter than the median PFS for the same patient 
population. To be conservative, we assume that the median TTD is 4 
months for patients on arm B, similar with our estimate for PFS in 
these patients. Assuming 9 patients (9/180=5%) will not start protocol 
therapy in each arm, with 171 evaluable patients per arm, there is 
88% power to detect a HR of 0.67 for arms A/B based on the log-rank 
test when the analysis is conducted 30 months after study activation 
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of 6 months on arm A (i.e., 50% improvement in median TTD), with a 
2.5% one-sided type I error rate.

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9.4 
Analysis Plan for Primary Endpoints, Objective Response, Toxicity and Time to 
Treatment Deterioration  
The primary endpoints are progression-free survival (PFS) and overall survival 
(OS). Both of the two endpoints will be used for potential entinostat registration 
with FDA. ORR, toxicity and TTD are secondary endpoints. The primary analysis 
of PFS will include follow-up through the 247th PFS event within the first 360 
patients enrolled. For the primary analysis, progression will be defined by central 
review. A sensitivity analysis for PFS will be performed using the first 360 
patients based on progression defined by local investigators. The TTD analysis 
will include similar follow-up. The primary analyses of ORR and toxicity will 
include the first 360 patients enrolled. Final analysis for OS is expected to be 
conducted at about 70 months after study activation (40 months of accrual + 24 
months of follow up + 6 months of data collection and cleaning). At the time of 
the final OS analysis, secondary analyses of the other endpoints (PFS, ORR and 
toxicity) including all cases enrolled will be conducted. The secondary analysis of 
PFS will be conducted in all 600 patients based on progression defined by the 
local investigators since central review is anticipated for the first 360 patients 
only. 
Tumor response will be assessed per Response Evaluation Criteria In Solid 
Tumors (RECIST) version 1.1 following the standard ECOG-ACRIN review 
procedures.46 PFS is 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 will continue 
until disease progression, even after non-protocol anti-cancer therapy is started. 
Cases with incomplete follow up or without adequate disease evaluations will be 
censored at the date last documented to be free of progression, regardless of 
whether non-protocol anti-cancer therapy is started or not. As a sensitivity 
analysis, PFS will also be defined in the following ways: 1) Considering the start 
of a new non-protocol anti-cancer therapy as a PFS event, in addition to disease 
progression, new primary breast cancer and death without progression. 2) 
Censoring PFS observation at the last assessment before a new non-protocol 
anti-cancer therapy is started for the patients who start new anti-cancer therapy 
without a documented PFS event. OS is defined to be time from randomization to 
death from any cause. Cases who are still alive will be censored at the date last 
known alive. ORR is defined as the proportion of patients with complete 
response (CR) or partial response (PR) among all patients (including patients 
with unevaluable tumor response). 
All primary analyses regarding PFS, OS and ORR will be based on intention-to-
treat population regardless of eligibility status. A secondary analysis for PFS, OS 
and ORR will be conducted in eligible patients. The distributions of PFS and OS 
will be estimated using the Kaplan- Meier method (1958)52, with 95% confidence 
intervals calculated using Greenwood’s formula. In the primary analyses of PFS 
and OS, differences in treatment effect will be tested using stratified log rank 
tests, stratifying on the randomization stratification factors. Stratified univariate 
and multivariable Cox proportional-hazard models (1972)53 will be built to 
estimate the hazard ratios (HRs) for treatment effect for PFS and OS as a 
supportive analysis. In the multivariable Cox models, known prognostic factors 
will be included as covariates when appropriate, such as age at diagnosis, 
race/ethnicity, body mass index (BMI), ECOG performance status, disease stage 
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at diagnosis, prior adjuvant chemotherapy, prior hormonal therapy, et al. The 
assumption of proportionality in the Cox models will be assessed by investigating 
the weighted Shoenfeld residuals for each predictor. Patients with missing values 
for covariates will be excluded from modeling when the proportion of missingness 
is less than 5% and will be imputed appropriately if the proportion of missingness 
≥5%. ORR will be summarized along with the exact binomial 95% confidence 
interval and compared between the two arms using Fisher's exact tests.54  
TTD is defined as time from randomization to disease progression or death or 
worsening of symptoms, whichever occurs first. All primary analysis for TTD will 
be based on all cases receiving at least one dose of protocol treatment (i.e., all 
treated population). The distribution of TTD will be estimated using Kaplan-Meier 
method, and TTD comparisons between treatment arms will be tested primarily 
using log-rank test. Cox proportional-hazards models will be conducted to 
estimate the HR for treatment effect for TTD as a supportive analysis. Same 
factors included in the multivariable Cox model for PFS and baseline symptom 
level will be included as predictors for TTD. 
Analyses pertaining to toxicity will be based on all treated cases. Adverse events 
will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE). All treatment-emergent and baseline 
adverse events and hematological/biochemical toxicities based on laboratory 
measurements, as well as drug related AE’s, will be summarized by treatment 
group and NCI CTCAE worst grade. The incidence of deaths and treatment-
emergent serious adverse events (defined as number of patients experiencing 
the AE divided by all treated patients) will be summarized and compared 
between treatment arms using Fisher’s exact test. Also, the incidence of adverse 
events leading to discontinuation of investigational product and/or withdrawal 
from the study will be summarized and listed. 
In all analyses, P-values will be two-sided. A level of 0.2% will be considered 
statistically significant for stratified log rank test for the primary PFS analysis. For 
OS comparison, the significance level for stratified log rank test will be 4.8%. For 
all other tests, a level of 5% will be considered statistically significant. 
9.5 
Integrated Pharmacodynamic Biomarker Study of Acute Change in Protein 
Lysine Acetylation 
HDAC inhibition leads to elevated protein lysine acetylation in tumor and 
peripheral-blood cells, which could serve as a surrogate early pharmacodynamic 
biomarker of entinostat activity. ENCORE 301 collected peripheral blood samples 
(PBMCs) for assessment of lysine acetylation, both prior to therapy and post-
therapy on Days 8 and 15, using an assay developed by the Trepel Laboratory, 
NCI/NIH. Protein lysine acetylation in the combined therapy subgroup (i.e., arm 
A) was associated with a striking improvement in PFS across all cell types (B 
cells, T cells and monocytes). In Exemestane +Entinostat-treated 
hyperacetylators (i.e., acetylatoin above the median) versus those with 
acetylation below the median, median PFS was 8.5 versus 2.7 months (HR=0.32, 
95% CI 0.13, 0.79) (B cells); 6.6 versus 3.6 months (HR=0.44, 95% CI 0.18, 
1.08) (T cells); and 6.2 versus 3.6 months (HR=0.50, 95% CI 0.21, 1.20) 
(monocytes). 
We will use the identical methodology, central laboratory (Trepel Laboratory, 
NCI/NIH), and timing (Day 15) for the integrated acetylation pharmacodynamic 

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biomarker studies planned in E2112. PBMCs will be collected at baseline and 15 
days after initiating therapy consisting of drawing 8cc of blood into one blue/black 
CPT citrate tube at each time point. 
Since exemestane is not expected to induce significant increase in protein lysine 
acetylation, we expect no significant increase in protein lysine acetylation after 
two weeks of arm B treatment on E2112. The primary test of association 
between increased protein lysine acetylation (as an early pharmacodynamic 
biomarker of entinostat activity) and PFS will be examined in arm A in E2112. 
However, since the study is blinded, the PBMCs will be collected on all patients 
(including both arm A and arm B). The prognostic value of increase of lysine 
acetylation will be conducted in arm B as well as an exploratory analysis. All 600 
patients enrolled in the main trial will be included in the integrated acetylation 
pharmacodynamic biomarker study. The analysis will be performed at about 70 
months after study activation (same time as that for final OS analysis). 
9.5.1 
Statistical consideration for integrated acetylation pharmacodynamic 
biomarker study 
The objective of this pharmacodynamic biomarker study is to examine 
the prognostic value of acute acetylation change for PFS in patients 
receiving Exemestane + Entinostat combination therapy. We 
hypothesize that patients with percentage change in protein lysine 
acetylation above median will have a prolonged PFS compared to 
those with changes in protein lysine acetylation below or equal to 
median in arm A. For this integrated pharcodynamic biomarker study, 
the endpoint is PFS. The group variable is change in protein lysine 
acetylation between baseline and 2 weeks after initiating therapy. 
Of the 300 refractory patients on arm A, 270 (90%) of them will be 
expected to have measures for protein lysine acetylation at both 
baseline and 2 weeks after initiating therapy. The percentage change 
in lysine acetylation will be calculated for all patients on arm A and the 
median percentage change will be determined and used as the 
threshold to dichotomize all patients into two groups on the arm: > 
median and ≤ median. There will be about 266 PFS events on arm A 
at the time of the analysis (70 months after study activation) under the 
alternative hypothesis. With a total of 266 PFS events and 270 
patients, there will be adequate power (80%) to detect a hazard ratio 
of 0.71 and excellent power (90%) to detect a hazard ratio of 0.67 
using log rank test with one-sided type I error equal to 2.5%. 
9.5.2 
Analysis plan for integrated acetylation pharmacodynamic biomarker 
study 
The primary analyses for this integrated acetylation pharmacodynamic 
biomarker study will be conducted in all patients on arm A who have 
data about the protein lysine acetylation at both baseline and 2 weeks 
after initiating therapy. The analysis time for this acetylation biomarker 
study is at about 70 months after study activation (same time as final 
analysis for OS). 
The distributions of PFS and OS will be estimated using the Kaplan-
Meier method, with 95% confidence intervals calculated using 
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Greenwood’s formula. Differences between patients with above or 
below median of percentage change in protein lysine acetylation will be 
tested using log rank test. Univariate and multivariable Cox models will 
be built to estimate the HRs for the effect of increased protein lysine 
acetylation for PFS and OS, respectively. The adjusting variables in 
the multivariable Cox model include patient demographics and disease 
characteristics, such as age at diagnosis, ECOG PS, disease stage, 
prior therapy, et al.  
Similar analysis will be conducted in patients on arm B to explore 
whether increase of protein lysine acetylation is prognostic for PFS and 
OS in patients with the exemestane monotherapy. 
In all the above survival analyses, landmark method55 will be used, 
with landmark set at 2 weeks. OS is defined to be week 2 to death 
from any cause, censoring cases who are alive at the date last known 
alive. PFS is defined to be week 2 to the earliest of documented 
disease progression as defined by the RECIST criteria, new primary 
breast cancer, or death without progression. Cases with incomplete 
follow up or without adequate disease evaluations will be censored at 
the date last documented to be free of progression. Patients who have 
events for OS or PFS within 2 weeks are excluded from the landmark 
analysis. 
The distribution of the percentage change in protein lysine acetylation 
will be plotted for the two treatment groups and difference will be 
compared using the Wilcoxon ranks sum test. Tumor response rate will 
be compared between the patients with percentage change in 
acetylation being above or below median using Fisher's exact tests in 
each treatment arm.54  
All above analyses for protein lysine acetylation change will be 
repeated for all three types of peripheral blood mononuclear cells 
(CD3+ T cells, CD19+ B cells and CD14+ monocytes). In all analyses, 
P-values will be two-sided and a level of 5% will be considered 
statistically significant. No adjustment will be made for multiple 
comparisons. 
If PFS endpoint is positive in the primary analysis within the first 360 
patients, the acetylation data will be analyzed for a subgroup analysis 
for PFS (all 360 patients will be dichotomized into one of two groups 
based on the whole sample median: > median and ≤ median) at the 
PFS primary analysis time. 
9.6 
Patient-Reported Outcomes Assessment 
There are two objectives in the patient-reported outcomes (PROs) assessment 
study. The first objective is to compare overall HRQL between treatment arms. 
The second objective is to compare symptoms associated with entinostat 
between arms. The type I error rate is equally split between the two objectives to 
control the overall one-sided type I error at 2.5% for the PROs analysis. In order 
to provide sufficient power for the two objectives, all 360 patients included for the 
PFS endpoint on the main study and receive at least one dose of protocol 
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not be evaluated on the additional 240 patients primarily enrolled for the OS 
endpoint. 
With the exception of the FBSI and the Medication Adherence Scale, the PROs 
assessment will be administered at the following time points: baseline, 3, 6, and 
12 months (the timing of these assessments coincides with the first, second and 
fourth disease assessments), at the end of protocol treatment/time of protocol 
treatment discontinuation and 4 weeks after protocol treatment is discontinued. 
Given that anticipated median survival is about 2 years and median PFS is about 
4-7 months, the 3-month assessment is expected to provide the best assessment 
of treatment-emergent symptoms. Hence the primary comparison of PROs 
between treatment arms is based on the month 3 assessment. 
9.6.1 
Statistical consideration for PROs  
The primary objective of the PROs study is to test whether the overall 
HRQL is significantly worse in the Exemestane + Entinostat arm (arm 
A) compared to the Exemestane + Placebo arm (arm B) at month 3. 
The null hypothesis is that patients on the two arms have same overall 
HRQL. The alternative hypothesis is that patients on arm A have worse 
HRQL than patients on arm B. The endpoint for the objective is the 
overall HRQL score measured by the Trial Outcome Index (TOI), an 
aggregate score of the 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). Higher 
score represents better HRQL (score range 0-44). 
Assuming an overall attrition rate of approximately 10% by month 3 for 
the PROs assessment in both arms, it is expected that about 324 
refractory patients will be included for the primary analysis for HRQL. 
At month 3, a difference of 5 points in the overall HRQL score between 
the treatment arms would be considered clinically meaningful. The 
common standard deviation is expected to be 12 points. With 162 
analyzable patients on each arm for the month 3 assessment, there 
will be about 93% power to test the difference using a two independent 
samples t test, assuming a two-sided type I error of 0.025. 
The second objective of the PROs study is to assess differences 
between the two arms in symptoms associated with entinostat at 
month 3 (i.e., fatigue, nausea, anorexia and diarrhea, measured by 
PROMIS Fatigue short form, FAACT-additional concerns and FACIT-
Diarrhea, respectively). The null hypothesis is that there is no 
difference between two arms regarding fatigue, nausea, anorexia and 
diarrhea at 3-month assessment. The alternative hypothesis is that 
patients on the Exemestane + Entinostat arm have more severe 
symptoms than patients on the Exemestane + Placebo arm. For each 
of the four symptoms, with 162 analyzable patients on each arm in the 
study, there will be an adequate power (80%) to detect an effect size of 
0.40 and an excellent power (90%) to detect an effect size of 0.45, 
using two independent samples t test, assuming a two-sided type I 
error of 0.00625 (=0.025/4). The effect size is the difference in the 
survey score between two arms divided by the population standard 
deviation for each symptom.  
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For the fatigue assessment, the clinically minimally important 
differences (MIDs) have been estimated for the PROMIS Fatigue short 
form in advanced-stage cancer patients, which is 3.0-5.0 points and 
corresponds to effect sizes between 0.4 and 0.6356.For the 
nausea/anorexia assessment, the clinically minimally important 
differences is estimated to be 6 points using the FAACT-additional 
concerns subscale, corresponding to an effect size of 0.53. For the 
diarrhea assessment, we are planning to use the FACIT-Diarrhea 
subscale, which does not yet have published MIDs57. We propose 
using 1/2 of the standard deviation of the FACIT-D scores (this is 
comparable to an effect size of 0.5) along with a general estimate of 
0.36 points per item. Since the FACIT-D has 11 items, the estimated 
MID would be 4 points. Overall, this study should have an at least 
adequate power to detect a clinically important difference in each of 
the four symptoms, controlling the overall type I error rate at 2.5% for 
the second objective. 
9.6.2 
Analysis plan for PROs 
The analysis time for PROs endpoints is at about 40 months (24 
months of accrual + 12 months of treatment + 1 month follow up after 
treatment + 3 months of data collection and cleaning) after study 
activation. Subscale scores for all endpoints will be prorated by 
multiplying the sum of the subscale by the number of items in the 
subscale, then dividing by the number of items actually answered: 
Prorated subscale score= (sum of items cores) * (number of items in 
subscale) /(number of items answered). When there are missing data, 
prorating by subscale in this way is acceptable as long as more than 
50% of the items are answered in each subscale. For overall QOL, the 
FACT-G scale is considered to be an acceptable indicator of patient 
quality of life as long as overall item response rate is greater than 80%. 
For the four symptoms, the measurement scales (i.e., PROMIS-
Fatigue, FAACT-Additional Concerns subscale, FACIT-Diarrhea) must 
be completed over 50% of the items (e.g., 4 of 7 items, 6 of 11 items 
and 7 of 12 items) in order to consider each subscale score valid.   
Standard descriptive and graphical analyses will be used initially to 
examine missing data patterns, and to understand the relationship 
between variables. The assessment scores for the four symptoms and 
HRQL will be compared between the two treatment arms at baseline, 
month 3, month 6, month 12, at the end of protocol treatment and 4-
week post-treatment (regardless of the reasons for off treatment), 
using two independent samples t test (or Wilcoxon rank sum test58 if 
the distribution of the score is not symmetric). Change in the four 
symptoms and HRQL between month 3 visit and the baseline visit will 
be compared between the two arms using two independent sample t 
tests. Similar analyses will be conducted for each FACT-G subscales 
as well. The mean score and proportion of moderate/severe symptoms 
will be compared between treatment arms for each individual FACT-G 
item at month 3 using Wilcoxon rank sum test and Fisher exact test, 
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Mixed effect models will be constructed as another exploratory 
analysis to estimate the time profile of HRQL in the two treatment arms 
and to evaluate treatment-by-time interactions. Time will be included 
as a continuous variable if there is a linear trend in HRQL over time or 
a set of dummy variables if non-linear trend exits for HRQL. Likelihood 
ratio test will be used for model selection. Adjusted covariates included 
in the mixed effect models will include patient demographic and 
disease characteristics, such as age, ECOG PS, disease stage, prior 
therapy, et al. 
As an exploratory analysis, patient-reported outcomes will be 
correlated with PFS (prognostic value of PROs) in the study patients. 
Patients will be dichotomized (e.g., by median) and/or categorized into 
groups (e.g, quantiles) based on their HRQL at baseline and 3-month 
assessment. Kaplan-Meier method, log rank test and Cox models will 
be used to compare PFS between patients with good QOL and those 
with poor QOL in the overall patient population. The predictive value of 
QOL for benefit from entinostat therapy will be examined via the QOL-
by-treatment interaction test in a Cox model for PFS. Landmark 
method will be used when we correlate QOL at month 3 with PFS, and 
PFS will be defined as time from landmark time point to disease 
progression or death for these analyses. 
In all analyses, P-values will be two-sided. A level of 2.5% will be 
considered statistically significant for QOL comparison between two 
arms. For the four symptoms, a level of 0.625% will be considered 
statistically significant for comparison between treatment arms. For all 
other analysis, a level of 5% will be considered statistically significant. 
No adjustment will be made for multiple comparisons for individual 
FACT-G items. 
9.7 
Adherence to Protocol Therapy  
Another secondary objective of the study is to measure adherence to protocol 
therapy. Patient’s adherence to protocol therapy will be quantified using pill count 
(entinostat/placebo) and diary methods (exemestane). The number of pills a 
patient has taken will be recorded for every cycle (4 weeks). Patients will be 
instructed to bring their medication bottles (entinostat/placebo) and diaries 
(exemestane) with them for clinic visits. Clinic or pharmacy staff will count the 
number of remaining pills (entinostat/placebo) or pill diary doses taken 
(exemestane), and will calculate the number of pills taken using a treatment form. 
As administration of entinostat/placebo is weekly, it will be 0-4 doses per cycle.  
Dose reduction (from 5mg to 3mg) is allowed for entinostat/placebo due to 
toxicity in the trial. If more than two consecutive doses of entinostat/placebo, or  
> two doses of entinostat/placebo per cycle are omitted due to toxicity, the 
patient will be permanently discontinued from protocol therapy. For exemestane, 
it will be administered once daily in each cycle, it will be 0-28 pills per cycle. 
Exemestane dose reductions are not allowed. If exemestane administration is 
held for > 7 days due to any reason, patient will be considered permanently off 
protocol treatment. 
The adherence score will be calculated as the proportion of the total number of 
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number of pills a patient should have taken. The strength of doses will be taken 
into account and the reduced dose of 3mg will be counted as 0.6 full dose (5mg) 
in adherence score calculation. The timing of doses will not be considered in the 
study. Data about adherence to protocol therapy will be collected for exemestane 
and entinostat /placebo separately for each arm. The adherence score will be 
calculated for each patient for each agent (exemestane and entinostat /placebo) 
separately. For the evaluation of each agent, patients will be categorized into 3 
groups based on the adherence score. An adherence score of > 85% will be 
considered as high adherence, and an adherence score of < 65% will be 
considered as low adherence, and patients with an adherence score of 65%-85% 
will be considered as medium adherence.  
The ECOG-ACRIN Medication Adherence Scale Modified from the Morisky Index 
will be administered to understand the reasons for non-adherence to protocol 
therapy. There will be one Medication Adherence Scale form for each agent 
(entinostat /placebo and exemestane) in the study and the Medication Adherence 
Scale form will be administered at 3, 6, 12 months and at the end of treatment 
(same time with PROs assessment). 
9.7.1 
Statistical consideration for adherence  
The primary analyses for this adherence study will be conducted in 
patients on arm A who have data about adherence to entinostat. All 
300 patients on arm A will be eligible for the analysis. It is expected 
that about 80% (240) of the 300 patients on arm A will have sufficient 
data for evaluation of adherence to entinostat therapy and will be 
included in the analysis. With 240 analyzable patients on the arm A, 
the binomial exact 95% confidence interval for high adherence rate 
(defined by adherence score > 85%) to entinostat would be no wider 
than 0.13. Comparing adherence to entinostat and placebo, there is 
84% power to detect a difference in high adherence rate of 75% vs. 
86% between arms A and B, assuming a one-sided type I error rate of 
2.5%, based on the Fisher’s exact test. 
9.7.2 
Analysis plan for adherence 
The analysis time for adherence endpoint is at about 70 months after 
study activation (same time as final OS analysis). All patients who 
receive at least one dose of protocol therapy and have sufficient 
adherence data will be included in the analysis. 
The distribution of the adherence score for each agent will be 
displayed via box-and-whisker plot. The proportion of high, medium 
and low adherence to each agent will be calculated along with the 
binomial exact 95% confidence interval. The proportion of high 
adherence to entinostat and placebo will be compared between arms A 
and B using Fisher exact test. The proportion of adherence to 
exemestane will be compared between treatment arms using Fisher 
exact test as well. In addition, the adherence score for each cycle will 
be calculated for each agent and plot by treatment cycle to examine 
how adherence changes over time. The reasons for non-adherence 
will be summarized for each agent on each arm. The agreement on 
adherence level during a treatment period will be examined between 
the pill counts method and the Medication Adherence Scale method. 
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As an exploratory analysis, the association between baseline HRQL 
(categorized as good, fair, poor) and adherence to protocol therapy 
(categorized as high, medium and low adherence or dichotomized as 
good or poor) during the whole treatment period will be examined in 
each treatment arm using Fisher exact test. Multivariable logistic 
regression analysis will be conducted to identify the baseline factors 
which can predict high adherence. The covariates will include HRQL 
and other patient demographics and disease characteristics, such as 
age at diagnosis, ECOG PS, disease stage, prior therapy, et al. 
The association between adherence to protocol therapy during the 
whole treatment period (categorized as high, medium or low) and 
HRQL (continuous score) at one-month after treatment discontinuation 
will be examined using ANOVA test and linear regression analysis, 
adjusting for HRQL at baseline and other demographic and disease 
characteristics. 
Another exploratory analysis is to examine the association between the 
occurrence of toxicity in the first two cycles and adherence to 
entinostat after cycle 2 in patients on arm A. 
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9.8 
Gender and Ethnicity 
Male breast cancer accounts for approximately 1% of all breast cancers. 
Meanwhile, some elderly male patients may not be eligible or consider trials. We 
could anticipate that about 5 male patients with HR-positive, HER2-negative 
metastatic breast cancer could enroll out of a sample size of 600, and all of them 
are expected to be non-Hispanic White patients. For the 600 patients, based on 
previous data from SWOG S0226 and ECOG E2100 studies, the anticipated 
accrual in subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
44 
0 
44 
Not Hispanic or Latino 
551 
5 
556 
Ethnic Category: Total of all subjects 
595 
5 
600 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
11 
0 
11 
Black or African American 
51 
0 
51 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
533 
5 
538 
Racial Category: Total of all subjects 
595 
5 
600 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
9.9 
Study Monitoring  
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
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10. 
Imaging Study 
ECOG-ACRIN plans to bank standard practice and protocol-defined imaging studies at 
the central ACR Imaging Core Laboratory for all 600 enrolled participants. An 
independent imaging review conducted by the ACR’s Image Metrix will centrally evaluate 
imaging (only for the first-360-enrolled subjects) in relation to therapeutic response, PFS, 
OS, differences among therapeutic arms, and histologic biology. The independent 
review will be performed after quality assurance and according to standard operating 
procedures of the ACR Imaging Core Laboratory. For the ECOG-ACRIN E2112 trial, we 
plan to evaluate specific clinical data elements to associate images with treatment 
milestones. In the future, the de-identified image bank may be used for additional 
research, such as retrospective reviews of disease or software validation. Patient 
identifiers will never be included in future research and no patients will be named in 
publications related to future research. 
10.1 
Imaging Recommended Parameters and Time Points 
10.1.1 
Images provided for the independent review will consist of CT scans 
of the chest, CT or MRI scans of the abdomen and pelvis, and bone 
scans. CT of the chest and CT or MRI of the abdomen and pelvis is 
required at baseline and for follow-up assessment of known sites of 
disease or as clinically indicated. Contrast-enhanced CT (intravenous 
[IV] and oral contrast appropriate to anatomic area of coverage) is the 
preferred imaging modality for this study. If IV contrast is medically 
contraindicated for CT examination, then IV-contrast-enhanced MRI is 
the secondary imaging modality preference for abdomen/pelvis 
imaging, and non-contrast CT is the secondary imaging modality 
preference for chest imaging. 
10.1.2 
Bone scans are required at Baseline for all subjects. On-study bone 
scan submission is expected in different circumstances and 
frequencies. Bone scanning is most commonly performed utilizing a 
Technetium-99m (Tc-99m)-diphosphonate radiotracer with a standard 
gamma camera; however, 18F-Sodium Fluoride (NaF) PET/CT bone 
imaging may be performed for this requirement. Adverse reactions to 
both tracers are rare, and with the exception of a previous 
hypersensitivity reaction, there are no contraindications. 
10.1.3 
Baseline CT or MRI and bone scan will be used to define target and 
non-target lesions to define future treatment response according to 
RECIST 1.1 criteria. 
10.1.4 
If additional anatomic sites of disease are known or suspected, these 
should be imaged with the appropriate exams at each time point. 
10.1.5 
For a given subject, the modality (or combination of modality-body 
region [e.g., CT Chest, MRI Abdomen] exams) used at Baseline 
should be used consistently for all follow-up time points throughout 
the trial. 
10.1.6 
The same scanner and same acquisition and reconstruction 
parameters should be used for a given participant throughout the trial 
(both on- and off-treatment imaging). 
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10.1.7 
Image slice thickness (reconstructed) should be 5 mm or less for CT 
and MRI, and contiguous slices are preferred to those with intervening 
gaps. 
10.1.8 
The specific contrast agent utilized, dose and injection parameters 
(including time of image collection after contrast) should be consistent 
across all time points for a subject. 
10.1.9 
Subject Preparation and Subject Positioning  
For subject preparation prior to imaging, the technologist/study 
coordinator should follow the local imaging facility’s standard 
procedures taking into account guidance from the Imaging Manual. 
For image acquisition, subject positioning and comfort should follow 
the same paradigm. Refer to the study’s Imaging Manual for more 
information. 
10.1.10 
Baseline Time Point 
According to the Schedule of Assessments, CT chest, CT (or) MRI 
abdomen and pelvis and a bone scan must be acquired as close as 
possible to randomization (within 28 days prior to randomization). 
Repeat baseline imaging is not required if the CT chest, CT (or MRI) 
abdomen and pelvis and the bone scan were performed ≤ 6 weeks 
prior to study randomization. Additional sites of known or suspected 
disease should be imaged at the Baseline visit as clinically indicated. 
Baseline time point images will be assessed for image quality by 
Image Metrix within five (5) business days of receipt, barring any 
exam date identification or subject verification issues preventing 
processing.  
• 
CT 
The CT exam should be performed with a slice thickness of 5 mm or 
less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of comparable 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  
• 
MRI 
In subjects where contrast-enhanced CT is contraindicated, an MRI 
may be performed to image the abdomen and pelvis.  
• 
Bone Scans 
Bone scans should include imaging of the entire axial skeleton as well 
as at least the proximal appendicular skeleton. For Tc-99m scans, this 
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and posterior) or as a complete set of spot scintigrams. For NaF 
scanning, both the non-attenuation corrected (NAC) and attenuation 
corrected (AC) image sets as well as the corresponding low-dose CT 
should be submitted. 
10.1.11 
On-Treatment Imaging 
Following randomization into the trial, subjects will be imaged at the 
end of 12 weeks from randomization and then every 12 weeks 
thereafter until disease progression. Additionally, subjects will be 
imaged within 28 days of treatment discontinuation. 
10.1.12 
Follow-Up Imaging 
If a subject discontinues treatment due to reasons other than disease 
progression, off-treatment imaging should be performed until disease 
progression is identified by the local site on the following schedule: 
every three (3) months if the subject is < 2 years from study entry, 
every six (6) months if patient is 2-5 years from study entry, and 
annually if patient is >5 years from study entry. No specific 
requirements if patient is more than 10 years from study entry. Tumor 
assessments for all subjects should continue as per protocol even if 
dosing is interrupted. 
For some subjects, it is expected that there will be discordance in the 
determination of progressive disease between the local site and 
independent review. Consequently, there will most likely be cases 
where follow-up imaging is expected based on the independent 
reviewer’s assessment (since PD is not identified), but no imaging 
was performed given an assessment of PD at the local site. 
10.1.13 
Unscheduled and Off-Protocol Imaging 
Exams performed outside the protocol-defined visit window 
(unscheduled exams) and off-protocol imaging (e.g., FDG PET and 
radiographs) also will be submitted to the ACR Imaging Core 
Laboratory/Image Metrix. 
Table 1 illustrates when scans are required for the duration of subject 
follow-up as well as instances where scans do not need to be 
performed nor submitted to the ACR Imaging Core Laboratory/Image 
Metrix. 

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Table 1: Schedule of Assessments 
Image 
Baseline 
(within 4 weeks 
of 
randomization)1 
End of 12 weeks 
of 
randomization 
and every 12 
weeks 
thereafter 
End of Treatment2 
(within 4 weeks of 
end of treatment) 
Post-
Treatment3 
CT Chest, CT or MRI 
Abdomen/ Pelvis 
Required 
As Clinically 
Indicated 
As Clinically Indicated 
As Clinically 
Indicated 
Bone Scan 
Required 
As Clinically 
Indicated 
As Clinically Indicated 
As Clinically 
Indicated 
CT/MRI Other Body3 
As Clinically 
Indicated 
As Clinically 
Indicated 
As Clinically Indicated 
As Clinically 
Indicated 
Off-Protocol4, 5 
As Clinically 
Indicated 
As Clinically 
Indicated 
As Clinically Indicated 
As Clinically 
Indicated 
1 Repeat baseline imaging is not required if already performed ≤ 6 weeks prior to study 
randomization. 
2. Repeat any imaging not performed in ≤ the prior 28 days. 
3  If subject discontinues treatment for reasons other than disease progression, imaging is to be 
repeated until progression every three months if patient is < 2 years from study entry, every six 
months if patient is 2-5 years from study entry, and annually if patient is >5 years from study entry. 
No specific requirements if patient is more than 10 years from study entry. 
3 Imaging of anatomic regions not covered by above mentioned scans must be obtained when there 
is clinical suspicion of metastasis. Such additional scans must be consistently repeated at all time 
points if a metastatic lesion is documented. 
4  FDG-PET scans, radiographs - as clinically indicated, based on local standards of care. 
5  Ultrasound, Other - as clinically indicated, based on local standards of care. 
10.1.14 
In general, all imaging studies (including CT, MRI, PET, or any 
combination), including all phases completed, conducted for the 
subject while participating in a study will be submitted to ACR per 
instructions in Section 10.3. 
10.1.15 
In addition to the images themselves, sites must provide: 
a. De-identified imaging reports for all required scans at each 
protocol-specified time point, and 
b. Copies of any other relevant de-identified source documents 
showing evidence of measurable and/or non-measurable disease 
not captured by the imaging reports (e.g., photographs of skin 
lesions). 
10.2 
Independent Imaging Review 
The independent imaging review will be conducted only on the first 360-
participants-enrolled cohort identified for the primary endpoint analysis. 
Radiologist readers will review each case’s series of imaging studies to identify 
progression using RECIST 1.1 criteria. Independent readers will be blinded to 
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local radiologist findings. Local reads will be used to define progression for study-
related treatment decisions. 
Subject scans will be considered ready for independent image review once the 
following occurs: 
• 
Applicable Baseline clinical data available; and 
• 
Baseline and one on-study time point available and acceptable; and 
• 
Subject has completed all imaging visits; or 
• 
Subject is off-treatment; or 
• 
Sponsor (or designee)-defined cutoff, if applicable. 
For each subject, the time point-by-time point imaging response evaluation will 
be performed by two (2) independent, qualified, and approved radiologist 
reviewers in a sequential locked-read paradigm. Neither primary reviewer will 
have access to the other reviewer’s annotations or tumor response data.  
Baseline clinical data, if applicable, will be provided. 
10.3 
Images Submission 
Imaging exams required for each time point for the first 360 enrollees are to be 
submitted to the ACR Imaging Core Laboratory/Image Metrix. Baseline images 
should be submitted within five (5) business days of registration and follow-up 
images within five (5) business days after image acquisition. This is a request of 
sites. It is the investigational site’s responsibility to ensure complete and timely 
collection of imaging and non-imaging data for submission to the core lab/Image 
Metrix. Imaging exams for all 600 subjects will be submitted to the ACR Imaging 
Core Laboratory, but rigid submission timeline may be looser than five (5) days 
after the first-360 subject cohort. 
For each individual time point, the investigational site (or imaging facility) 
personnel will submit images in standard DICOM format along with a completed 
Image Transmittal WebForm/Worksheet (ITW). All images must be submitted in 
DICOM format. 
There are two (2) methods for subject image submission: 
• 
TRIADTM: Electronic submission utilizing software provided by Image Metrix 
• 
Media (DVD/CD), using a trackable courier (not recommended) 
There are two (2) methods for ITW completion and submission: 
• 
Electronically, utilizing ACR Image Metrix’s Clinical Conductor Enterprise 
(CCE); 
• 
Using a paper ITW form and submitting via courier or email. 
Clinical sites/imaging facilities will submit subject images to Image Metrix via 
electronic submission through TRIAD or on hard-copy media (CD) via a trackable 
courier. Clinical sites/imaging facilities will submit ITWs for subject images via 
electronic submission through CCE or as hard-copy (paper) via a trackable 
courier or via fax/email. 
Regardless of the submission method employed by the site, all subject images 
are routed through TRIAD and all ITW information maintained in CCE. 
TRIAD® is ACR’s proprietary image exchange application that will be used as the 
sole method of data transfer to the ACR Clinical Research Center Core 
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Laboratory for this trial. ACRIN will provide installation on one or several 
computers of choice within the institutional “firewall” and on the institutional 
network; internet access is required. The TRIAD application can then be 
configured as a DICOM destination on either scanner(s) and/or PACS system for 
direct network transfer of study related images into the TRIAD directory. When 
properly configured, the TRIAD software de-identifies, encrypts, and performs a 
lossless compression of the images before they are transferred to the ACRIN 
image archive in Philadelphia. Once equipment-readiness has been determined, 
imaging personnel from ACRIN will coordinate installation and training for the 
software. 
For more information, contact:  
TRIAD-support@phila.acr.org or call 703-390-9858. 
If images are submitted to the ACR Imaging Core Laboratory on media, subject 
personal identifiers must be removed by the investigational site prior to 
submission. To promote the de-identification of all personal identifier information, 
the sites are instructed to make specific DICOM-tag replacements, which will be 
inserted into the DICOM header wherever personal information exists. The 
DICOM tag replacement guidelines are included in the Imaging Manual. If the 
site/imaging facility submits a CD with personal identifiers intact, the CD will be 
returned to the site with a query requesting resubmission with prior de-
identification, as per the Informed Consent Form for this study. 
De-identified media will be submitted to: 
American College of Radiology Independent Review Facility 
Attn: ECOG-ACRIN 2112 
1818 Market Street 17th floor Suite 1720 
Philadelphia, PA 19103 
Phone: 215-574-3150 
Fax: 215-717-2764 
 
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11. 
Biological Sample Submissions 
Whole blood is to be submitted from consenting patients for laboratory research studies 
and/or future undefined research. These studies are defined in Section 12. Tumor tissue 
(primary and metastatic) is to be submitted from consenting patients for future undefined 
research. Plasma samples are to be submitted for population pharmacokinetic studies 
as defined in Section 11.4. 
The IRB approved consent must allow patients the option to provide samples for use in 
the optional laboratory research studies and/or for undefined future research studies. 
Logging and tracking of sample submissions: It is required that all samples 
submitted on this trial be entered and tracked using the ECOG-ACRIN Sample Tracking 
System (see Section 11.5). An STS shipping manifest form is to be included with every 
submission. 
Labeling of samples: All samples must be labeled clearly with the ECOG-ACRIN 
protocol number (E2112), ECOG-ACRIN patient sequence number, patient’s initials, 
date and time of collection, time point, and sample type (e.g. primary tumor, PB citrate 
CPT). 
11.1 
Sample Collection and Submission Schedule 
Samples are to be submitted as follows: 
• 
Pathology samples are to be submitted to the ECOG-ACRIN CBPF within 
one (1) month following randomization. See Section 11.3. 
• 
Whole blood samples (for future undefined research) are to be submitted to 
the ECOG-ACRIN CBPF as outlined in Section 11.3 on the day of collection. 
Samples are to be collected at the following time point: 
− 
Baseline [after randomization, prior to start of treatment] 
• 
Whole blood samples (for laboratory research studies) are to be submitted to 
the Trepel Laboratory as outlined in Section 12.2 on the day of collection. 
Samples are to be collected at the following time points: 
− 
Baseline [within two (2) days prior to start of treatment] 
− 
Cycle 1, Day 15 [two (2) weeks after initiating therapy, prior to 
entinostat/placebo] 
NOTE: 
Do not start treatment on Fridays as the baseline and day 15 
blood collections cannot be shipped on Fridays. 
• 
Plasma samples are to be submitted for population pharmacokinetic studies 
to Covance Central Laboratory Services as outlined in Section 11.4 per 
patient consent. Samples are to be collected at the following time points: 
• 
Cycle 1, Day 1 [two samples drawn at least 2 hours apart, 2-5 hours 
after dosing] 
• 
Cycle 1, Day 15 [one sample drawn 1 hour after dosing] 
• 
Within 72 hours prior to the start of Cycle 2 
11.2 
Submissions to Trepel Laboratory 
Kits for the collection and shipment of the blood samples are ordered online from 
Cenetron Central Laboratories. Instructions are provided in Appendix VI. 
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Questions regarding kits can be directed to projectmanagement@cenetron.com 
or call the Cenetron Clinical Trials group at (512) 439-2000. Kits must be ordered 
after the patient has been registered to the trial and will generally arrive within 
three (3) business days from when the order was placed. A single kit will contain 
three “sub-kits” with all supplies for the collection and shipment of the three blood 
samples to be collected. 
Whole blood samples should be shipped the day they are drawn. If you have any 
questions concerning blood sample collection and shipment, please contact Min-
Jung Lee at leemin@mail.nih.gov or Jane Trepel at trepelj@mail.nih.gov or by 
phone at (240) 760-6330. 
Submit from patients who answer “Yes” to “I agree to participate in the laboratory 
research studies that are being done as part of this clinical trial.” 
11.2.1 
Sample Preparation Guidelines 
Whole blood samples are to be collected prior to start of treatment 
and on cycle 1, day 15 and are to be shipped at ambient temperature 
the day they are drawn (do not freeze) with cool packs during hot 
season. 
Draw 8mL of whole blood into one (1) blue/black CPT citrate tube 
(provided in kit) at each time point. Mix gently by inverting tube 
several times. Ship day of collection. 
Please completely fill CPT citrate tube as full as possible. 
NOTE: 
Do not start treatment on Fridays as the baseline and day 
15 blood collections cannot be shipped on Fridays. 
11.2.2 
Shipping Procedures 
Blood samples should be mailed the day they are obtained and 
shipped FedEx overnight priority to arrive during normal working 
hours.  
Ship using the CBPF's FedEx account using the FedEx on-line Ship 
Manager. 
Access to the shipping account can only be obtained by logging into 
fedex.com with an account issued by the ECOG-ACRIN CBPF. For 
security reasons, the account number will no longer be given out in 
protocols, over the phone, or via email. If your site needs to have an 
account created, please contact the ECOG-ACRIN CBPF by email at 
eacbpf@mdanderson.org. 
The laboratory is open to receive shipments Monday through Friday.  
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE AVOIDED.  
The link to the holiday closures for the laboratory: 
http://www.opm.gov/policy-data-oversight/snow-dismissal-
procedures/federal-holidays/ 
NOTE: 
International institutions should contact the laboratory to 
discuss processing and shipping guidelines. 
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Ship to: 
Trepel Laboratory  
Preclinical Development Research Core, NCI, NIH 
Building 10, Room 12C208 
10 Center Drive 
Bethesda, MD 20892 
Phone: (240) 760-6330 
Please e-mail Min-Jung Lee at leemin@mail.nih.gov and Jane Trepel 
at trepelj@mail.nih.gov to notify the laboratory when the patient is 
scheduled and when the blood is shipped. Indicate the ECOG-ACRIN 
protocol number, FedEx tracking number, and site contact 
information. 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
11.3 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
Submit blood and tissue samples for future undefined research to the CBPF from 
patients who answer “Yes” to “I agree to provide additional specimens for 
research”. 
If you have any questions concerning sample collection and shipment, please 
contact the CBPF at 1-844-744-2420 or eacbpf@mdanderson.org. 
11.3.1 
Tissue Submissions 
Submitting pathologist and clinical research associate may refer to 
Appendix I, which outlines the Pathology Submission Guidelines.  
The tissue samples are to be labeled with the Pathology ID as well as 
the information above.  
11.3.1.1 
Required Materials 
Forms: Must be submitted with all tissue submissions. 
• 
STS generated shipping manifest form 
• 
Copy of the surgical pathology report 
Pathology Submissions:  
• 
Representative primary tumor diagnostic formalin 
fixed paraffin embedded [FFPE] tumor tissue block 
• 
Representative metastatic tumor diagnostic formalin 
fixed paraffin embedded [FFPE] tumor tissue block 
NOTE: 
If blocks are unavailable for submission, 
cores and slides are to be submitted. All 
cores and slides must be adequately 
labeled, with slides numbered sequentially 
in the order cut. Alternative submission 
requirements: 
− One (1) H&E slide, and  
− Twenty (20) 4 µm unstained air-dried 
plus slides, and 
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− One (1) or more core punches (minimum 
of 4mm diameter). If core punch tool is 
unavailable, request core punch kit from 
the ECOG-ACRIN CBPF at 1-844-744-
2420. Adequately label every slide and 
core submitted. 
If these criteria cannot be met, please contact the ECOG-
ACRIN CBPF (eacbpf@mdanderson.org) to obtain 
alternative submission requirements. 
11.3.2 
Blood Submissions 
Kits for the collection and shipment of the blood samples are ordered 
online from Cenetron Central Laboratories. Instructions are provided 
in Appendix VI. Questions regarding kits can be directed to 
projectmanagement@cenetron.com or call the Cenetron Clinical 
Trials group at (512) 439-2000. Kits must be ordered after the patient 
has been randomized to the trial and will generally arrive within three 
(3) business days from when the order was placed. A single kit will 
contain three “sub-kits” with all supplies for the collection and 
shipment of the three blood samples to be collected. 
Whole blood samples are to be collected at baseline, after 
randomization, prior to start of treatment. 
Draw 8mL of whole blood into one (1) ACD yellow top tube (provided 
in the kit). Mix gently by inverting tube several times. 
11.3.3 
Shipping Procedures 
Pathology materials are to be shipped at ambient temperature within 
one (1) month following patient randomization.  
Blood samples are to be shipped the day of collection via overnight 
delivery at ambient temperature (do not freeze) with cool packs during 
hot season.   
Friday shipments are ill advised, similarly shipping before a long 
holiday is often problematic. The laboratory is closed Saturday, 
Sunday and holidays. 
Ship using the CBPF's FedEx account using the FedEx on-line Ship 
Manager. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Toll Free Phone: 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
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Access to the shipping account for shipments to the CBPF can only 
be obtained by logging into fedex.com with an account issued by the 
CBPF. For security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. If your site needs 
to have an account created, please contact the CBPF by email at 
eacbpf@mdanderson.org. 
11.4 
Submissions to Covance Central Laboratory Services for Population 
Pharmacokinetics [OPTIONAL] 
Plasma samples are to be collected at the following time points per patient 
consent: 
• 
Cycle 1, Day 1 [two samples drawn at least 2 hours apart, 2-5 hours after 
dosing] 
• 
Cycle 1, Day 15 [one sample drawn 1 hour after dosing] 
• 
Within 72 hours of the start of Cycle 2 
Collection and shipping kits are available and will contain the materials 
necessary for the preparation and shipment of the plasma samples, including 
tubes, labels, shippers, preprinted air bills, and bar-coded requisition forms. 
To obtain starter kits and the Site Laboratory Instruction Manual please Email or 
Fax Appendix IX E2112 Covance Site Information/Initial Kit Order Form to 
Syndax. Please note Covance requires ten (10) days to process the form and 
ship out the initial kits. 
Covance will ship out three (3) initial kits upon receipt of the above form. Once 
Covance receives two (2) of the kits, they will send out an auto-resupply of one 
(1) kit. If you require more kits than provided through the auto-resupply, please 
contact Covance directly at the number provided in the Site Laboratory 
Instruction Manual. Shipment usually takes about five (5) to seven (7) business 
days. Please refer to the Site Laboratory Instruction Manual provided in the initial 
kits for details on Specimen Collection, Processing, Packaging, and Shipping 
Guidelines. 
If you have any questions concerning plasma sample collection and shipment 
please refer to the contact information provided in the Site Laboratory Instruction 
Manual for the Covance Site Support Group. 
The exact date and time of entinostat/placebo administration and of PK plasma 
sample collection must be entered into the ECOG-ACRIN Sample Tracking 
System, and provided with the documentation submitted with the plasma 
samples. 
11.5 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
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Important: Any case reimbursements associated with specimen submissions will 
not be credited if specimens are not logged into STS. Additionally, please note 
that the STS software creates pop-up windows, so you will need to enable pop-
ups within your web browser while using the software. A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html.   
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.  
Study Specific Notes 
The exact date and time of entinostat/placebo administration and of PK plasma 
sample collection must be entered into the ECOG-ACRIN Sample Tracking 
System, and provided with the documentation submitted with the plasma 
samples. 
Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. Indicate the appropriate 
Lab ID# on the submission form: 
• 
ECOG-ACRIN CBPF 
• 
Trepel Laboratory 
• 
Covance Central Laboratory Services 
NOTE:  
Covance Central Laboratory Services will not be utilizing the STS to 
confirm receipt. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
11.6 
Reimbursements for Population Pharmacokinetic Plasma Sample Submissions 
11.6.1 
Institutional Reimbursements 
To offset research-related costs associated with the collection and 
submission of the plasma samples at the four time points outlined 
above in Section 11.4, institutions are eligible to receive 
reimbursements. Please see the Funding Sheet for further details. 
Plasma samples must be collected and submitted to trigger payment. 
Receipt of the plasma samples will be verified prior to the release of 
funds. 
NOTE: 
Neither patients nor their insurance companies are to be 
billed for the collection or submission of the 
pharmacokinetic plasma samples. 
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Distribution of the reimbursements requires: 
• 
Submission of the required pharmacokinetic plasma samples 
using the ECOG-ACRIN Sample Tracking System (STS) [Refer to 
Section 11.5 for STS requirements] 
• 
Receipt and verification of the plasma samples by Covance 
Central Laboratory Services 
11.6.2 
Patient Vouchers 
Vouchers will be distributed to institutions for use by the patients to 
off-set expenses incurred during the 2-5 hour time period of the cycle 
1, day 1 pharmacokinetic plasma sample collections. Vouchers will be 
sent to the contact person and institutional shipping address provided 
in OPEN. 
Vouchers are being provided by Syndax. 
11.7 
Use of Specimens in Research  
Blood will be distributed to investigators for the laboratory research studies 
defined in Section 12.  
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies will be retained in an ECOG-
ACRIN designated central repository.  
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA 
and plasma (if appropriate) will be isolated from the submitted peripheral blood 
specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
Residuals/derivatives from the plasma samples submitted for the population 
pharmacokinetic studies will not be retained for future research studies. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site. All 
other specimens will be destroyed per guidelines of the respective repository. 
11.8 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of samples forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office – Boston. 
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12. 
Correlative Studies 
The results of these studies are for the purposes of the trial only and will not be returned 
to the site or reported to the patient. 
12.1 
Acute Change in Protein Lysine Acetylation as a Predictor of Benefit from 
Entinostat 
This analysis will be performed in the laboratory of Dr. Jane Trepel at NCI/NIH 
(See Section 12.2). Protein lysine acetylation will be measured by multiparameter 
flow cytometry in peripheral blood mononuclear cells (PBMCs; CD19+ B cells, 
CD3+ T cells, and CD14+ monocytes). Dr. Trepel and her team have developed 
and published the method to be utilized to perform this correlative analysis, which 
includes determination of the stability of acetylation in PBMC samples64. In 
addition the team has been coauthors on four clinical trials, including ENCORE 
301, in which the flow cytometric pharmacodynamic assay has been 
performed65,66,67,68. 
Peripheral blood mononuclear cells (PBMCs) offer an opportunity to assess 
pharmacodynamic effects of entinostat and to correlate the observed effects with 
breast cancer outcome. In PBMCs, the effects of entinostat will be measured by 
global protein acetylation using multi-parameter flow cytometry. 
We hypothesize that patients with increased protein lysine acetylation in the two 
weeks after initiating therapy will have a prolonged PFS compared to those 
without changes in protein lysine acetylation. 
To briefly review, ENCORE 301 collected PBMCs for assessment of lysine 
acetylation prior to therapy, and post-therapy on Days 8 and 15 using an assay 
developed by the Trepel Laboratory, NCI/NIH. Protein lysine acetylation in the 
combined therapy subgroup was associated with a striking improvement in PFS 
across all cell types. In EE-treated hyperacetylators versus those with acetylation 
below the median, median PFS was 8.5 versus 2.7 months (HR=0.32, 95% CI 
0.13, 0.79) (B cells); 6.6 versus 3.6 months (HR=0.44, 95% CI 0.18, 1.08) (T 
cells); and 6.2 versus 3.6 months (HR=0.50, 95% CI 0.21, 1.20) (monocytes).  
We will use the identical methodology, central laboratory (Trepel Laboratory, 
NCI/NIH), and timing (Day 15) for the acetylation studies planned in E2112. 
While our data will not independently contribute to the validation effort, it will 
further expand the pharmacodynamic data and add measurably to our 
interpretation of the clinical data. 
12.2 
Population Pharmacokinetics 
The population pharmacokinetic analysis for entinostat will be used to describe 
the pharmacokinetics of entinostat in patients and to assess the effects of patient 
factors on the entinostat pharmacokinetics. Specific details for this analysis will 
be provided in a separate population pharmacokinetic analysis plan. 
12.3 
Future Research Studies 
The following correlative studies are proposed as outlined below. Final analysis 
of the proposed studies requires the results of the parent study. When sufficient 
information is available from the parent study a full correlative science proposal 
or amended protocol document detailing the scientific hypothesis, research plan, 
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assay methods for use of the biospecimens, and a formal statistical analysis plan 
with adequate power justification will be submitted to and reviewed by CTEP.  
12.3.1 
Pharmacogenomics 
Genomic DNA isolated from whole blood at baseline can be used to 
genotype candidate genes that may affect pharmacodynamic effects 
of response and toxicity. We will store the sample obtained at 
baseline for potential future analyses in the event that further 
information becomes available from the literature about promising 
candidate genes that may predict response to exemestane and/or 
entinostat. 
12.4 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
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13. 
Electronic Data Capture 
Please refer to the E2112 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
13.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
15. 
References 
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30. Kelly WK, Richon VM, O'Connor O, et al. Phase I clinical trial of histone deacetylase 
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32. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in 
patients with persistent, progressive, or treatment refractory cutaneous T-cell 
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33. Luu TH, Morgan RJ, Leong L, et al. A phase II trial of vorinostat (suberoylanilide 
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34. Tabe Y, Konopleva M, Kondo Y, al e. Effects of histone deacetylase inhibitor 
suberoylanilide hydroxamic acid (SAHA) and DNA methylation inhibitor 5-aza-2'-
deoxycytidine (DAC) on the transcriptional activation of RAR and p21WAF in acute 
promyelocytic leukemia cells. Blood 2002;44:3028. 
35. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA 
methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem 
Anti-Canc Agents 2003;3:187-99. 

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Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
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36. Di Gennaro E, Bruzzese F, Romano G, al e. Antitumor effect of histone deacetylase 
inhibitor SAHA alone and combined with cytotoxic drugs in human colorectal cancer 
cells. Proc Am Assoc Cancer Res 2003; 44:A3636. 
37. Munster PN, Marchion D, Thomas S, et al. Phase I trial of vorinostat and doxorubicin 
in solid tumours: histone deacetylase 2 expression as a predictive marker. Br J 
Cancer 2009;101:1044-50. 
38. He LZ, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission 
in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 
2001;108:1321-30. 
39. Hodges-Gallagher L, Valentine CD, Bader SE, Kushner PJ. Inhibition of histone 
deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer 
cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res 
Treat 2007;105:297-309. 
40. Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase 
inhibitor vorinostat combined with tamoxifen for the treatment of patients with 
hormone therapy-resistant breast cancer. Br J Cancer;104:1828-35. 
41. Ordentlich P. Pharmacodynamic analysis of ENCORE 301, a placebo-controlled, 
randomized phase 2 study of exemestane with and without entinostat in 
postmenopausal ER+ breast cancer patients demonstrates an association of lysine 
hyperacetylation with clinical outcome. In: AACR Molecular Targets Conference 
(abstract PR-6); 2011. 
42. Mohla S, Stearns V, Sathyamoorthy N, Rosenfeld MG, Nelson P. The biology of 
hormone refractory breast and prostate cancer: An NCI workshop report. Cancer Biol 
Ther 2009;8:1975-85. 
43. Juergens RA, Wrangle J, Vendetti FP, et al. Combination Epigenetic Therapy Has 
Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer. Cancer 
Discovery 2011. Epub ahead of print. November 9, 2011; DOI:10.1158/2159-
8290.CD-11-0214. 2011. 
44. Pili R, Salumbides B, Zhao M, et al. Phase I study of the histone deacetylase 
inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid 
tumours. Br J Cancer 2011;106:77-84. 
45. Stathis A, Hotte SJ, Chen EX, et al. Phase I study of decitabine in combination with 
vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. 
Clin Cancer Res 2011;17:1582-90. 
46. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-
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47. Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009;28:739-61. 
48. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III 
study of fulvestrant and anastrozole in combination compared with anastrozole alone 
as first-line therapy for patients with receptor-positive postmenopausal breast cancer. 
J Clin Oncol 2012;30:1919-25. 
49. Freidlin B, Korn EL, Gray R. A general inefficacy interim monitoring rule for 
randomized clinical trials. Clin Trials 2010;7:197-208. 

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Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
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50. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika, 
1983; 70 (3); p. 659-63. 
51. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
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52. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. 
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53. Cox DR. Regression models and life tables (with discussion). Journal of the Royal 
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55. Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin 
Oncol 1983;1:710-9. 
56. Yost KJ, Eton DT, Garcia SF, Cella D. Minimally important differences were 
estimated for six Patient-Reported Outcomes Measurement Information System-
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57. Yost KJ, Cella D, Chawla A, et al. Minimally important differences were estimated for 
the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using 
a combination of distribution- and anchor-based approaches. J Clin Epidemiol 
2005;58:1241-51. 
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1945. 
59. Cella D, Fallowfield L, Barker P, Cuzick J, Locker G, Howell A. Quality of life of 
postmenopausal women in the ATAC ("Arimidex", tamoxifen, alone or in 
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cancer. Breast Cancer Res Treat 2006;100:273-84. 
60. Wagner LI, Zhao F, Chapman JA, . Patient-reported predictors of treatment 
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presentation at the 34th Annual San Antonio Breast Cancer Symposium. Abstract: 
Cancer Research. 2011;71(24):S6. 
61. Ribaudo JM, Cella D, Hahn EA, et al. Re-validation and shortening of the Functional 
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versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall 
survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 
2013 May;14(6):552-62. 
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Motzer R. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell 
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64. Chung EJ, Lee S, Sausville EA. et al. Histone deacetylase inhibitor 
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Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
112 
65. Yardley DA, Ismail-Khan RR, Melichar B. et al. Randomized Phase II, Double-Blind, 
Placebo-Controlled Study of Exemestane With or Without Entinostat in 
Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-
Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase 
Inhibitor. JCO published online on May 6, 2013; DOI:10.1200/JCO.2012.43.7251. 
66. Giaccone G, Rajan A, Berman A. et al. Phase II study of belinostat in patients with 
recurrent or refractory advanced thymic epithelial tumors. J. Clin. Oncol. 29:2052-
2059, 2011. 
67. Gojo I, Jiemjit A, Trepel JB. et al. Phase 1 and pharmacologic study of MS-275, a 
histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. 
Blood 109:2781-2790, 2007. 
68. Kummar S, Gutierrez M, Gardner ER. et al. Phase I trial of MS-275, a histone 
deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid 
malignancies. Clin. Cancer Res. 13:5411-5417, 2007. 
69. Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication 
adherence measure in an outpatient setting. J Clin Hypertens (Greenwich). 
2008;10(5):348-54. PMCID: 2562622. 
70. Muntner P, Joyce C, Holt E, He J, Morisky D, Webber LS, et al. Defining the minimal 
detectable change in scores on the eight-item Morisky Medication Adherence Scale. 
Ann Pharmacother.45(5):569-75. 
71. Hay, J.L., Atkinson, T.M., Reeve, B.B., Mitchell, S.A., Mendoza, T.R., et al. Cognitive 
interviewing of the US National Cancer Institute's Patient-Reported Outcomes 
version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). 
Qual Life Res 2013;1-13. 
72. Rini B et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal 
cell carcinoma (AXIS): a randomized phase 3 trial, Lancet 2013. 
73. Yost et al. Validation of the Functional Assessment of Cancer Therapy-Breast 
Symptom Index (FBSI).Breast Cancer Res Treat. 2005; 90 (3):295-298. 
74. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology (NCCN Guidelines): Breast cancer. Version1.2014. Available at: 
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.  

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A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
114 
Guidelines for Submission of Pathology Materials 
E2112 A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in 
Patients with Hormone Receptor-Positive Advanced Breast Cancer 
Instructions: 
1. Pathology submissions: 
• 
Representative primary tumor FFPE block 
• 
Representative metastatic tumor FFPE block 
NOTE: If blocks are unavailable for submission, cores and slides are to be 
submitted. All cores and slides must be adequately labeled, with slides 
numbered sequentially in the order cut. Alternative submission 
requirements: 
− 
One (1) H&E slide, and  
− 
Twenty (20) 4 µm unstained air-dried plus slides, and 
− 
One (1) or more core punches (minimum of 4mm diameter). If core 
punch tool is unavailable, request core punch kit from the ECOG-
ACRIN CBPF (1-844-744-2420). Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
2. The following items are to be included with the pathology materials. 
• 
Copy of the surgical pathology report and surgical procedure report.  
• 
STS generated shipping manifest form 
NOTE:  
Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be 
provided. The information will be used only to identify patient materials, 
for interactions between the ECOG-ACRIN CBPF, the central testing 
laboratory and the site, and will help to expedite any required 
communications with the institution (including site pathologists). 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility MD Anderson Cancer 
Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any 
problems in submitting the required pathology material, contact the Pathology 
Coordinator at the ECOG-ACRIN CBPF by telephone 1-844-744-2420, by fax (713) 563-
6506, or by email eacbpf@mdanderson.org. 
 
 
Rev.4/15 
Rev. 10/16 
Rev. 9/17 

 
115 
MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for E2112: A Randomized Phase III 
Trial of Endocrine Therapy plus Entinostat/Placebo in Patients with 
Hormone Receptor-Positive Advanced Breast Cancer. 
 
A patient has been entered onto an ECOG-ACRIN protocol by 
_____________________________ (ECOG-ACRIN Investigator). This protocol requires 
the submission of pathology materials for banking for future undefined research. 
Return the surgical pathology report(s), the slides and/or blocks and any other required 
material to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology material to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF). 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN CBPF for 
undefined future research studies. Paraffin blocks will be returned upon written request 
for purposes of patient management. If you have any questions regarding this request, 
please contact the ECOG-ACRIN CBPF at 1-844-744-2420, or by fax (713) 563-6506. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 
Rev.4/15, 
10/15 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
116 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
117 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
118 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix III 
 
Patient Pill Calendar 
NOTE TO SITES: 
Local study teams may use a different calendar format as long as 
all drug dates/doses are recorded for study reporting/data 
completion.  These should be shared with the Protocol 
Chair/Study Liaison, and approved by local IRBs per local 
guidelines, prior to use. 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. If you forget, the missed pills will not be taken later. 
3. Please bring the empty bottle or any leftover tablets and your  
pill calendar to your next clinic visit. 
 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
119 
Patient Pill Calendar-Exemestane and Entinostat/Placebo 
This is a calendar on which you are to record the time and number of pills you take each day for 
the study. You should take your scheduled dose of each pill. If you develop any side effects, 
please record them and anything you would like to tell the doctor in the space provided.  
Instructions: 
Exemestane: 
 
Take by mouth once every day with food. 
 
 
Dose of each pill:  25 mg 
 
 
Number of pills to take at each dose:  1 
Total dose to take each day:  25 mg 
 
Entinostat/Placebo:  
Take by mouth once each week on an empty stomach (either 1 hour 
before and 2 hours after meals). 
 
 
Dose of each pill:  _____ 
 
 
Number of pills to take at each dose:  _____ 
 
 
Total dose to take each week:  _____ 
Please bring this study diary/calendar and your bottle of entinostat/placebo to each study visit. 
 
CYCLE 
DAY 
Date 
Exemestane 
Entinostat/ 
Placebo 
Use the space below to make 
notes about things you would 
like to tell the doctor (including 
unusual symptoms you 
experience, other medicine you 
have taken and anything else 
you think would be of interest.) 
(Month / Day / Year) 
# pills 
Time 
# pills 
Time 
1 
 
 
 
1 
 
 
 
 
2 
 
 
 
1 
 
 
 
3 
 
 
 
1 
 
 
 
4 
 
 
 
1 
 
 
 
5 
 
 
 
1 
 
 
 
6 
 
 
 
1 
 
 
 
7 
 
 
 
1 
 
 
 
8 
 
 
 
1 
 
 
 
 
9 
 
 
 
1 
 
 
 
10 
 
 
 
1 
 
 
 
11 
 
 
 
1 
 
 
 
12 
 
 
 
1 
 
 
 
13 
 
 
 
1 
 
 
 
14 
 
 
 
1 
 
 
 
15 
 
 
 
1 
 
 
 
 
16 
 
 
 
1 
 
 
 
17 
 
 
 
1 
 
 
 
18 
 
 
 
1 
 
 
 
19 
 
 
 
1 
 
 
 
Rev.10/16 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
120 
 
CYCLE 
DAY 
Date 
Exemestane 
Entinostat/ 
Placebo 
Use the space below to make 
notes about things you would 
like to tell the doctor (including 
unusual symptoms you 
experience, other medicine you 
have taken and anything else 
you think would be of interest.) 
(Month / Day / Year) 
# pills 
Time 
# pills 
Time 
20 
 
 
 
1 
 
 
 
21 
 
 
 
1 
 
 
 
22 
 
 
 
1 
 
 
 
 
23 
 
 
 
1 
 
 
 
24 
 
 
 
1 
 
 
 
25 
 
 
 
1 
 
 
 
26 
 
 
 
1 
 
 
 
27 
 
 
 
1 
 
 
 
28 
 
 
 
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ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
121 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix IV 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b.  Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c.  Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
122 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6.  Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date 
of receipt for review. Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
123 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
124 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix VI 
 
E2112 Collection and Shipping Kit Order Instructions 
As of February 12, 2016 Specimen Collection/Shipping Kits are provided by CENETRON 
CENTRAL LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made AFTER patient randomization. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call the 
Cenetron Clinical Trials Group at 512-439-2000. 
Ordering process: 
• 
At time of patient randomization, provide the contact for kit ordering in OPEN 
• 
Following randomization of the patient to the trial, Go to the website www.cenetron.com and 
Click on the “Order Kits” button at the top right. It is recommended that kits be ordered same 
day as patient randomization. 
• 
The Order Form is not study specific and can be used for any study. Complete the online 
form as follows 
• 
Sponsor (REQUIRED): ECOG-ACRIN 
• 
Contact Name (REQUIRED): Name of the site’s kit contact. Should match the name of 
the individual provided in OPEN as the kit contact 
• 
Protocol Number (REQUIRED): E2112 
• 
Phone Number (REQUIRED): Phone number of the kit contact. Please insure that this 
is a number that can be reached from an external caller. 
• 
FAX Number: Fax number of the kit contact 
• 
Investigator: Last name of the kit contact is adequate 
• 
Email (REQUIRED): The email of the site’s kit contact. Must be entered twice to confirm 
• 
Date Supplies Needed (REQUIRED): Add 3 business days or more to order date. E.g. 
if ordering on 2/5/2016, indicate 2/10/2016 to accommodate the weekend. Reminder that 
holidays must also be considered in this timeline. 
• 
KIT NAME (required):  E2112 Collection Kit 
• 
Quantity: 1 
• 
Comments: Provide E2112 Case ID and full shipping address 
• 
“Patient case ID =” ##### 
• 
Ship kit to Name of the individual to whom the kit is shipped. May be different than 
the kit contact provided above. 
• 
Full street address, town, state and zip code 
• 
Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN case number and 
complete shipping address. If information is missing kit processing will be delayed. 
Rev.10/16 
Rev. 9/17 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
125 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix VII 
 
E2112 Mandatory Participating Site Training Form 
Protocol Number 
E2112 
Protocol Name 
A Randomized Phase III Trial of Endocrine Therapy Plus Entinostat/Placebo 
in Patients with Hormone Receptor-Positive Advanced Breast Cancer 
Instructions for Mandatory Participating Site Training Course: 
• 
Each site participating in E2112 is required to have at least one person (i.e. research 
coordinator or investigator, etc) from the research staff complete ECOG-ACRIN’s E2112 
mandatory participating site training course. 
• 
This course must be completed PRIOR to the first patient enrollment for the site.   
• 
An ENROLLMENT BLOCK is in place within the OPEN system which will prevent the site 
from enrolling patients until this training requirement is complete.   
• 
Please note that ECOG-ACRIN recommends all research staff (CRAs, Data Managers, 
Imaging Staff, Investigators, Pharmacy Staff, etc) involved in E2112 complete the training 
course. 
The training course is available 24/7 via the following URL: 
http://coccg.mindflash.com/PublicCoursePage.aspx?c=832897692 
Please complete the bottom of this form and submit it directly to the CTSU Regulatory Office 
via Fax: 215-569-0206 or Email: CTSURegulatory@ctsu.coccg.org. 
Section A:  
Please provide the name of one of the individuals who completed the E2112 
mandatory participating site training course. 
Name 
CTEP ID (Associate or Investigator) 
Section B:  
Please provide ALL Site Name(s) and Site CTEP IDs where the research staff 
that completed this course may enroll a patient to E2112: 
Site Name 
Site CTEP ID (example: AL000) 
Section C:  Please complete.   
_______________________________ 
Name 
_______________________________ 
Signature 
_______________________________ 
Date 
Thank you for your participation.

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
126 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix VIII 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive 
pregnancy test regardless of age or disease state) of a female patient while she is on 
Entinostat/Placebo, or within 3 months of the patient’s last dose of Entinostat/Placebo 
must be reported in an expeditious manner. The outcome of the pregnancy and neonatal 
status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERs) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 
24-hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, 
puerperium and perinatal conditions – Other (pregnancy)” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event. 
• 
The start date of the pregnancy should be reported as the calculated date of 
conception. 
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report. 
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status via CTEP-AERs. 
• 
The decision on whether an individual female patient can continue protocol treatment 
will be made by the site physician in collaboration with the study chair and ECOG-
ACRIN Operations Office – Boston. Please contact the ECOG-ACRIN Operations 
Office – Boston to ask for a conference call to be set up with the appropriate 
individuals. 
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and 
counseling. 
Rev.10/15 
Rev.10/16 
Rev. Add5 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
127 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-
AERs report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-
AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  
For assistance in recording the grade or category of these events, please contact the 
CTEP AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be 
discussed on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERs as Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life 
occurring during the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention. However, for this protocol, any 
neonatal death that occurs within 28 days of birth, without regard to causality, must be 
reported via CTEP-AERs AND any infant death after 28 days that is suspected of being 
related to the in utero exposure to Entinostat/Placebo must also be reported via CTEP-
AERs. 
It must be reported via CTEP-AERs as Grade 4 “Death neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf) 
Rev. Add7 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
128 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
Appendix IX 
 
E2112 Covance Site Information/Initial Kit Order Form 
***If your site is not participating in the optional population PK study, this form is not 
required*** 
Please complete this form for the initial shipment of three (3) kits and the Site Laboratory 
Instruction Manual. Covance requires ten (10) days to process this form and ship out the initial 
kits. Please complete and Email this form to Syndax (E2112@Syndax.com) or Fax to (781-419-
1420, Attn: MaryAnn Ashley) as soon as possible. 
Once two of the three initial kits are received by Covance an auto-resupply of one kit will be sent 
out by Covance. If more kits are needed than provided by the auto-resupply, please contact 
Covance directly at the number provided in the Site Laboratory Instruction Manual. Shipment 
usually takes about five (5) to seven (7) business days. 
Attn: Clinical Trials Manager 
Date: 
NCI CTEP ID#: 
Please write using block letters 
STUDY COORDINATOR WHERE KITS SENT TO 
LAST NAME 
 
FIRST NAME 
 
STUDY ROLE 
 
INSTITUTION 
 
DEPARTMENT 
 
BUILDING/FLOOR/ ROOM*  
 
STREET 
 
CITY/POSTAL CODE/COUNTRY 
 
TELEPHONE 
 
FAX 
 
EMAIL 
 
INVESTIGATOR LAST NAME 
 
INVESTIGATOR FIRST NAME 
 
*Mandatory information for hospital, clinic or large sites. 
Rev.10/16 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
129 
A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients 
with Hormone Receptor-Positive Advanced Breast Cancer 
 
Appendix X 
 
Sarcopenia Imaging Substudy  
Impact of muscle quality and quantity on outcome in patients receiving endocrine based 
therapy for metastatic breast cancer in ECOG- 2112 
Investigator: Tarah Ballinger, M.D., Indiana University 
Statistician: Constantine Gatsonis, PhD, Brown University 
Background 
Observational data investigating the relationship between body habitus and outcome or toxicity 
in breast cancer has been largely centered on weight-based metrics such as BMI, with variable 
and inconsistent results. Body weight alone does not tell a full story, as body composition is 
highly variable with respect to muscle and adipose tissue. Muscle is a large, active endocrine 
organ affecting physical function, quality of life, metabolism, and inflammation, and may impact 
outcome or toxicity in metastatic breast cancer (MBC) patients receiving endocrine based 
therapies. 
Low muscle mass (LMM) has been associated with poorer outcome and increased toxicity in 
advanced cancer1.  Low muscle attenuation (LMA), reflecting muscle “quality” and intramuscular 
fat infiltration, is also associated with poor outcome. In comparison to muscle mass, muscle 
attenuation correlates better with muscle strength and function2. The few studies that have 
investigated these parameters in patients with MBC have been small and focused on patients 
receiving cytotoxic chemotherapy3-5. The largest of these was a retrospective study of patients 
receiving first line chemotherapy, finding no significant difference in overall survival based on 
LMM (40 versus 30 months, p=0.07), but a significantly reduced survival for those patients with 
LMA (23 versus 15 months, p = 0.005)5. 
To date, there has been no evaluation of how muscle characteristics affect outcome or toxicity 
in patients receiving endocrine therapy for MBC. The ongoing study E2112, a randomized, 
double-blinded phase III study of exemestane with or without the HDAC inhibitor entinostat with 
co-primary objectives of progression free survival (PFS) and/or overall survival (OS), offers a 
homogeneous population with centrally collected imaging and outcome follow-up to investigate 
this question. 
Specific hypotheses: 
1. Primary: Low muscle attenuation (LMA) is prognostic of poor overall survival in patients 
receiving endocrine based therapy for metastatic breast cancer (MBC) 
2. Secondary: Low muscle mass (LMM) is prognostic of poor overall survival in patients 
receiving endocrine based therapy for MBC.  
Objectives: 
1. Primary: To determine the prognostic value of baseline LMA by CT imaging on overall 
survival in patients receiving endocrine based therapy for MBC. 
2. Secondary: 
• 
To determine the prognostic value of baseline LMM by CT imaging on overall survival in 
patients receiving endocrine based therapy for MBC.  
Rev. Add7 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
130 
• 
To determine the prognostic value of LMA and LMM on overall survival in the subset of 
patients receiving endocrine based therapy for metastatic breast cancer who have 
sarcopenic obesity at study entry.  
• 
To assess the correlation between LMA, LMM, and sarcopenic obesity with 
PRO_CTCAE of muscle ache and joint pain at 3 months. 
• 
To assess the correlation between LMA, LMM, and sarcopenic obesity with patient 
reported health related quality of life score at 3 months. 
• 
To determine the optimal stratification for LMA and LMM to predict overall survival.  
Study Design: 
In this proposed imaging correlative study, evaluation of muscle attenuation and mass will be 
determined using baseline CT scans collected for central review. A transverse cut at the L3 
level will be extracted, as muscle area at this level is linearly related to whole body muscle 
mass6. SliceOmatic software (version 5, Tomovision) will be used to process images, providing 
a highly accurate estimation of cross-sectional skeletal muscle area and muscle attenuation with 
high inter-observer reliability7. The software is semi-automated and will be run by two 
independent investigators, with a subset of images read by both investigators to determine a 
coefficient of variation.  LMM is defined as skeletal muscle index (SMI, lean muscle area/height, 
cm2/m2) less than 41 and LMA will be defined as average muscle density less than 25 HU, or 
less than 33 HU if the patient is overweight/obese by BMI. These cut-points are based on 
previously determined thresholds associated with reduced survival in patients with metastatic 
solid tumors1. An additional exploratory objective will be to determine whether there are 
alternate cut-points predictive of survival in this particular population based on optimal 
stratification. 
This evaluation will allow us to establish prevalence of LMM and LMA in this population, and to 
investigate the importance of muscle mass and quality, rather than body weight alone, on 
outcomes and toxicity in patients receiving AI-based therapy for MBC. This may lead to further 
refinement of prognostic/stratification criteria, support development of targeted exercise 
interventions, and investigation of AI drug resistance or alternate dosing strategies.  In addition, 
the use of CT software to quickly calculate body composition measures may have important 
clinical applications across many treatments and disease types within ECOG-ACRN trials. 
Statistical Design and Analysis: 
Primary Endpoint:  
• 
Overall Survival (OS) defined as time from start of on-study therapy to death from any 
cause. 
Sample size and power justification: 
We will plan initially to evaluate the study population as a whole (n=600), and later analyze the 
treatment and placebo groups separately (n=300 per group) once primary data are available. 
For the primary objective, assuming 60% of participants have LMA, we will have a 95% power 
to detect a difference in median survival time between 20 and 28 months (HR 1.4) for those with 
LMA versus those without LMA, based on a two- sided log rank test with type I error rate of 
0.05. Reducing the sample size to 300 participants, we will achieve a 73% power to detect the 
same difference in median survival time. 

ECOG-ACRIN 
E2112 
Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
131 
Study 
population 
% LMA 
Median survival for 
LMA (month) 
Median survival for 
non-LMA (month) 
Hazard 
ratio 
Study 
power(%) 
600 
60% 
20 
28 
1.4 
95 
300 
60% 
20 
28 
1.4 
73 
Statistical analysis plan: 
1. Primary aim:  
• 
To determine the prognostic value of LMA on overall survival in patients receiving 
endocrine based therapy for metastatic breast cancer.  
o Kaplan Meier survival curve and log-rank test are used to test the difference in OS 
between the LMA participants and the non-LMA participants. Multivariable Cox 
proportional hazard model will be used to model the association between LMA and 
OS while adjusting for age, race, prior chemotherapy, ECOG PS and BMI.  
2. Secondary aims: 
• 
To determine the prognostic value of LMM on overall survival in patients receiving 
endocrine based therapy for metastatic breast cancer.  
o Kaplan Meier survival curve and log-rank test are used to test the difference in OS 
between the LMM participants and the non-LMM participants.  
• 
To determine the prognostic value of LMA and LMM on overall survival in the subset of 
patients receiving endocrine based therapy for metastatic breast cancer who have 
sarcopenic obesity at study entry.  
o Kaplan Meier survival curve and log-rank test are used to test the difference in OS 
between the sarcopenic obese participants who had LMA or LMM and those without 
LMA or LMM. 
• 
To assess correlation between LMA, LMM, and sarcopenic obesity with PRO_CTCAE of 
muscle ache and joint pain at 3 months 
We will use two sample t-test to compare the muscle ache score or joint pain score 
between participants who had LMA (or LMM, or sarcopenic obesity) with those who 
didn’t.  
• 
To assess the correlation between LMA, LMM, and sarcopenic obesity with patient 
reported health related quality of life score at 3 months. 
We will use two sample t-test to compare the quality of life score between participants 
who had LMA (or LMM, or sarcopenic obesity) with those who didn’t.  
• 
To determine the optimal stratification for LMA and LMM to predict overall survival.  
o We will use a search algorithm, together with the method of the time-dependent ROC 
curve to determine the optimal cut-off point for the determination of LMA and LMM to 
identify groups with differential overall survival.  
References 
1. 
Martin L, Birdsell L, Macdonald N, et al: Cancer cachexia in the age of obesity: skeletal 
muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin 
Oncol 31:1539-47, 2013 
2. 
Williams GR, Deal AM, Muss HB, et al: Skeletal muscle measures and physical function in 
older adults with cancer: sarcopenia or myopenia? Oncotarget 8:33658-33665, 2017 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: May 22, 2019 
 
NCI Update Date: October 4, 2017 
132 
3. 
Prado CM, Baracos VE, McCargar LJ, et al: Sarcopenia as a determinant of chemotherapy 
toxicity and time to tumor progression in metastatic breast cancer patients receiving 
capecitabine treatment. Clin Cancer Res 15:2920-6, 2009 
4. 
Shachar SS, Deal AM, Weinberg M, et al: Skeletal Muscle Measures as Predictors of 
Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving 
Taxane-Based Chemotherapy. Clin Cancer Res 23:658-665, 2017 
5. 
Rier HN, Jager A, Sleijfer S, et al: Low muscle attenuation is a prognostic factor for survival 
in metastatic breast cancer patients treated with first line palliative chemotherapy. Breast 
31:9-15, 2017 
6. 
Mourtzakis M, Prado CM, Lieffers JR, et al: A practical and precise approach to 
quantification of body composition in cancer patients using computed tomography images 
acquired during routine care. Appl Physiol Nutr Metab 33:997-1006, 2008 
7. 
van Vugt JL, Levolger S, Gharbharan A, et al: A comparative study of software 
programmes for cross-sectional skeletal muscle and adipose tissue measurements on 
abdominal computed tomography scans of rectal cancer patients. J Cachexia Sarcopenia 
Muscle 8:285-297, 2017