Clinical trial NCT03018249
Conditions: FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma FIGO Grade 3 Endometrial Endometrioid Adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-10-11; Completion date: 2021-03-12
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized surgical window trial evaluates the effect of adding entinostat to medroxyprogesterone acetate before surgery works on progesterone receptors on endometrioid endometrial tumors. Medroxyprogesterone acetate is a progesterone, a hormone produced by body normally. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving medroxyprogesterone acetate with or without entinostat may effect tumors from endometrioid endometrial cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether the addition of the histone deacetylase inhibitor, entinostat, in combination with medroxyprogesterone acetate in the pre-operative setting results in up-regulation of activated progesterone receptors (PR) compared to medroxyprogesterone acetate alone.

SECONDARY OBJECTIVES:

I. To assess the response rate (as measured by cellular morphology and proliferation) and change in activated receptor levels with the addition of entinostat at the time of hysterectomy.

OUTLINE: Two arms were randomly allocated to eligible patients with equal probability.

ARM I: Patients receive medroxyprogesterone acetate intramuscularly (IM) on day 1 and undergo hysterectomy between days 21-24.

ARM II: Patients receive medroxyprogesterone acetate IM on day 1 and entinostat orally (PO) on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.

Arms: arm 1: Patients receive medroxyprogesterone acetate IM on day 1 and undergo hysterectomy between days 21-24. arm 2: Patients receive medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.
Interventions: intervention 1: Entinostat intervention 2: Hysterectomy intervention 3: Laboratory Biomarker Analysis intervention 4: Medroxyprogesterone Acetate
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo hysterectomy intervention 3: Correlative studies intervention 4: Given IM

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
i 
SUMMARY OF CHANGES 
 
For Protocol Amendment #1: 
 
NCI Protocol #: NRG-GY011 
Local Protocol #: NRG-GY011 
 
NCI Version Date: 11/20/2018 
Protocol Date: 11/20/2018 
 
This amendment is being submitted in response to an RA from Dr. Richard Piekarz 
(piekarzr@mail.nci.gov) 
 
# 
Section 
Page(s) 
Comments 
1 
Title 
Page 
1-2 
 
NCI Version Date has been updated throughout the protocol. 
Document History has been updated 
 
 
7.2 
 
 
The CAEPR for entinostat has been replaced per request for 
amendment from NCI. 


NCI Protocol #: NRG-GY011 
Version Date: 11-20-18 
 
 
1
NRG-GY011 
(ClinicalTrials.gov NCT #TBD) 
 
A Randomized Surgical Window Pilot Investigation of the Relationship of Short Term 
Medroxyprogesterone Acetate (NSC #26386) Compared to Medroxyprogesterone Acetate 
Plus Entinostat (NSC #706995) on the Morphologic, Biochemical, and Molecular Changes 
in Primary Endometrioid Adenocarcinoma of the Uterine Corpus 
NCI Version Date: 11-20-18 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
Lead Organization: NRG / NRG Oncology 
 
 
 
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020;  
Philadelphia, PA 19103 
 
Study Team 
Study Chair 
Study Co-Chair 
Linda Duska, M.D., M.P.H. 
Rebecca Brooks MD 
University of Virginia Health System 
University Of Chicago 
Division of Gynecology Oncology 
5841 S. Maryland Ave 
PO Box 800712 
MC 2050 
Charlottesville VA 22908 
Chicago, IL 60637 
434-924-1851/FAX: 434-982-1840 
415-819-5977/FAX: 773-702-5411 
lrd5d@virginia.edu 
rbrooks@bsd.uchicago.edu 
 
 
Translational Science Chair 
Statistician 
Kimberly K. Leslie, M.D. 
Virginia Filiaci, Ph.D. 
University of Iowa  
NRG Oncology Statistics and Data 
Management Center-Buffalo  
Obstetrics and Gynecology 
Roswell Park Cancer Institute 
200 Hawkins Drive 
Elm and Carlton Streets 
31140 A PFP 
Buffalo, NY 14263 
Iowa City, IA 52242  
716-854-5702/FAX: 716-845-8393 
319-356-1976/FAX: 319-356-3901 
filiaciv@nrgoncology.org 
 
Kimberly-leslie@uiowa.edu 
 
 
 
Research Nurse 
 
Translational Scientist 
Heather Lothamer RN 
Heather A Lankes, PhD, MPH 
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 


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2
University of Virginia Health System 
NRG Oncology Statistics and Data 
Management Center-Buffalo  
Division of Gynecology Oncology 
Roswell Park Cancer Institute 
PO Box 800712 
Elm and Carlton Streets 
Charlottesville VA 22908 
Buffalo NY 14263 
434-924-1851/FAX: 434-982-1840 
716-845-8508/FAX: 716-845-8393 
HLL5Y@hscmail.mcc.virginia.edu 
lankesh@nrgoncology.org 
 
 
Data Manager 
Protocol Coordinator 
Lynne Anderson 
Samuel DiBernardo, B.A. 
NRG Oncology Statistics and Data 
Management Center-Pittsburgh 
NRG Oncology-Philadelphia East 
201 N. Craig St., Suite 500 
Four Penn Center, 1600 JFK Blvd, Ste 1020 
Pittsburgh, PA 15213 
Philadelphia, PA 19103 
412-383-1203/FAX: 412-624-1082 
215-854-0770/FAX: 215-854-0716 
Andersonl@nrgoncology.org  
dibernardos@nrgoncology.com 
 
 
Pathologist 
 
Megan Samuelson, M.D. 
 
The University of Iowa 
 
200 Hawkins Drive 
 
Department of Pathology, 5244B RCP 
 
Iowa City, IA  52242 
 
319-353-6796/FAX:  319-356-2243 
 
Megan-samuelson@uiowa.edu 
 
 
Protocol Agent 
       IND Sponsor: DCTD, NCI 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
 
 
Amendment 2 
 
 
NCI-Supplied Agent(s): Entinostat, NSC 706995 
Other Agent(s): Medroxyprogesterone Acetate, NSC 26386, Commercial 
 
 


NCI Protocol #: NRG-GY011 
Version Date: 11/05/18 
 
 
2
Update 
 
 
Amendment 1 
November 20, 2018 
 
Update 
 
 
Activation 
August 1, 2017 
August 25, 2017 
Pre-Activation 
 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 


NCI Protocol #: NRG-GY011 
Version Date: 11/05/18 
 
 
3
NRG-GY011 
A Randomized Surgical Window Pilot Investigation of the Relationship of Short Term 
Medroxyprogesterone Acetate (NSC #26386) Compared to Medroxyprogesterone Acetate Plus 
Entinostat (NSC #706995) on the Morphologic, Biochemical, and Molecular Changes in Primary 
Endometrioid Adenocarcinoma of the Uterine Corpus 
 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation can 
be submitted to the CTSU via: 
 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.o
rg (regulatory documentation 
only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
For regulatory questions call the 
CTSU Regulatory Help Desk at 
1-866-651-CTSU 
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_SYS
TEM/ 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 exclusively 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 Lead 
Protocol Organization. 
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 Website is located at https://www.ctsu.org. 
 
 
 


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TABLE OF CONTENTS 
NRG-GY011 .................................................................................................................................... i 
SCHEMA .........................................................................................................................................6 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objective ....................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Progesterone signaling through its receptor (PR) is the ultimate tumor 
suppressor of the ......................................................................................................7 
2.2 
Modulation of progesterone receptor expression .....................................................9 
2.3 
Rationale for the combination of hormones and epigenetic therapies ...................12 
2.4 
Feasibility and Rationale for the Neoadjuvant Model ...........................................12 
2.5 
Inclusion of Women and Minorities ......................................................................12 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .................12 
3.1 
Patient Selection Guidelines ..................................................................................13 
3.2 
Eligibility Criteria ..................................................................................................13 
3.3 
Ineligibility Criteria ...............................................................................................14 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........15 
5. 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE ....................16 
5.1 
When a suitable candidate has been obtained for protocol entry, the 
following steps should be taken: ............................................................................16 
5.2 
Treatment Plan .......................................................................................................16 
5.3 
Standard Surgical Therapy for All Patients. ..........................................................16 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................16 
5.5 
Duration of Therapy ...............................................................................................16 
6. 
TREATMENT MODIFICATIONS/management .............................................................17 
6.1 
No dose escalations or reductions will be used. ....................................................17 
6.2 
All patients will have a second CBC drawn prior to surgery (may range 
from 7 days ............................................................................................................17 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................17 
7.1 
Protocol Agents ......................................................................................................17 
7.2 
Adverse Events and Serious Adverse Events ........................................................17 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
Study Agents ..........................................................................................................18 
7.4 
Adverse Events for the Commercial Study Agent, Medroxyprogesterone 
Acetate ...................................................................................................................20 
7.5 
Expedited Reporting of Adverse Events ................................................................21 


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8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ..............23 
8.1 
Access requirements for OPEN and Medidata Rave: Site staff will need to 
be ............................................................................................................................23 
8.2 
Site Registration Requirements..............................................................................24 
8.3 
Patient Enrollment .................................................................................................26 
8.4 
Agent Ordering and Agent Accountability ............................................................27 
9. 
DRUG INFORMATION ...................................................................................................28 
9.1 
Entinostat (NSC 706995) .......................................................................................28 
9.2 
Medroxyprogesterone Acetate ...............................................................................29 
10. 
Pathology/BIOSPECIMEN................................................................................................30 
10.1 
Central Pathology Review Guidelines ...................................................................30 
10.2 
Biospecimen Selection for Integral Biomarker Testing .........................................30 
10.3 
Biospecimen Selection for Integrated Biomarker Testing .....................................30 
10.4 
Biospecimen Submission Tables ...........................................................................32 
10.5 
Exploratory Biomarker Laboratory Testing ...........................................................33 
11. 
SPECIAL STUDIES (Non-Tissue)....................................................................................33 
12. 
ASSESSMENT OF EFFECT ............................................................................................33 
12.1 
Histologic Response...............................................................................................33 
12.2 
Steroid Receptor, Ki67 and p21 Status ..................................................................33 
13. 
DATA AND RECORDS ...................................................................................................35 
13.1 
Data Management/Collection ................................................................................35 
13.2 
Summary of Data Submission ...............................................................................35 
13.3 
Global Reporting/Monitoring ................................................................................36 
14. 
STATISTICAL CONSIDERATIONS...............................................................................36 
14.1 
Study Design ..........................................................................................................36 
14.2 
Study Endpoints .....................................................................................................36 
14.3 
Primary Objectives Study Design ..........................................................................37 
14.4 
Study Monitoring of Primary Objectives ...............................................................39 
14.5 
Accrual/Study Duration Considerations ................................................................39 
14.6 
Dose Level Guidelines ...........................................................................................39 
14.7 
Secondary or Exploratory Endpoints (including correlative science aims) ...........39 
14.8 
Gender/Ethnicity/Race Distribution.......................................................................40 
REFERENCES ..............................................................................................................................42 
APPENDIX I – PERFORMANCE STATUS CRITERIA ............................................................44 
APPENDIX II- NYHA CLASSIFICATION .................................................................................45 
APPENDIX III – COLLABORATIVE AGREEMENT................................................................46 
APPENDIX IV – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES .................48 


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     NRG-GY011 
SCHEMA 
DIAGNOSIS OF PRIMARY ENDOMETRIOID ADENOCARCINOMA OF THE UTERINE CORPUS 
BY D&C OR BIOPSY (FORMALIN-FIXED, PARAFFIN-EMBEDDED TUMOR TISSUE MUST BE 
SUBMITTED) 
 
PATIENT ENTRY 
 
MEDROXYPROGESTERONE ACETATE 400 MG IM, GIVEN ONCE, 21-24 DAYS PRIOR 
TO HYSTERECTOMY on day 1 
Randomize 
 
                  ENTINOSTAT 5 mg PO 
 
            NO TREATMENT 
 
Days 1, 8 and 15 
 
  
 
STANDARD SURGICAL THERAPY 
 (HYSTERECTOMY, BSO, +/- LYMPH NODE SAMPLING; FORMALIN-FIXED, PARAFFIN-
EMBEDDED TUMOR TISSUE MUST BE SUBMITTED) 
 
 
OFF TREATMENT 
30-45 day follow-up for safety  
Safety assessment must occur prior to beginning any adjuvant therapy 
 
 
 
Safety exam will coincide with post-operative visit 
 
 
 
 


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1. 
OBJECTIVES 
1.1 
Primary Objective 
To determine whether the addition of the histone deacetylase inhibitor, entinostat, in 
combination with medroxyprogesterone acetate in the pre-operative setting results in up-
regulation of activated progesterone receptors (PR) compared to medroxyprogesterone 
acetate alone.  
 
1.2 
Secondary Objectives 
To assess the response rate (as measured by cellular morphology and proliferation) and 
change in activated receptor levels with the addition of entinostat at the time of 
hysterectomy. 
 
 
2. BACKGROUND 
2.1 
Progesterone signaling through its receptor (PR) is the ultimate tumor suppressor of the  
endometrium.19 However, long-term progestin treatment is associated with the down-
regulation of PR; this down-regulation is hypothesized as the reason why hormonal 
therapy with progestin for endometrial cancer has limited long-term effectiveness.20 The 
purpose of this trial is to demonstrate that PR remains upregulated and sensitive to 
progestin when the progesterone medroxyprogesterone acetate is given with the HDAC 
inhibitor entinostat, more than when compared with medroxyprogesterone acetate alone. 
 
Endometrial cancer is a hormone-dependent malignancy, and hormone therapy has long 
been applied to treat endometrial cancer patients.  Endometrial cancer patients treated 
with synthetic progesterone/progestin have achieved promising clinical outcomes; overall 
response rates are 50-70% for primary (mainly pre-menopausal) endometrial cancer 
patients10 and 27-33% for advanced endometrial cancer patients.4 The presence of PR on 
endometrial cancer cells has been shown to be strongly associated with response to 
progesterone treatment.7 The overall response rate to progesterone treatment has been 
reported to be 72% in patients with PR-positive tumors but only 12% in patients with PR-
negative lesions.7  Additionally, in advanced and recurrent disease, a difference in 
response with respect to grade can be seen: in GOG-0081, the ORR was 37% in the 
patients whose cancer was PR positive (16/46) compared to 8% (7 of 86) in the patients 
whose cancer was PR negative.17 Overall expression of progesterone receptor correlates 
with a good prognosis and response to progestin treatment. For clinical purposes (and in 
the studies mentioned), merely the presence or absence of IHC expression of PR is used 
to make decisions regarding appropriate use of hormonal therapy. The presence of PR is 
recorded as either positive or negative, with the actual quantity of PR expression 
unmeasured.  
 
In GOG-0119, which considered patients with measurable, advanced or recurrent 
endometrial cancer, 45% of the lesions were demonstrated to be PR positive, and the 
level of PR expression decreased significantly with increasing tumor grade (see Table, 
below).15  In GOG-0119, the immune-staining for ER and PR was semi-quantified using 
the HSCORE method.11 In GOG-0119, a threshold of > 75 for ER as a positive result was 
chosen to provide the maximum sensitivity and specificity and as a benchmark for tumors 


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8
that responded to therapy. 
 
Table 1:  Adapted from GOG 11915 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 3 or 
unspecified 
PR negative 
6 
7 
14 
PR positive 
6 
9 
7 
 
GOG-0211 was the first non-therapeutic pre-operative window trial in women with 
endometrial cancer.23 After diagnosis of endometrial cancer by endometrial biopsy, patients 
were enrolled to receive medroxyprogesterone acetate 21-24 days prior to planned surgery.  
The biopsy and hysterectomy specimens were evaluated for estrogen and progesterone 
receptor expression, as well as other markers for proliferation and apoptosis. As in GOG-
0119, the receptor IHC was semi-quantified. 
 
Fifty-nine women received treatment with progestin per protocol and had available slides.  
One complete histologic response was seen, and 37 tumors (64%) had a partial response. The 
low complete response rate seen in GOG-0211 might have been in part due to the older age 
of the women in the study, the (very) short duration of progesterone treatment, and the large 
percentage of women with grade 3 tumors (15%). Nevertheless, there were significant 
histologic changes seen in the majority of patients following treatment that suggest a higher 
rate of progesterone response than evidenced by complete regression of disease. Specific 
quantifiable, statistically significant histologic changes that occurred in the carcinomas 
following administration of progestin included: 1) a decrease in the number of mitotic 
figures; 2) a decrease in high nuclear grade; 3) acquisition of more abundant eosinophilic 
cytoplasm; 4) a decrease in mean gland cellularity; 5) a decrease in the frequency of nucleoli; 
6) increased mucinous and/or squamous metaplasia; and 7) the presence of subnuclear, apical 
or intraluminal secretion. The tumors that displayed a partial or complete histologic response 
following treatment differed initially from those that did not respond in that the responders 
had a lower initial mitotic index and lower initial nuclear grade than the non-responders (with 
response defined with very specific pathologic parameters).23  
 
The model used in GOG-0211 also allowed assessment of the tumor microenvironment: in 
the case of endometrial cancer, this includes the adjacent normal endometrium as well as the 
endometrial stroma. Decidual change (a histologic marker of stromal progesterone effect) 
was entirely confined to the stroma surrounding benign appearing glands in 12 of the 14 
cases in GOG-0211.  Interestingly, the decidual change was more likely to occur in the 
benign portions of endometrium adjacent to carcinomas that showed a histologic response.23 
This finding suggests a paracrine effect in which some gland:stromal interaction may be 
essential for either decidualization or complete tumor cell differentiation to occur.  This 
mechanism may be critical to tumor response. 
 
Most germane to the current study, GOG-0211 demonstrated a down-regulation of PR 
following progesterone treatment. A statistically significant decrease was identified in the 


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9
mean ER, PR, and PRB following 21 days of progestin treatment.  The table below, adapted 
from GOG-0211, demonstrates the change in hormone receptor expression in the total 
population of patients as well as in responders and non-responders to progesterone treatment. 
 
Table 2: Immunohistologic characteristics for ER, PRA, PRB, before and after medroxy-
progesterone acetate. Adapted from GOG-0211.23 The numbers shown in Table 3 represent 
modified H scores defined by the proportion of nuclei staining (0-1) X the intensity (1+-3+) 
  
 
 
 
2.2 
Modulation of progesterone receptor expression 
In hormonally responsive tissues, PR is activated by ligand, then binds to DNA and is 
thereafter rapidly removed from DNA by ubiquitination.  This is followed by degradation 
in the proteasome.  Rapid cycling on/off DNA enhances PR activity.  Hence, short term 
PR depletion is a natural result of PR activity, and PR protein levels will wax and wane 
within a modest range as long as new PR molecules are replenished by PgR gene 
transcription.  Yet, in many endometrial cancers, PgR is epigenetically silenced leading 
to long-term downregulation of PR and hormonal insensitivity.  Persistent 
downregulation of PR removes one of the least toxic and most effective therapeutic 
opportunities for treatment of endometrioid endometrial cancer.  The PR gene has been 
shown to be methylated in its promoter and exons, both in tumors from patients and in 
existing endometrial cancer cell lines, in response to progestational therapy.13 It is 
postulated to be a major reversible mechanism of PR regulation and one that, as yet, has 
not been exploited therapeutically. 
 
A principal goal of this trial is to determine the impact of progestin +/- entinostat on the 
activity of progesterone receptors (PR) in endometrial cancer.  PR activity will be 
determined by the expression of an integrated biomarker, Ki67.  Progestin binding 
activates PR as a differentiating transcription factor and results in inhibition of cellular 
proliferation, which can be assessed by observing a significant reduction in Ki67, and in 


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10
cell cycle arrest as determined by the significant induction of the cyclin dependent kinase 
p21.  The expression of Ki67 (integrated) and p21 (exploratory) by 
immunohistochemistry on pre- versus post-treatment endometrial cancer samples reliably 
indicates both the activity of PR (p21 is a known gene that is highly induced by PR) and 
the inhibition of proliferation (reduced Ki67) resulting from hormonal therapy.  PR levels 
per se are also somewhat informative and will be assessed by immunohistochemistry for 
PR, which is another integrated biomarker.  However, levels of PR protein alone are not a 
completely reliable indication of PR activity because even active PR may be down-
regulated in the short term as a result of the normal ligand-dependent PR shuttling to the 
proteasome.   Hence, we propose that adding an integrated biomarker strongly indicative 
of PR activity and therapeutic effectiveness (Ki67) will allow a more complete 
understanding of the impact of treatment at the molecular level.     
 
Histone deacetylation is an important epigenetic modulator. The two FDA-approved 
HDAC inhibitors vorinostat (SAHA) and depsipeptide (romidepsin) are intravenously 
administered HDAC inhibitors; several others are under development, including the 
orally administered entinostat.  DNA methylation is another method of re-regulation. 
Two DNA methyltransferase (DNMT) inhibitors have been approved by the FDA, 5-
azacytidine (Vidaza) and 5-aza-deoxycytidine (decitabine).  These agents are 
administered IV.  The oral agent was chosen for the current study as it is logistically less 
complicated in this setting.   
 
There are many promising preclinical reports to encourage the study of epigenetic 
therapies for endometrial cancer.21 Treatment with DNMT inhibitors restores expression 
of several genes that have been shown to be methylated in endometrial and ovarian 
tumors, including PR.  For example, the DNMT inhibitor 5-azacytidine restored PR 
expression in KLE endometrial cancer cells, which are normally negative for PR.14 
Additionally, the HDAC inhibitor vorinostat (SAHA) inhibited growth of endometrial 
cancer cells in vitro and in vivo in xenograft models of endometrial cancer, with no 
toxicity.16  The work from Dr. Leslie’s laboratory (shown below) suggest that the 
combination of entinostat and progesterone upregulates and maintains PR levels and 
induces cellular differentiation.21 Additionally, the concentrations achieved in vitro are 
clinically relevant and achievable.1  
 
 
 
 
 
 
 
 
 
 
 
 
Preliminary Data Supporting the Biologic Endpoints and Study Rationale: 


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Figure 1. Multiple HDAC inhibitors have the capacity to induce functional PR expression. Functional expression of PR 
was examined in endometrial cancer cells in response to treatment with entinostat. The anticipated upregulation in PRA and 
B protein expression and progesterone-dependent downstream genes including FOXO1, AREG, and p21 was observed.  
Histone 3 acetylation was also induced as an effect of the drugs. Preliminary data provided by S. Yang and K. Leslie, the 
University of Iowa.   
 
 
 
 
Figure 2. Molecularly enhanced progestin therapy with HDACi. Xenografts were created with Ishikawa cells and treated with 
MPA (1mg weekly i.m.) -/+ entinostat (15mg/kg, oral, daily). Inset: qRT-PCR analysis of PR and downstream gene PAEP at day 24. 
Note: tumors from entinostat+MPA group (but not control or MPA alone) were primarily necrotic tissue (80%, shown with arrows), 
which may explain the low PR mRNA levels at day 24. * p<0.05 vs. control.  NOTE:  Of the total tumor cross sectional area in the 
entinostat + MPA group, only 20% remained viable tumor, the rest was necrosis.  Hence, the total area of the tumor under-
estimated the therapeutic effect specifically with the combination regimen.  Preliminary data provided by S. Yang and K. Leslie, 
the University of Iowa.   
 
 
 
 
0
50
100
150
200
250
1
4
8
11
15
18
21
24
tumor cross sectional area (mm2)
Days
Control (n=7)
MPA (n=6)
Entinostat+MPA (n=8)
*
0
5
10
PGR
PAEP
Fold change
*
Control
MPA
Entinostat
+MPA


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2.3 
Rationale for the combination of hormones and epigenetic therapies 
Hormone therapy has shown promising clinical outcomes, but response is often short-
lived, possibly partially due to down-regulation of PR, and endocrine agents are less 
likely to be effective in higher grade endometrial cancers, due to lower expression of PR 
in high grade cancers. We hypothesize that exposure to epigenetic therapy will sustain 
and potentially boost PR expression, and further study of this combination will result in 
improved response rate due to enhanced PR activity.  We propose this randomized non-
treatment trial to examine this novel and potentially therapeutic mechanism and to 
provide preliminary clinical data to lead into a randomized phase II study.  
  
2.4 
Feasibility and Rationale for the Neoadjuvant Model  
The successful completion and publication of GOG-0211 suggests that a non-therapeutic 
surgical window study design can be performed in the Network Group.  Other 
investigators have demonstrated the feasibility of complex surgical window trials with 
multiple translational endpoints in endometrial cancer patients.  Dr. Duska has 
successfully completed a surgical window trial of dasatinib prior to hysterectomy for 
endometrial cancer; these results have been presented at SGO (2013, 2014)5, 6 and are 
currently being prepared for publication.  The study format was both acceptable to 
patients and safe.  The MD Anderson group presented a similar concept study at ASCO 
2014.  These studies and others suggest these purely scientific studies are feasible and 
safe. 
 
The effect of the combination of progesterone and entinostat on PR expression in 
endometrial cancer can best be studied via the neoadjuvant mechanism proposed above 
because there is no need for extra non-clinical biopsies to be performed, thus increasing 
patient acceptability and decreasing cost.  The flexibility of using the diagnostic biopsy 
followed by ascertainment of the clinical material after a lead-in treatment phase makes 
this proposed process cost and time efficient with little or no downside to patients who 
are already planning surgery for their endometrioid endometrial cancer. 
 
2.5 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research. 
 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 


NCI Protocol #: NRG-GY011 
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13
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the NRG web site).  
 
3.1 
Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
 
3.1.1 Women of childbearing potential must be willing and able to use medically acceptable 
forms of non-hormonal contraception (barrier methods) during the trial and for 3 months 
after the use of entinostat (if surgery is not performed). 
 
3.1.2 Submission of tumor tissue is required for all patients. Investigators should check with 
their site Pathology department regarding release of biospecimens before approaching 
patients about participation in the trial. 
 
3.2 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 Patients must have a histologically proven diagnosis of endometrioid endometrial 
adenocarcinoma by endometrial curettage or biopsy within 8 weeks prior to registration. 
Central pathology review will be required as part of the study but not for registration 
purposes. 
3.2.2 History/physical examination within 42 + 5 days of planned surgical procedure (18-21 
days from day 1Further protocol-specific assessments as detailed in the table in Section 4. 
3.2.3 Age ≥ 18 
3.2.4 The trial is open only to women with primary endometrioid adenocarcinoma of the 
uterine corpus (all histologic grades and stages) who are planned and appropriate for 
primary surgical treatment to include removal of the uterine corpus via any surgical 
modality. The patient must be considered a suitable surgical candidate. 
3.2.5 Patients must have an ECOG Performance Status of 0, 1, 2, or 3 within 28 days prior to 
registration (See Appendix I) 
3.2.6 Formalin-fixed, paraffin-embedded tumor tissue from the biopsy or curettage must be 
submitted along with the corresponding pathology report. (See Section 10.3 for details.) 
3.2.7 Adequate hematologic function defined as follows: 
• Platelets ≥ 100,000/μl  
• Granulocytes (ANC) ≥ 1,500/μl  
3.2.8 Adequate renal function defined as follows: 
• Creatinine ≤ 1.6 mg/dl 
3.2.9 Adequate hepatic function defined as follows: 
• SGPT (ALT) ≤ 3 x upper limits of normal 
• Bilirubin within institutional normal limits. 


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14
3.2.10 The patient must provide study-specific informed consent and authorization permitting 
release of personal health information prior to study entry. 
3.2.11 Any patients of childbearing potential must have a negative pregnancy test. 
 
 
3.3 
Ineligibility Criteria 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.3.1 Patients with any non-endometrioid histology (such as serous, clear cell, or 
carcinosarcoma). 
3.3.2 Patients who have received prior progestin or anti-estrogen therapy during the 3 months 
before the diagnosis of endometrioid adenocarcinoma of the uterine corpus is established.   
Estrogen therapy alone is allowed. 
3.3.3 Patients with ECOG Performance Grade of 4. (See Appendix I) 
3.3.4 Patients with history of thrombophlebitis within the past 2 years or ongoing 
thromboembolic disorders. 
3.3.5 Patients who have previously received systemic, radiation or other treatment for uterine 
cancer 
3.3.6 Patients for whom formalin-fixed, paraffin-embedded tumor  tissue from the biopsy or 
curettage is unavailable 
3.3.7 Patients must not have previously received a non FDA approved HDAC inhibitor in a 
clinical trial setting (entinostat, belinostat. ).  
3.3.8 Patients must not be currently taking or have ever taken vorinostat (Zolinza, Merck), 
panobinostat (Farydak, Novartis) or romidepsin (Istodax, Gloucester Pharmaceuticals). 
 
 


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15
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
Procedure 
Screening/Baseline 
(preop visit – 
within 42 days 
plus or minus 5 
days of surgery 
Day 1 
(day of 
MPA 
treatment) 
Day 
8 
Day 
15 
Day 
15-
18 
Day 
22-
25 
30-45 
days 
post 
surgery 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
X 
Vital Signs (BP, 
Temp, Pulse, RR), 
ECOG PS 
X 
 
 
 
 
 
X 
Height/Weight 
X 
 
 
 
 
 
 
Randomization 
3 
 
 
 
 
 
 
Concomitant 
Treatment 
Assessment 
X 
 
 
 
 
 
 
Adverse Event 
Assessment 
 
X 
1 
1 
2 
X 
X 
Laboratory Tests 
CBC, CMP 
X 
 
 
 
4 
 
 
Pregnancy Test 
(WOCBP) 
X 
 
 
 
 
 
 
medroxyprogesterone 
 
X 
 
 
 
 
 
Entinostat (Arm B 
Only) 
 
X 
X 
X 
 
 
 
 
1. For Arm B, within 3 days of each entinostat administration, may be done by telephone 
2. Within 7 days of surgery, may be done by telephone 
3. May occur on day of screening or any time prior to day 1 (including day 1). 
4. Only CBC needed, between 7 days pre-op and immediately pre-operatively 
 
 
 
 


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16
5. TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
 
5.1 
When a suitable candidate has been obtained for protocol entry, the following steps 
should be taken:  
5.1.1 The institution must follow registration information in Section 8. 
 
5.1.2 Request one bottle of entinostat 5 mg tablets, if the patient is randomized to the entinostat 
arm and the site does not have a bottle in stock. 
5.2 
Treatment Plan  
5.2.1 Medroxyprogesterone acetate Administration in All Patients. Patients must be registered 
into study prior to administration of medroxyprogesterone acetate. All women will 
receive medroxyprogesterone acetate, 400 mg IM, given once 21-24 days prior to 
definitive surgical therapy. The date of medroxyprogesterone acetate injection will be 
designated as day 1. 
5.2.2 Patients who are randomized to receive entinostat will be treated with entinostat 5 mg PO 
on day 1 (with medroxyprogesterone acetate injection). The remaining doses will be 
dispensed to the patient to be taken at home on days 8 and 15. 
5.3 
Standard Surgical Therapy for All Patients.  
All women will receive standard surgical therapy (Hysterectomy, BSO, +/- lymph node 
sampling) 21-24 days following medroxyprogesterone acetate administration.  
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
5.4.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
The most commonly reported non-hematologic adverse events for entinostat are nausea, 
fatigue, and dry skin. The majority of these AE’s are grade 1 or 2.  It is suggested that 
anti-nausea medication be prescribed by the enrolling physician to be used at patient 
discretion. No other supportive medications are required for this study. 
 
5.4.2 Prohibited Therapies:  Patients must not have previously received an HDAC inhibitor in a 
clinical trial setting (entinostat, belinostat,).  Patients must not be currently taking or have 
ever taken vorinostat (Zolinza, Merck) or panobinostat (Farydak, Novartis) or romidepsin 
(Istodax, Gloucester Pharmaceuticals). 
 
 
5.5 
Duration of Therapy 
 
All patients will receive a single dose of medroxyprogesterone acetate followed by 
surgery 21-24 days later.  Patients who receive a treatment assignment that includes 
entinostat are expected to complete all 3 doses of drug pre-operatively.  Patients may stop 
entinostat for the following indications: 
 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), as described in Section 6 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 


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17
for further treatment in the judgment of the investigator. Follow up should continue 
however. 
 
Patients who complete 2 doses will be allowed to stay on study and will be considered 
evaluable.  Patients who complete 0 or 1 dose will still be followed per protocol (they 
will still be followed by their doctors and surgeons for consideration of surgery, and will 
still be followed for toxicity since they will have received the dose of 
medroxyprogesterone Acetate).   
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
No dose escalations or reductions will be used. 
6.2 
All patients will have a second CBC drawn prior to surgery (may range from 7 days  
prior to day of surgery).  A preoperative platelet value of less than 50,000/µl will delay 
surgery until resolution to greater than 50,000/µl.  
 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Protocol Agents 
Investigational Agents 
Entinostat is investigational agent administered on NRG-GY011, and is available under 
IND# TBD sponsored by DCTD, NCI.  For patients receiving entinostat, determination 
of whether an adverse event meets expedited reporting criteria, see the reporting table in 
Section 7.5.2.1 of the protocol. 
Commercial Agents 
Medroxyprogesterone acetate is commercial agent administered on NRG-GY011. For 
patients receiving medroxyprogesterone acetate, determination of whether an adverse 
event meets expedited reporting criteria, see the reporting table in Section 7.5.2.2 of the 
protocol. 
 
7.2 
Adverse Events and Serious Adverse Events 
7.2.1 Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following lists of AEs (Sections 7.3 and 7.4) and the characteristics of an observed AE 
(Sections 7.2.2 and 7.2.3) will determine whether the event requires expedited reporting 
via the CTEP Adverse Event Reporting System (CTEP-AERS) in addition to routine 
reporting 
7.2.2 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
7.2.3 Definition of an 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 (investigational) product, whether or not 


NCI Protocol #: NRG-GY011 
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18
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study Agents 
 
7.3.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MS-275 (SNDX-275, entinostat, NSC 706995) 
 
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 AdEERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 221 patients. Below is the CAEPR for MS-275 (SNDX-275, entinostat). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
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 
  


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19
 
 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%)  
 
 
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) 
 
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 
  
 
1This 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. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATION SOC. 
 
3Gastrointestinal 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: 
 


NCI Protocol #: NRG-GY011 
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20
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 
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 agent. 
 
7.4 
Adverse Events for the Commercial Study Agent, Medroxyprogesterone Acetate  
• breakthrough bleeding  (premenopausal)  
• spotting (premenopausal) 
• change in menstrual flow (premenopausal) 
• amenorrhea, headache 
• nervousness 


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21
• dizziness 
• edema 
• change in weight (increase or decrease) 
• changes in cervical erosion and cervical secretions  
• cholestatic jaundice including neonatal jaundice  
• breast tenderness and galactorrhea  
• skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash  
• acne, alopecia and hirsutism  
• rash (allergic) with and without pruritis  
• anaphylactoid reactions and anaphylaxis 
• mental depression  
• pyrexia  
• fatigue  
• insomnia  
• nausea  
• somnolence 
 
Refer to the package insert for detailed pharmacologic and safety information and for a 
more comprehensive list of adverse events.  
 
7.5 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP for this study by telephone at 301-897-7497 and to the NRG Regulatory 
Affairs by phone at 215-854-0770. An electronic report must be submitted immediately 
upon re-establishment of the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
• Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-
AERS 24-hour notification must be submitted within 24 hours of learning of the 
adverse event.  Each CTEP-AERS 24-hour notification must be followed by a 
complete report within 3 days.  
• Supporting source documentation is requested by the IND Sponsor for this study 
(CTEP/DCTD) and NRG as needed to complete adverse event review.  When 


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22
submitting supporting source documentation, include the protocol number, patient ID 
number, and CTEP-AERS ticket number on each page, and fax supporting 
documentation to CTEP at 301-230-0159 and to the NRG Regulatory Affairs at 215-
854-0716. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
7.5.2 Expedited Reporting Requirements for Adverse Events  
 
 
7.5.2.1 
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/Intervention1, 2 
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 electronic 
submission 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: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 


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23
1Serious 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 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.5.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
Other protocol-specific text to be added as needed 
 
8. REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
 
8.1 
Access requirements for OPEN and Medidata Rave: Site staff will need to be  
registered with CTEP and have a valid and active CTEP Identity and Access 
Management (IAM) account.  
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 


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24
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). Associates will 
use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account.  
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures below for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.)  
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
 
8.1.1 Investigator Registration Requirements  
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Lead Protocol Organization.  Food and Drug Administration (FDA) 
regulations and National Cancer Institute (NCI) policy require all investigators 
participating in any NCI-sponsored clinical trial to register and to renew their registration 
annually. Registration requires the submission of: 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature; 
• a current Curriculum Vitae (CV); 
• a completed and signed Supplemental Investigator Data Form (IDF); 
• a completed Financial Disclosure Form (FDF) with an original signature. 
 
 Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
 
8.2 
Site Registration Requirements  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
8.2.1 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 


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25
not limited to: an active Federal Wide Assurance (FWA) number, an active roster 
affiliation with the Lead Network or a participating organization, a valid IRB approval, 
and compliance with all protocol specific requirements. 
 
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 IRB Manager 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. 
 
Protocol documents can be downloaded from the NRG Oncology website:  
www.nrgoncology.org  
 
Requirements For NRG-GY011 Site Registration:  
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, where they 
will be entered and tracked in the CTSU RSS.  
 
ONLINE: www.ctsu.org  (members’ section) → Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
      1818 Market Street, Suite 1100 
      Philadelphia, PA 19103 
 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-


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IAM username and password 
• Click on the Regulatory tab at the top of your screen 
• 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 as 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. 
 
8.3 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients 
must have signed and dated all applicable consents and authorization forms.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
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-
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 position in the Rave database. OPEN can be accessed at https://open.ctsu.org or 
from the OPEN tab on the CTSU members’ web site 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).  
• If specific tests and/or bio-specimen is required before enrollment, add to bulleted list 
above. 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your records.  
 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: [email to come] or call the NRG 
Registration Desk at [phone number to come], Monday through Friday, 8:30 a.m. to 5:00 
p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will need the 


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27
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration system 
(e.g. drug shipment and confirmation of registration) will occur.  
 
8.4 
Agent Ordering and Agent Accountability 
 
8.4.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through 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.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
 
8.4.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Oral Drug Accountability Record Form (Oral 
DARF) available on the CTEP forms page.  (See the NCI Investigator’s Handbook for 
Procedures for Drug Accountability and Storage.) 
 
8.4.3 The current versions of the entinostat IB for the agents will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
coordinator via email. 
 
8.4.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 


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28
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
• PMB IB Coordinator: IBCoordinator@mail.nih.gov   
 
 
9. DRUG INFORMATION  
 
9.1 
Entinostat (NSC 706995) 
 
9.1.1 Other names: MS-27-275, MS-275, SNDX-275 
 
Classification: 
      Histone deacetylase inhibitor (HDACi)  
 
Molecular formula:  C21H20N4O3 
 
M.W.: 376.41 
 
9.1.2 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. 
 
9.1.3 How Supplied: Entinostat is supplied by the Syndax Pharmaceuticals, Inc. and 
distributed by DCTD, NCI as 5 mg (yellow, in bottles of 5) 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.   
 
9.1.4 Storage: 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). 
 
If a storage temperature excursion is identified, promptly return the entinostat to 25°C 
and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 


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9.1.5 Stability: Shelf life stability studies of the intact bottles are on-going. 
 
9.1.6 Route of Administration: Oral, on an empty stomach, at least 1 hour before or 2 hours 
after a meal.  Entinostat tablets should not be split, crushed, or chewed. 
 
9.1.7 Potential Drug Interactions:  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.  
 
 
9.1.8 Patient Care Implications:  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.  (Section 3.1.1) 
 
9.2 
Medroxyprogesterone Acetate 
 
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
Product description:  Medroxyprogesterone acetate injection contains 
medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. 
Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. 
It is a white to off-white, odorless crystalline powder that is stable in air and that melts 
between 200° C and 210° C. It is freely soluble in chloroform, soluble in acetone and 
dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and 
insoluble in water. 
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-
(acetyloxy)-6-methyl-, (6α)-.  


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Medroxyprogsterone Injection for intramuscular (IM) injection is available in vials and 
prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous 
suspension 150 mg/mL. 
Each mL contains: 
Medroxyprogesterone acetate 
Polyethylene glycol 3350 Polysorbate 80 
Sodium chloride Methylparaben Propylparaben 
Water for injection 
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. 
Solution preparation (how the dose is to be prepared):  Refer to the package insert for 
standard preparation instructions. 
Route of Administration:  Medroxyprogesterone acetate is given as a single 
intramuscular (IM) dose.  Either the vial or the prefilled syringe should be vigorously 
shaken just before each use to ensure that the dose being administered represents a 
uniform suspension.  The injection should be given as a deep IM injection in the gluteal 
or deltoid muscle. 
Availability/Supply:  The agent is commercially available. Institutions may receive up to 
$250 per patient for cost of medroxyprogesterone acetate.  See Funding Sheet for more 
information.   
 
 
 
 
 
 
10. PATHOLOGY/BIOSPECIMEN    
 
10.1 
Central Pathology Review Guidelines   
Not applicable.  
 
10.2 
Biospecimen Selection for Integral Biomarker Testing 
Not applicable 
 
10.3 
Biospecimen Selection for Integrated Biomarker Testing 
 
10.3.1 Biomarker to be Tested 
 


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31
Progesterone receptor (PR) and Ki67 
As described in the preliminary data (Section 2), progestins result in endometrial 
differentiation and are useful in the treatment of endometrial cancer. Our principal 
translational goal is to test the hypothesis that the addition of entinostat, an epigenetic 
agent, will amplify the therapeutic effectiveness of MPA as determined by integrated 
molecular biomarkers of differentiation and response. 
 
Progestins bind to the progesterone receptor (PR) and activate downstream genes 
involved in epithelial cell growth arrest including the cyclin dependent kinase inhibitor 
p21. In turn, Ki67 levels, a well-established marker for proliferation, are predicted to 
decrease significantly. Thus, we have chosen these two predictive markers, PR and Ki67, 
as integrated readouts of molecular response for this trial.  
 
10.3.2 Testing Requirements and Reporting 
Formalin-fixed, paraffin-embedded (FFPE) primary tumor tissue must be submitted for 
PR and Ki67 immunohistochemistry. See Mandatory Biospecimen Submission Table 
(Section 10.4.1) for details. 
 
10.3.3 Method of Testing 
Immunohistochemistry 
A polymer-based detection system with Dako autostainer and the FDA 510(k)-cleared 
pharmDx assay kit (Dako, Glostrup, Denmark) will be used.  Please see the appended 
specific IHC protocols for PR and Ki67 as integrated biomarkers. 
 
Antibodies 
Antibody dilutions will be according to the manufacturer’s recommendations. 
PR: Mouse monoclonal antibody PgR636, 1A6, and Dako-PR  
Ki67: Clone MIB-1 from Dako 
 
Test Report Range 
Positive results for all biomarkers require at least 1% of tumor cells express the 
biomarker. Tumors with less than 1% staining are considered negative. For PR, the 
degree of positivity will be determined according to College of American 
Pathologists/ASCO guidelines using the modified H score (percent of cells staining x 
intensity [1 to 3+], converted to a continuous variable).  For Ki67, the number of positive 
staining nuclei per high power field averaged over 3 fields will be evaluated.  
 
Invalid Test Results 
Invalid test results include no tumor, wrong diagnosis, and lack of staining or nonspecific 
staining using the positive control tissue. If a specimen contains no tumor or the tumor is 
not determined to be an endometrioid endometrial carcinoma, the patient will be 
excluded from the analysis. If immunostaining results are non-specific or negative using 
the positive control run with each cycle, the immunohistochemistry will be repeated. 
 
10.3.4 Location of Testing 
Each month, the NRG Oncology Biospecimen Bank (NRG BB)-Columbus will batch 


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ship seven fresh cut unstained sections (charged, 4μm) to Dr. Megan Samuelson (Central 
Pathology Core Laboratory, University of Iowa). The Central Pathology Core Laboratory 
is CLIA certified and College of American Pathologists (CAP) accredited.  
 
10.3.5 Biospecimen Submission for Testing 
FFPE tumor blocks (or seven unstained sections [charged, 4μm]) must be shipped to the 
NRG BB-Columbus. Unstained sections must be shipped to the NRG BB-Columbus 
immediately after sectioning. See Mandatory Biospecimen Submission Table (section 
10.4.1) for details. Note: The time from surgical removal to processing (i.e., time in 
formalin) should be documented on Form TR (i.e., Estimated Processing Time). For 
optimal assessment of molecular markers, this time should be less than one hour. 
 
10.4 
Biospecimen Submission Tables 
Biospecimens listed below should not be submitted until after patient registration and 
Bank ID assignment. 
 
A detailed description of biospecimen procedures can be found in Appendix IV. 
 
10.4.1 Mandatory Biospecimen Submissions 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below. 
Required Biospecimen (Biospecimen Code) 
Collection Time Point 
Sites Ship 
Biospecimens To 
FFPE Pre-treatment Primary Tumor (FP01)1 
1st Choice: block 
2nd Choice: 17 unstained fresh cut sections 
(charged, 4μm)2 
Collected during D&C or 
biopsy, prior to study 
treatment.3 
NRG Oncology BB-
Columbus  within 8 
weeks of registration4 
FFPE Post-treatment Primary Tumor (FP02)1 
(at least 80% tumor required) 
1st Choice: block 
2nd Choice: 17 unstained fresh cut sections 
(charged, 4μm)2 
Collected during hysterectomy 
or BSO, after receiving study 
treatment.3 
NRG Oncology BB-
Columbus  within 12 
weeks of registration4 
1 A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the NRG BB-
Columbus. 
2 Unstained fresh cut sections must be shipped to the NRG BB-Columbus immediately after sectioning. 
3 The time from surgical removal to processing (i.e., time in formalin) should be documented on Form TR (i.e., 
Estimated Processing Time). For optimal assessment of molecular markers, this time should be less than one hour. 
4 NRG Oncology BB-Columbus / Protocol NRG-GY011, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org. 
 
10.4.2 Optional Biospecimen Submissions 
            If the patient gives permission to participate in this optional study component, then    
            participating sites are required to submit the patient’s biospecimens as outlined below. 
Required Biospecimen (Biospecimen Code) 
Collection Time Point 
Sites Ship 
Biospecimens To 
Snap Frozen Post-treatment Primary Tumor 
(RP01)1 
at least 0.2g in foil 
Collected during hysterectomy or 
BSO, after receiving study 
treatment2 
NRG Oncology BB-
Columbus  within 4 
weeks of registration3 
1 A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the NRG BB-


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Columbus. 
2 The time from surgical removal to freezing should be documented on Form TR (i.e., Estimated Processing Time).  
3  NRG Oncology BB-Columbus / Protocol NRG-GY011, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org. 
 
10.5 
Exploratory Biomarker Laboratory Testing 
Note: Exploratory biomarker testing of banked specimens will not occur until an 
amendment to this treatment protocol (or separate correlative science protocol) is 
reviewed and approved in accordance with National Clinical Trials Network (NCTN) 
policies. 
 
10.5.1 Immunohistochemistry 
Pre- and post-treatment FFPE will be used to assess p21, PRB, ER, amphiregulin, 
FOXO1, and methylation markers indicative of HDACi activity. The NRG Oncology 
Biospecimen Bank (NRG BB)-Columbus will batch ship ten unstained sections (charged, 
4μm) to Drs. Kimberly Leslie and Shujie Yang (University of Iowa). 
 
11. SPECIAL STUDIES (NON-TISSUE) 
Not applicable. 
 
12. ASSESSMENT OF EFFECT  
No clinical evaluation criteria or endpoints are applicable to this protocol.  The evaluation 
criteria are histologic, immunohistochemical and molecular as indicated below.  
 
12.1 
Histologic Response   
 
An endpoint of the study is the histologic response (complete or partial) in endometrial 
adenocarcinomas 21-24 days following administration of  medroxyprogesterone acetate 
with or without entinostat.  The slide from the initial sample will be compared to the slide 
from the matching hysterectomy specimen without knowledge of treatment given.18, 23   
 
12.1.1 Complete Histologic Response: indicates the presence of diffuse glandular secretory 
change, involution or atrophy, with loss of mitotic activity, and presence of stromal 
decidualization throughout the tumor sample from the hysterectomy.   
 
12.1.2 Partial Histologic Response: represents a mixture of foci with glandular secretion or 
atrophy, loss of mitotic activity, and the presence of stromal decidualization, and foci of 
persistent adenocarcinoma with cell stratification, nuclear pleomorphism, mitoses, and 
the absence of stromal decidualization.   
 
12.1.3 No Histologic Response: reflects the diffuse persistence of histologic features diagnostic 
of adenocarcinoma.   
 
12.2 
Steroid Receptor, Ki67 and p21 Status 
 
This trial incorporates three integrated biomarkers, PR, Ki67 and p21.  


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34
Immunohistochemical staining for PR (integrated biomarker) and ER (exploratory 
biomarker) will be evaluated in a semi-quantitative manner following the initial work of 
Carcangiu et al and Chambers et al, who demonstrated excellent correlation in the 
assessment of ER and PR level using immunohistochemistry compared with 
biochemical methods such as ligand binding.2, 3  The College of American Pathologists 
guidelines will be followed.7 An experienced pathologist will review each slide in a 
blinded fashion and indicate the percent of immunopositive tumor cells. Per the 
guidelines, at least 1% of the cells in the specimen must be immunoreactive to consider 
the tissue positive. The intensity of staining (1+ to 3+ will also be scored, using the 
positive control tissue sample as 3+.  +.  Two additional pathologists (the chair and co-
chair of the Pathology Committee) will independently review a sample of 50 slides to 
provide an estimate of the interobserver variability (see Sections 12.2.1, 12.2.2, and 
12.2.3 for scoring).  If the reproducibility is less than 90%, then a complete review of all 
steroid receptor immunohistochemistry may be performed.  In general, the technique 
provides reliable semi-quantitation of receptor expression using a review and scoring 
method now employed by most academic health centers on clinical reports.   
 
Ki67 is a nuclear protein that is tightly linked to the cell cycle. It is a marker of cell 
proliferation and has been used to stratify good and poor prognostic categories in 
invasive breast cancer and other tumor types. Immunostaining for Ki67 using the MIB-1 
antibody strongly correlates with expression of the Ki67 gene and with tumor 
invasiveness and inhibition of apoptosis11. Immunohistochemistry for Ki67 is an 
integrated biomarker for this trial. Ki67 protein expression is predicted to be down-
regulated in endometrial cancer cells in response to activated PR and histologic response. 
Immunohistochemistry scoring will be carried out by assessing the number of cells with 
positive nuclear staining/high power field (averaged over 3 fields) as previously 
performed for Study GOG-0211. 
 
The third integrated biomarker for this trial is p21WAF/Cip1/Sdi1/Pic1, a cyclin-dependent 
kinase inhibitor and tumor suppressor, induced by progesterone through activated PR. 
This assay will be used to indicate PR transcriptional activity.  Immunohistochemistry for 
p21 will be scored using the percent of cells staining positively X the intensity of staining 
(1+ - 3+) using colon cancer specimens as a positive control.  
 
12.2.1 PR or ER Negative: when less than 10% of the tumor cells exhibit nuclear staining for 
PR or ER, respectively. 
 
12.2.2 PR or ER Positive: when 10-50% of the tumor cells exhibit nuclear staining for PR or 
ER, respectively. 
 
12.2.3 Strongly Positive for PR or ER: when greater than 50% of the tumor cells exhibit 
nuclear staining for PR or ER, respectively. 
 
 


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13. DATA AND RECORDS 
13.1 
Data Management/Collection 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave, the 
site user must have an active CTEP-IAM account and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
rosters at the enrolling site. 
 
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 
(iMedidata-Notification@mdsol.com) to activate their account. 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 will be listed in the 
upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will 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 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. 
 
13.2 
Summary of Data Submission 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for timelier monitoring of patient 
safety and care. See Sections 7.2 and 7.5 for information about expedited and routine 
reporting.   
 
For reporting of second primary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
Summary of Data Submission: Refer to the NRG website [Insert weblink to data 
submission summary] for the table of Required Forms and Materials.  


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13.3 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
Monitoring Method for Protocol NRG-GY011: CDUS Abbreviated 
 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
The overall objective of this study is to assess the short-term biologic activity of an 
HDAC inhibitor preceded by progestin in comparison to progestin alone in patients 
newly diagnosed with endometrioid endometrial carcinoma.  This study is designed as a 
two-arm, open label, randomized, surgical window trial with a short term 
medroxyprogesterone acetate reference arm and an experimental arm of short term 
medroxyprogesterone acetate followed by entinostat (given over three doses).  Treatment 
will be given prior to standard of care surgery, hysterectomy, to test the validity of the 
proposed mechanism of action of entinostat in the short term.   
 
Prior to patient registration, eligibility will be reviewed by Entry Form verification.  The 
sequence of treatment assignments will be concealed from institutions and patients until 
registration with verification of eligibility.   Patients will be registered by the 
participating site through OPEN and randomization will be carried out centrally by the 
NRG Statistics and Data Management Center.  Treatment group assignment will be 
determined using a procedure that tends to randomly allocate study treatment s at a 1 to 1 
ratio. 
 
Reports and publications will include a complete accounting of all patients registered to 
this study. 
 
14.2 
Study Endpoints 
Primary endpoint:  
• The mean post-treatment tumor progesterone receptor score (percent cells staining 
positive multiplied by the staining intensity) compared between treatment arms to 
evaluate the association of the addition of entinostat treatment on tumor progesterone 
receptor expression.  
Secondary endpoints:  
• The difference in the proportion of patients with a histologic tumor response 
(complete or partial) between treatment arms. 
• The mean post-treatment tumor Ki67 positive cell counts compared between 
treatment arms. 
• The frequency and maximum severity of acute drug emergent and post-surgical 
adverse events by treatment arm as graded and categorized by CTCAE v4.0. 
Exploratory endpoints 
• The mean post-treatment tumor estrogen receptor score (percent cells staining 


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positive multiplied by the staining intensity) compared between treatment arms.  
• The mean post-treatment tumor p21 receptor score (percent cells staining positive 
multiplied by the staining intensity) compared between treatment arms. 
• Co-expression of PR, Ki67 and p21 compared between the treatment arms (an 
increase in PR, accompanied by a decrease in Ki67 and an increase in p21) 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints 
The design will provide a direct assessment of the null hypothesis that there is no 
difference in mean post-treatment tumor progesterone receptor scores in those treated 
with progestin followed by entinostat compared with those treated with progestin alone. 
 
14.3.2 How Primary Endpoints Will Be Analyzed 
A treatment difference in the distribution of post-treatment progesterone receptor scores 
will be tested using a Mann-Whitney test. 
 
14.3.3 Sample Size and Power Calculations:  
A sample size of 40 patients (20 in each treatment group) with associated evaluable pre- 
and post-treatment specimens will be targeted for testing for a treatment difference in the 
distribution of post-treatment progesterone receptor scores using a Mann-Whitney test.  
Type I error is set at 0.05 for a two-sided hypothesis test.  Data from GOG-0211 were 
used to set the design assumptions.22It is assumed that progestin treatment alone will 
result in a down regulation of receptor levels from a mean of 1.7 pre-treatment to a mean 
of 0.7 post-treatment (mean score decrease of 1.0).  With 40 evaluable participants there 
is 90% power to detect a treatment difference of -1.0 assuming a standard deviation of 
0.8 in the reference group and 1.0 in the experimental treatment group.  A primary 
endpoint inevaluability rate of 20% of patients enrolled is planned for due to the 
expectation that some assay results will be inevaluable or non-compliance with treatment.  
Thus a total sample size of 50 patients is planned to achieve the primary objective of this 
study with the desired precision and error tolerance.    
 
The primary analysis will adhere to the intention-to-treat principle for those with 
evaluable specimens; this is expected to be equally likely on each arm.  A sensitivity 
analysis will be performed by removing patients on the experimental arm that do not 
receive at least two doses of entinostat.  This sensitivity analysis is intended to evaluate 
the effect in an idealized subgroup recognizing that removing these patients through a 
non-random process can lead to bias since we cannot identify cases on their counterparts 
on the reference arm. 
 
Other testing procedures were considered.  For example, an ANCOVA model could be 
used to test the treatment difference while adjusting for pre-treatment progesterone 
receptor scores or testing the mean post-treatment – pre-treatment differences could be 
compared between arms with a T test.  T tests are generally less powerful than 
ANCOVA.  The ANCOVA model and a T test require paired samples from each 
individual. Stronger assumptions about normality of model residuals are required that do 
not appear to hold (see histograms in Figure S1).  Further ANCOVA assumptions 


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presume that there is a linear relationship between pre- and post-test scores and equal 
variances between treatment groups.   Finally, the correlation between pre- and post-
treatment samples is only 0.3 (Table S1) and adjustment for baseline levels in an 
ANCOVA model will only account for 9% of the within group variance.  An ANCOVA 
model can be fit to the data as an exploratory analysis to estimate the difference in post-
treatment progesterone receptor means accounting for the pre-treatment scores after 
assessment of assumptions and adjustments for departures from the assumptions.     
 
Table S1.  Mean, standard deviation and correlation of pre- and post-treatment 
progesterone receptor from GOG-0211 
 
 
Sample 
Size 
Sample 
Mean 
Sample 
Standard 
Deviation 
Sample 
Correlation
Pre-treatment progesterone 
receptor score 
53 
1.78 
1.02 
0.3 
Post-treatment progesterone 
receptor score 
53 
0.66 
0.80 
 
Figure S1.  Histograms and scatter plots of pre- and post-treatment progesterone receptor 
scores from GOG-0211 
 
 
 


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Table S2.  Sample Sizes for Various Two Sample Tests – the largest sample size was 
chosen to accommodate possible scenarios 
 
Test (Distribution) 
N1 
N2 
T Test 
19 
19 
M-W Test (Uniform) 
19 
19 
M-W Test (Logistic) 
18 
18 
M-W Test (Normal) 
20 
20 
ANCOVA (Normal) 
17 
17 
 
Null Hypothesis: Mean1=Mean2. Alternative Hypothesis: Mean1<>Mean2 
N1 and N2 are the number of patients in each treatment group.  
Calculations were done using PASS 2008 version 08.0.16 release date:  January 27, 
2011.9  
 
Simulation results using historical post-treatment data are consistent with the power 
calculations under test assumptions.   
 
14.4 
Study Monitoring of Primary Objectives 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. There is no formal interim analysis 
planned.  The DMC may also elect to review the study on an “as needed” basis.  
 
14.5 
Accrual/Study Duration Considerations 
Between 1/2005 and 9/2008, accrual on GOG-0211 averaged 18 enrollments per year; at 
its maximum it was 30 per year. The expected annual rate is 18 per year over 3 years 
without any interruptions; this includes a 3 month start-up time with little to no accrual.  
Operationally, accrual will automatically be paused by OPEN when the 50th patient is 
enrolled.  Final analysis will require distribution of specimens, resolution of queries, 
completion of all laboratory tests, and collation of laboratory data with clinical data.  
These can be accomplished within 6-12 months of final patient entry.    
 
14.6 
Dose Level Guidelines 
There are no dose level changes defined in this study. 
 
14.7 
Secondary or Exploratory Endpoints (including correlative science aims) 
 
14.7.1 Secondary Hypotheses and Endpoints:  
There will be an assessment of the null hypothesis that there is no difference in 
proportion of patients with a complete or partial histologic tumor response and Ki67 
expression in those treated with progestin followed by entinostat compared with those 
treated with progestin alone.   
 
Data from GOG-0211 suggest that responders will have a significant decrease in Ki67 
expression (approximately 50% decrease in the average number of cells staining positive 


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40
for Ki67) when compared to non-responders (22% decrease) when treated with 
medroxyprogesterone acetate.  With the addition of entinostat, the number of responders 
is expected to increase and Ki67 is expected to be lower.   
 
Based on data from GOG-0211, the mean number of cells staining for ki67 post treatment 
ki67 is estimated to be 136 with a standard deviation of 119. There is 80% power to 
detect a treatment difference of  80 (mean of 56) using a Mann-Whitney test with 42 
patients equally allocated and setting type 1 error to 10%.  Power to detect this difference 
with 40 patients is 78%. 
 
 
14.7.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Similar testing procedures as used for the primary endpoint can be applied to Ki67 
scores.  A confidence interval around the estimate of the treatment difference in the 
proportion with a histologic response will be constructed.  Correlation between Ki67 and 
histologic response will be evaluated by treatment arm.   
The frequency and maximum severity of acute drug emergent and post-surgical adverse 
events will be tabulated by treatment arm as graded by CTCAE v4.0. 
 
14.7.3 Monitoring of Adverse Events 
Clinical data collected on this protocol will be reviewed by the study data manager and 
will also be reviewed by the Study Chairperson in conjunction with the Statistics and 
Data Management Center (SDMC) on an ongoing basis.  In some instances, because of 
unexpectedly severe toxicity, early closure of a study may be elected. 
 
The frequency and severity of all toxicities are tabulated from submitted case report 
forms and summarized for review by the study chairperson, disease site committee and 
the committee charged with monitoring safety in conjunction with each semi-annual 
meeting.  
 
All serious adverse events (SAEs) are reported to the Study Chair, Sponsor, 
Pharmaceutical Company, and regulatory agencies as mandated in the protocol. SAE 
reports are reviewed by the Study Chair (or designated co-chair) immediately for 
consideration of investigator notification of a suspected unexpected serious adverse 
reaction (SUSAR), protocol amendment, and/or immediate study suspension. All 
participating institutions will receive notification of the SUSAR from NRG as well as the 
reason for study suspension (if applicable). Under these circumstances, accrual cannot be 
re-activated until the study is reviewed by the committee charged with monitoring safety. 
However, patients currently receiving treatment may continue to receive treatment in 
accordance with protocol guidelines at the discretion of their physicians, unless directed 
otherwise. 
 
 
 
14.8 
Gender/Ethnicity/Race Distribution 
 
The expected enrollment data is based on accrual from GOG-0210.   
 


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Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
1 
0 
0 
0 
1 
Asian 
1 
0 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
6 
0 
0 
0 
6 
White  
40 
0 
2 
0 
42 
More Than One Race 
0 
0 
0 
0 
0 
Total 
48 
0 
2 
0 
50 
 
 
 
 
 


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REFERENCES 
1. Br J Cancer 2102 jan 3; 106(1):77-84 koi:  10. 1038/bjc.2011.527.  Epub 2011 Dec 1 
2. Carcangiu, ML, Chambers JT, Voynick IM, Pirro M, and Schwartz PE.  
Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 
patients with endometrial carcinoma.  Part I:  Clinical and histologic correlations. Am J Clin 
Pathol  94:247-54, 1990. 
3. Chambers JT, Carcangiu ML, Voynick, IM, and Schwartz PE.  Immunohistochemical 
evaluation of estrogen and progesterone receptor content in 183 patients with endometrial 
carcinoma.  Part II:  Correlation between biochemical and immunohistochemical methods 
and survival.  Am J Clin Pathol  94:255-60, 1990. 
4. Decruze SB, Green JA. Hormone therapy in advanced and recurrent endometrial cancer: a systematic 
review. International journal of gynecological cancer : official journal of the International 
Gynecological Cancer Society. Sep-Oct 2007;17(5):964-978. 
5. Duska L, Lothamer H, Faust W, Petroni G, Fracasso PM, Parsons S.  Phase 0 studies in 
gynecologic malignancies are feasible and acceptable to patients. Abstract presented for the 
2013 Society of Gynecologic Oncology 44th Annual Meeting on Women’s Cancer 
6. Duska L, Lothamer H, Faust W, Petroni G, Fracasso PM, Parsons S.  A phase 0 study of 
dasatinib in endometrial cancer.  Abstract presented for the 2014 Society of Gynecologic 
Oncology 45th Annual Meeting on Women’s Cancer March 22 – March 25, 2014 Tampa 
Convention Center Tampa, FL 
7. Ehrlich CE, Young PC, Stehman FB, Sutton GP, Alford WM. Steroid receptors and clinical 
outcome in patients with adenocarcinoma of the endometrium. American journal of obstetrics 
and gynecology. Apr 1988;158(4):796-807. 
8. Hammond MEH, Hayes DF, Dowsett M, et al.  American Society of Clinical 
Oncology/College of American Pathologists guideline/recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer.  Arch 
Pathol Lab Med 2010:134:907-922. 
9. Hintze, J.  2008.  PASS 2008 NCSS, LLC.  Kaysville, Utah.  www.ncss.com 
10. Kim JJ, Chapman-Davis E. Role of progesterone in endometrial cancer. Seminars in 
reproductive medicine. Jan 2010;28(1):81-90. 
11. McCarty KS, Jr., Miller LS, Cox EB, Konrath J, McCarty KS, Sr. Estrogen receptor 
analyses. Correlation of biochemical and immunohistochemical methods using monoclonal 
antireceptor antibodies. Archives of pathology & laboratory medicine. Aug 1985;109(8):716-
721. 
12. Modern Pathology (2005) 18, 374-381, doi:10.1038/modpathol.3800254 
13. Muraki Y, Banno K, Yanokura M, et al. Epigenetic DNA hypermethylation: clinical 
applications in endometrial cancer (Review). Oncology reports. Nov 2009;22(5):967-972. 
14. Ren Y, Liu X, Ma D, Feng Y, Zhong N. Down-regulation of the progesterone receptor by the 
methylation of progesterone receptor gene in endometrial cancer cells. Cancer genetics and 
cytogenetics. Jun 2007;175(2):107-116. 
15. Singh M, Zaino RJ, Filiaci VJ, Leslie KK. Relationship of estrogen and progesterone 
receptors to clinical outcome in metastatic endometrial carcinoma: a Gynecologic Oncology 
Group Study. Gynecologic oncology. Aug 2007;106(2):325-333. 
16. Takai N, Desmond JC, Kumagai T, et al. Histone deacetylase inhibitors have a profound 
antigrowth activity in endometrial cancer cells. Clinical cancer research : an official journal 
of the American Association for Cancer Research. Feb 1 2004;10(3):1141-1149. 


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17. Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the 
treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the 
Gynecologic Oncology Group. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. Jun 1999;17(6):1736-1744. 
18. Wheeler DT, Bristow RE, Kurman RJ. Histologic alterations in endometrial hyperplasia and 
well-differentiated carcinoma treated with progestins. Am J Surg Pathol. 2007; 31:988–98. 
[PubMed: 17592264] 
19.  Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. 
Trends in endocrinology and metabolism: TEM. Apr 2011;22 (4):145-152. 
20. Yang S, Thiel KW, De Geest K, Leslie KK. Endometrial cancer: reviving progesterone 
therapy in the molecular age. Discovery medicine. Sep 2011;12 (64):205-212. 
21. Yang S, Jia Y, Liu X, et al. Systematic dissection of the mechanisms underlying progesterone 
receptor downregulation in endometrial cancer. Oncotarget. Oct 30 2014;5 (20):9783-9797. 
22. Zaino RJ, Brady WE, Todd W, Leslie K, Fischer EG, Horowitz NS, Mannel RS, Walker JL, 
Ivanovic M, Duska LR.  Histologic effects of medroxyprogesterone acetate on endometrioid 
endometrial adenocarcinoma: A Gynecologic Oncology Group study.  Int J Gynecol Pathol. 
2014 Oct 1. 
23. Zaino RJ, Brady WE, Todd W, et al. Histologic effects of medroxyprogesterone acetate on 
endometrioid endometrial adenocarcinoma: a Gynecologic Oncology Group study. 
International journal of gynecological pathology: official journal of the International Society 
of Gynecological Pathologists. Nov 2014;33 (6):543-553. 
 
 
 


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APPENDIX I – PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX II- NYHA CLASSIFICATION 
 
Congestive Heart Failure – New York Heart Association Classification 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 
114. 
 
 


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APPENDIX III – COLLABORATIVE AGREEMENT 
 
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. 


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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. 
 
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. 
 
 


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APPENDIX IV – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES 
 
I. Obtaining a Bank ID for Translational Science Biospecimens 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational science 
biospecimens and accompanying paperwork must be labeled with this coded patient number.  
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates that 
a patient has agreed to participate in the translational science component. If a patient has 
previously been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the same as 
the previously assigned Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID to a 
patient (Email: support@nrgoncology.org; Phone: 716-845-7767). 
 
II. Requesting Translational Science Biospecimen Kits 
One single chamber kit will be provided per patient for the collection and shipment of frozen 
tissue.  
 
Sites can order kits online via the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). Each site may order two kit types per 
protocol per day (daily max = 6 kits).  
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
Note: Unused materials and kits should be returned to the NRG BB-Columbus. 
 
III. FFPE Shipped to the NRG BB-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (i.e., primary tumor). 
 
Pre-treatment primary tumor (FP01) should be collected from D&C or biopsy prior to 
treatment. 
 
Post-treatment primary tumor (FP02) should be collected during hysterectomy or BSO. 
 
Only one block may be submitted per tissue type. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
Every attempt should be made to provide an FFPE block; however, if a block cannot be provided 
on a permanent basis, then 17* unstained sections (charged, 4µm) should be submitted. If 
submitting unstained sections, your pathology department must cut fresh 4μm sections 


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sequentially from one block at the time of your request. These fresh cut sections must be 
shipped to the NRG BB-Columbus within 48 hours of sectioning. 
 
*Seven unstained slides (charged, 4μm) must be shipped to the NRG BB-Columbus to satisfy the 
mandatory biospecimen requirement for integrated biomarker testing.  
 
Completing Form TR for FFPE Biospecimens 
• The type of biospecimen (block, slides) should be specified on Form TR. If submitting slides, 
the slide type, thickness, and count should also be specified. 
• The time from surgical removal to processing (i.e., time in formalin) should be 
documented on Form TR (i.e., Estimated Processing Time). For optimal assessment of 
molecular markers, this time should be less than one hour. 
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational 
science tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY # # #) 
specimen code (see above) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
IV. Frozen Tissue Shipped to the NRG BB-Columbus 
1.  Label the zip-lock bag as described below. If using an adhesive label, place it inside the bag. 
2. Snap freeze tissue within 15 minutes after surgery for optimal preservation. Place tissue on a 
piece of foil and fold foil around tissue as shown in diagram below. Snap freeze tissue on dry 


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50
ice or in the vapor phase liquid nitrogen (do not submerge the tissue in liquid nitrogen). If 
neither dry ice nor liquid nitrogen is available, slow freeze tissue in a -70°C to -80°C freezer. 
 
3. Once the tissue is frozen, place in pre-labeled zip-lock bag. 
4.  Immediately store snap frozen tissue in a liquid nitrogen freezer (at vapor phase), a -70°C to -
80°C freezer, or by direct exposure with dry ice until ready to ship. 
 
Completing Form TR for FFPE Biospecimens 
• The time from surgical removal to freezing should be documented on Form TR (i.e., 
Estimated Processing Time). 
 
Labeling Frozen Tissue 
A waterproof permanent marker or printed label should be used to label each translational 
science tissue biospecimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (NRG - GY # # #) 
specimen code (see protocol section 10.4.2) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
V. Submitting Form TR 
An electronically completed copy of Form TR must accompany each biospecimen shipped to the 
NRG BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not 
collected. 
 
Form TR should be printed from the Translational Research Form screen in Rave using the 
“PDF File” link at the top of the form. Clicking this link will generate a single page PDF. Do 
not use the “Printable Version” or “View PDF” links at the bottom of the form or any other 
method to print the form, as these formats will not be accepted.  
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@nrgoncology.org; Phone: 
716-845-7767). 
 
VI. Shipping Translational Science Biospecimens 
Translational science biospecimens should not be shipped until after patient registration 
and Bank ID assignment. 
 
An electronically completed copy of Form TR must be included for each translational 
science biospecimen.  
 


NCI Protocol #: NRG-GY011 
Version Date: 11/05/18 
 
 
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A. FFPE Tissue 
FFPE tissue* and a copy of the corresponding pathology report should be shipped using your 
own container at your own expense to: 
 
NRG BB-Columbus / Protocol NRG-GY011 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Do not ship FFPE tissue for Saturday delivery. 
 
Upon receipt at the NRG BB-Columbus, all unstained sections will be vacuum sealed. 
 
B. Frozen Tissue 
Frozen tissue, including a copy of the corresponding pathology report for frozen tissue, should be 
shipped using the biospecimen kits provided to the NRG BB-Columbus (address above). 
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through 
Friday delivery. Do not ship frozen biospecimens on Friday or the day before a holiday. Note: 
Saturday delivery is not available for frozen biospecimens.  
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-
70oC freezer, liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be 
shipped. 
 
Shipping Frozen Translational Science Biospecimens in a Single Chamber Kit  
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen biospecimens a s zip-lock bag. 
3. Place the zip-lock bag in the biohazard envelope containing absorbent material. Put the 
secondary envelope into a Tyvek envelope. Expel as much air as possible before sealing both 
envelopes. 
4. Place the Tyvek envelope containing the frozen biospecimens into the kit and fill the chamber 
to the top with dry ice. 
5. Insert a copy of Form TR and corresponding pathology report for the biospecimen. 
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other 
durable sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management link   
(https://ricapps.nationwidechildrens.org/KitManagement). Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
VII. Banking Translational Science Biospecimens for Future Research 
Biospecimens will remain in the NRG BB-Columbus and made available for approved research 


NCI Protocol #: NRG-GY011 
Version Date: 11/05/18 
 
 
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projects if the patient has provided permission for the use of her biospecimens for future health 
research. 
 
Note: Testing of banked biospecimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in accordance with 
National Clinical Trials Network (NCTN) policies. 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent 
document and electronically via the Specimen Consent form. At the time of biospecimen 
selection for project distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any 
time if the patient changes her mind. 
 
If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy 
or return any remaining biospecimens. The patient’s biospecimens will not be used for any 
further research; however, any biospecimens distributed for research prior to revoking consent 
cannot be returned or destroyed. In addition, the patient cannot be removed from any research 
that has been done with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense.