A Phase II Study of Tazemetostat (EPZ-6438) in Recurrent or Persistent Endometrioid or Clear Cell Carcinoma of the Ovary, and Recurrent or Persistent Endometrioid Endometrial Adenocarcinoma
Phase: PHASE2
Conditions: Recurrent Endometrial Endometrioid Adenocarcinoma, Recurrent Malignant Uterine Corpus Neoplasm, Recurrent Ovarian Carcinoma, Recurrent Ovarian Clear Cell Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

 
NRG-GY014 
 
NCI Version Date: January 11, 2023 
i
 
 SUMMARY OF CHANGES 
 
For Protocol Amendment #6 to: NRG-GY014 
 
NCI Protocol #: NRG-GY014 
Local Protocol #: NRG-GY014 
 
NCI Version Date: January 11, 2023 
 
This amendment is in response to an RRA from Dr. Richard Piekarz (rpiekarz@nih.gov) 
 
 
Section 
Comments 
Title Page 
The NCI Version Date is now January 11, 2023 
7.3 
The Tazemetostat CAEPR has been updated to Version 2.5, November 
16, 2022: 
 
• Added New Risk: 
• Less Likely: Alkaline phosphatase increased; Bronchial 
infection; Creatinine increased 
• Also Reported on Tazemetostat Trials But With 
Insufficient Evidence for Attribution: Activated partial 
thromboplastin time prolonged; Death NOS; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Skin 
and subcutaneous tissue disorders - Other (HSV oral 
infection); Thrush 
 
• Increase in Risk Attribution: 
• Changed to Likely from Less Likely: Anemia; Fatigue; 
Nausea; Vomiting 
• Changed to Less Likely from Also Reported on 
Tazemetostat Trials But With Insufficient Evidence for 
Attribution: Abdominal pain; Alanine aminotransferase 
increased; Aspartate aminotransferase increased; Edema 
limbs; Fever; Headache; Hyperglycemia; 
Hypertriglyceridemia; Hyponatremia; 
Hypophosphatemia; Lymphocyte count decreased; Tumor 
pain; Upper respiratory infection; White blood cell 
decreased 
 
• Modified Specific Protocol Exceptions to Expedited Reporting 
(SPEER) reporting requirements:  

 
NRG-GY014 
 
NCI Version Date: January 11, 2023 
ii 
Section 
Comments 
• Added: Anemia; Abdominal pain; Anorexia; 
Constipation; Cough; Diarrhea; Dyspnea; Fever; 
Headache; Lymphocyte count decreased; White blood cell 
decreased 
 
ICD 
Please see the ICD for additional changes. 
 

 
NRG-GY014 
 
NCI Version Date: January 11, 2023 
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NRG ONCOLOGY 
NRG-GY014 
(ClinicalTrials.gov NCT # 03348631) 
 
A PHASE II STUDY OF TAZEMETOSTAT (EPZ-6438) IN RECURRENT OR 
PERSISTENT ENDOMETRIOID OR CLEAR CELL CARCINOMA OF THE OVARY, 
AND RECURRENT OR PERSISTENT ENDOMETRIOID ENDOMETRIAL 
ADENOCARCINOMA 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
Philadelphia, PA 19103 
Study Team (08/13/2019) (07-JUL-2020) (20-OCT-2021) 
Principal Investigator/Gyn Oncology 
Medical Oncology Co-Chair 
Ramez N. Eskander, M.D. 
Alison M. Schram, M.D. 
UCSD Moores Cancer Center 
Memorial Sloan Kettering Cancer Center 
3855 Health Sciences Drive 
300 East 66th Street 
La Jolla, CA 92093 
New York, NY 10065 
858-822-6199/FAX: 858-822-6319 
646-888-5388/FAX: 646-888-4268 
reskander@health.ucsd.edu  
schrama@mskcc.org  
 
 
Developmental Therapeutics Committee 
Chair 
 
Roisin O’Cearbhaill, M.D. 
 
Memorial Sloan Kettering Cancer Center 
 
300 East 66th Street 
 
New York, NY 10065 
 
646-888-4227/FAX: 646-888-4265 
 
ocearbhr@mskcc.org  
 
 
 

 
NRG-GY014 
 
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Statistician 
Translational Science Co-Chair 
Michael Sill, Ph.D. 
Michael J. Birrer, M.D, PhD 
NRG Oncology Biostatistical Office-Buffalo 
Slot 623 
Elm and Carlton Streets 
4301 West Markham 
Buffalo, NY 14263 
Winthrop P. Rockefeller Cancer Institute 
716-854-5702/FAX: 716-845-8393 
Little Rock, AR 72205  
sillm@nrgoncology.org  
501-526-2272 
 
mjbirrer@uams.edu  
Translational Scientist  
 
Heather A Lankes, PhD, MPH 
 
NRG Oncology 
Data Manager 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
Nicholas Celender 
Philadelphia, PA 19103 
NRG Oncology SDMC-Pittsburgh 
215-854-0770/FAX: 215-854-0716 
201 N. Craig St., Suite 500 
lankesh@nrgoncology.org 
Pittsburgh, PA 15213 
 
412-383-4916/FAX: 412-624-1082 
 
celendern@nrgoncology.org  
Protocol Coordinator (06-APR-2022) 
 
Meg Colahan 
 
NRG Oncology 
 
Four Penn Ctr, 1600 JFK Blvd, Ste 1020 
 
Philadelphia, PA 19103 
 
215-854-0770/FAX: 215-854-0716 
 
colahanm@nrgoncology.org    
 
SWOG Champion 
William R Robinson III, MD 
University of Mississippi Medical Center 
Jackson, MS 
602-984-1962 
Email: wrobinson1@umc.edu   

 
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NRG Oncology Contact Information (08/13/2019) (20-OCT-2021) 
Data Management 
For questions concerning data 
submission 
Nicholas Celender 
NRG Oncology SDMC-Pittsburgh  
201 N. Craig St., Suite 500 
Pittsburgh, PA 15213 
412-383-4916/FAX: 412-624-1082 
celendern@nrgoncology.org   
Protocol Development 
For questions concerning 
protocol and informed consent 
versions and amendments 
Meg Colahan (06-APR-2022) 
NRG Oncology-Philadelphia East 
1600 JFK Blvd, Suite 1020 
Philadelphia, PA 19103 
215-854-0770/FAX 215-854-0716 
colahanm@nrgoncology.org    
Biospecimen Bank 
 
NRG BB-Columbus 
Biopathology Center, Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 866-464-2262/FAX: 614-722-2897 
Email: bpcbank@nationwidechildrens.org 
Gynecologic Oncology 
Committee Chair 
Carol Aghajanian, M.D. 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Tazemetostat 
CTEP 
791066 
 
DCTD 
 
Participating Sites 
 U.S. 
  Canada 
 Approved International Member Sites 
 
Document History 
 
Version Date 
Amendment 6 
January 11, 2023 
Amendment 5 
April 06, 2022 
Amendment 4 
December 9, 2021 
Amendment 3 
October 20, 2021 
Amendment 2 
July 7, 2020 
Amendment 1 
08/13/2019 
Initial 
01/25/2019 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with 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. 

 
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CONTACT INFORMATION (08/13/2019) (07-JUL-2020) (20-OCT-2021) (06-APR-2022) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal.  
(Sign in at https://www.ctsu.org,      
and select Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email: 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Refer to 
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 page located on the CTSU members’ website 
(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 log in with a 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 Regulatory Support System (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.  
 
 
 

 
NRG-GY014 
 
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TABLE OF CONTENTS 
1. 
OBJECTIVES (20-OCT-2021) ....................................................................................... - 9 - 
1.1 
Primary Objective ................................................................................... - 9 - 
1.2 
Secondary Objectives .............................................................................. - 9 - 
1.3 
Exploratory Objectives ........................................................................... - 9 - 
2. 
BACKGROUND ............................................................................................................ - 9 - 
2.1 
Background on tazemetostat ................................................................. - 13 - 
2.2 
Translational Science Background ....................................................... - 16 - 
2.3   
Stage 1 data informing protocol modification for patients enrolled after 20-
OCT-2021 version date ......................................................................... - 16 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ........... - 17 - 
3.1 
Patient Selection Guidelines ................................................................. - 17 - 
3.2 
Eligibility Criteria (09-DEC-2021) ....................................................... - 17 - 
3.3 
Ineligibility Criteria (09-DEC-2021) .................................................... - 20 - 
4 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 21 - 
4.1 
PRE-TREATMENT ASSESSMENTS (08/13/2019) (20-OCT-2021) (06-APR-
2022) ..................................................................................................... - 21 - 
4.2 
ASSESSMENTS DURING TREATMENT * (08/13/2019) ................ - 22 - 
4.3 
ASSESSMENTS IN FOLLOW UP ...................................................... - 23 - 
5.  
TREATMENT PLAN/REGIMEN DESCRIPTION ..................................................... - 23 - 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy ......... - 23 - 
5.2 
Radiation Therapy ................................................................................. - 23 - 
5.3 
Surgery .................................................................................................. - 23 - 
5.4 
Device ................................................................................................... - 24 - 
5.5 
Imaging ................................................................................................. - 24 - 
5.6 
Integral Biomarker Assay ..................................................................... - 24 - 
5.7 
Intervention Not Otherwise Categorized .............................................. - 24 - 
5.8 
General Concomitant Medication and Supportive Care Guidelines ..... - 24 - 
5.9 
Duration of Therapy (20-OCT-2021) ................................................... - 26 - 
6.  
TREATMENT MODIFICATIONS/MANAGEMENT ................................................ - 27 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 28 - 
7.1   
Protocol Agents ..................................................................................... - 28 - 
7.2  
Adverse Events and Serious Adverse Events ....................................... - 28 - 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Tazemetostat (NSC 791066) (07-JUL-2020) (20-OCT-2021) ............. - 29 - 
7.4 
Expedited Reporting of Adverse Events (06-APR-2022) ..................... - 31 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (08/13/2019) (07-JUL-2020)- 34 - 
8.1 
CTEP Registration Procedures ............................................................. - 34 - 
8.2 
CTSU Registration Procedures (06-APR-2022) ................................... - 35 - 
8.3 
Patient Enrollment (20-OCT-2021) (09-DEC-2021) (06-APR-2022) .. - 37 - 

 
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8.4 
Data Submission / Data Reporting (20-OCT-2021) (06-APR-2022) ... - 38 - 
9.0 
DRUG INFORMATION .............................................................................................. - 40 - 
9.1 
Tazemetostat (EPZ-6438, E7438), NSC #791066, IND  (06-APR-2022)- 40 - 
10. 
PATHOLOGY/BIOSPECIMEN (20-OCT-2021) ........................................................ - 43 - 
10.1 
Central Pathology Review .................................................................... - 43 - 
10.2 
Biospecimen Selection for Integral Biomarker Testing (20-OCT-2021)- 43 - 
10.3 
Biospecimen Selection for Integrated Biomarker Testing (20-OCT-2021)- 43 - 
NOTE: As of version date 20-OCT-2021, Sections 10.3.1-10.3.5 are no longer 
applicable. ............................................................................................. - 43 - 
10.4 
Biospecimen Submission Tables .......................................................... - 44 - 
10.5 
Exploratory Biomarker Testing (08/13/2019) ...................................... - 45 - 
10.6 
Banking Biospecimens for Future Research ......................................... - 45 - 
11. 
SPECIAL STUDIES (NON-TISSUE) .......................................................................... - 45 - 
12. 
MODALITY REVIEWS .............................................................................................. - 45 - 
13. 
ASSESSMENT OF EFFECT ....................................................................................... - 45 - 
13.1 
Antitumor Effect – Solid Tumors ......................................................... - 45 - 
14. 
DATA AND RECORDS .............................................................................................. - 51 - 
14.1 
Data Management/Collection ............................................................... - 51 - 
14.2 
NRG Data Management Forms ............................................................ - 52 - 
14.3 
Summary of Data Submission .............................................................. - 52 - 
14.4 
Global Reporting/Monitoring ............................................................... - 52 - 
15. 
STATISTICAL CONSIDERATIONS.......................................................................... - 52 - 
15.1 
Study Design (-20-OCT-2021) ............................................................. - 52 - 
15.2 
Study Endpoints .................................................................................... - 53 - 
15.3 
Sample Size and Power Calculations (20-OCT-2021) ......................... - 54 - 
15.4 
Study Monitoring of Primary Objectives 20-OCT-2021) ..................... - 54 - 
15.5 
Accrual/Study Duration Considerations (20-OCT-2021) ..................... - 55 - 
15.6 
Secondary, Translational Research, or Exploratory Endpoints (including 
correlative science aims) (08/13/2019) ................................................. - 55 - 
15.7 
Gender/Ethnicity/Race Distribution ...................................................... - 57 - 
16. 
REFERENCES (20-OCT-2021) ................................................................................... - 58 - 
APPENDIX I FIGO OVARIAN CANCER STAGING 2014 .................................................. - 61 - 
APPENDIX II FIGO STAGING OF ENDOMETRIAL CARCINOMA 2009 ........................ - 63 - 
APPENDIX III PERFORMANCE STATUS CRITERIA ........................................................ - 64 - 
APPENDIX IV CLINICAL TRIAL WALLET CARD  (20-OCT-2021) ................................ - 65 - 

 
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APPENDIX V- PATIENT MEDICATION CALENDAR – TAZEMETOSTAT (20-OCT-2021) (09-
DEC-2021) (06-APR-2022) .......................................................................................... - 66 - 
APPENDIX VI – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (20-OCT-2021) 
(09-DEC-2021) ............................................................................................................. - 68 - 
APPENDIX VII – COLLABORATIVE AGREEMENT ......................................................... - 73 - 
 
 
 

 
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As of Version Date 20-OCT-2021, NRG-GY014 is only enrolling Ovarian Clear 
Cell Carcinoma (OCCC) patients with documented ARID1A mutations 
Step 2 Registration for treatment 
  
NRG-GY014 
SCHEMA (20-OCT-2021) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recurrent or Persistent Endometrioid 
Endometrial Adenocarcinoma with 
measurable disease by RECIST v 1.1 
Patients no longer being accrued to 
this cohort as of version date       
20-OCT-2021 
Step 1 Registration for Eligibility 
• Submit pathology report from primary surgery/diagnosis 
• Submit pathology report from specimen used for NGS (if different) 
• Submit NGS report showing ARID1A mutation 
Tazemetostat 800 mg PO BID until disease progression 
or unacceptable toxicity. See Sec. 5.1. 
Recurrent or Persistent Clear Cell 
Ovarian Cancer (OCCC) with 
measurable disease by RECIST v 1.1 
 
Study is ONLY enrolling OCCC 
patients with documented ARID1A 
mutations as of version date        
20-OCT-2021 

 
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1. 
OBJECTIVES (20-OCT-2021) 
1.1 
Primary Objective 
To assess the clinical activity (overall response rate) of tazemetostat in patients with recurrent 
or persistent endometrioid or clear cell ovarian carcinoma, and patients with recurrent or 
persistent endometrioid endometrial adenocarcinoma. 
1.1.1 As of version date 20-OCT-2021: The primary objective is to assess the clinical activity 
(response frequency) of tazemetostat in patients with recurrent or persistent clear cell 
ovarian carcinoma with an ARID1A mutation. 
 
1.2 
Secondary Objectives 
1.2.1 To examine the nature and degree of toxicity in patients treated with this regimen. 
1.2.2 To examine the progression free survival and overall survival for this patient population 
receiving tazemetostat. 
1.2.3 As of version date 20-OCT-2021: additional secondary objective: to examine the 6 
month clinical benefit rate in patients treated with this regimen. (20-OCT-2021) 
 
1.2.4 To evaluate BAF250a expression in patient samples as an indicator of ARID1A mutation 
status and correlation with the clinical response to study drug. Note: this only applies to 
patients enrolled prior to the 20-OCT -2021 version date. (20-OCT-2021) 
 
1.3 
Exploratory Objectives 
1.3.1 Translational Research Integrated Objective: Whether or not the patient has an ARID1A 
mutation. (08/13/2019)  Note: this only applies to patients enrolled prior to the 20-OCT-
2021 version date. (20-OCT-2021) 
1.3.2 To examine the correlation between ARID1A mutation and BAF250a expression and to 
identify potential mutations predictive of response in patients with preserved BAF250a 
expression. Note: this only applies to patients enrolled prior to the 20-OCT-2021 version 
date. (20-OCT-2021) 
 
2. 
BACKGROUND 
 
 
The treatment of solid tumor malignancies has gradually evolved over the past decade.  
Perhaps best exemplified in the treatment of lung cancer, molecular characterization and 
utilization of targeted agents has emerged as a preferred therapeutic paradigm.  Given the 
above, The Cancer Genome Atlas (TCGA), a collaboration between the National Cancer 
Institute (NCI) and National Human Genome Research Institute (NHGRI), has generated 
comprehensive, multi-dimensional maps of the key genomic changes in 33 types of cancer.  
Recently, the TCGA completed and published the integrated genomic and molecular 
characterization of cervical cancer (Cancer Genome, Atlas 2017).  In addition to data 
previously released for both ovarian (high grade serous) and endometrial (endometrioid and 
serous) cancers, this publication completed the molecular and genomic evaluation of the most 
common gynecologic malignancies, many of which represent an area of un-met clinical need 
(Cancer Genome Atlas, 2013) (Cancer Genome Atlas, 2011). 
 
 

 
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The ARID1A Gene 
 
 
The ARID1A gene has been identified as a frequently mutated tumor suppressor in several 
gynecologic malignancies (Takeda et al, 2016). ARID1A encodes the BAF250a protein, a 
member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, participating in 
chromatin remodeling and transcriptional regulation (Lowery et al, 2012). Aberrations in 
chromatin remodeling have been identified in approximately 20% of all human cancers 
(Bogelstein et al, 2013). Specifically, the SWI/SNF complex is involved in activation or 
inhibition of transcription, and plays a crucial role in carcinogenesis (Takeda et al, 2016). 
Most ARID1A mutations are frameshift or nonsense mutations, and in preclinical studies, 
silencing of ARID1A in non-transformed epithelial cells enhanced cellular proliferation and 
tumorigenesis in mice (Guan et al, 2011).  Similarly, ARID1A knockdown in esophageal 
cancer cell lines enhanced cellular proliferation, whereas increased expression in ARID1A-
deficient cells resulted in an inhibition of proliferation (Streppel et al, 2014). More recently, 
studies have shown that ARID1A mutations are involved in carcinogenesis via the PI3K/AKT 
pathway, with resultant cellular proliferation and inhibition of apoptosis (Takeda et al, 2016). 
 
Genetic studies have revealed an evolutionarily conserved antagonistic relationship between 
the SWI/SNF complex and polycomb group proteins (Kim and Roberts, 2016).  The loss of 
SWI/SNF complex subunits (ARID1A, SMARCB1, SMARA4) results in unopposed zeste 
homolog 2 (EZH2) activity, promoting carcinogenesis, and oncogenic transformation (Figure 
1: available on epizyme.com) (Kim and Roberts, 2016). 
 
Figure 1: Schematic representing the relationship between the SWI/SNF complex and 
PRC2. With loss of SWI/SNF activity, there is 
uninhibited EZH2 activity, resulting in oncogenic 
downstream signaling. 
 
 
 
 
 
 
 
 
 
 
 
 
ARID1A and Endometriosis-Associated Ovarian Cancers (EAOC) 
 
 
Historically, patients with endometrioid and clear cell ovarian cancer have been included in 
larger trials exploring new treatment paradigms in advanced or recurrent ovarian cancer, 
despite differing prognostic and molecular profiles, when compared to the more common high 
grade serous histology (Storey et al, 2008) (Quirkand Natarajan, 2005) (Sugiyama et al, 2000) 
(Winter et al, 2007).  Given the above, a push has been made to examine these entities 

 
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independently. Endometrioid and clear cell ovarian carcinomas are uniquely associated with 
endometriosis, and have been recently referred to as endometriosis-associated ovarian cancer 
(EAOC).   In a landmark study, Wiegand et al, implicated ARID1A as a tumor suppressor gene 
frequently disrupted in ovarian endometrioid and clear cell carcinomas (Wiegand et al, 2010).  
In a cohort of 152 cancer specimens, ARID1A mutations were identified in 46% of clear cell 
ovarian cancers, and 30% of the endometrioid ovarian carcinoma specimens (Table 1). 
Importantly, none of the 76 high grade serous cancer specimens exhibited an identifiable 
mutation (Wiegand et al, 2010).  Furthermore, ARID1A mutations, and lack of BAF250a 
protein expression, were identified in neighboring, contiguous pre-neoplastic atypical 
endometriotic lesions, establishing ARID1A mutation as a potential early event in the 
transformation of endometriosis into cancer (Wiegand et al, 2010). 
 
Table 1. Frequency of ARID1A mutation in endometrioid and clear cell ovarian cancer 
 
 
Endometrioid 
Clear cell 
Wiegland et al.  
30% 
46% 
Rambau et al.  
48% 
-- 
Takeda et al.  
30% 
57% 
*Chene et al.  
22% 
47% 
Mao et al.  
30% 
57% 
Ayhan et al.  
55% 
75% 
*Lowery et al.  
48% 
41% 
 
* expression assessed by BAF250a immunohistochemistry alone 
 
 
In addition to the above, institutional data from the Memorial Sloan Kettering Cancer Center, 
as well as the endometrial TCGA show ARID1A mutation rates ranging from 40-80% in the 
EAOC cohorts as well as the endometrioid endometrial adenocarcinoma specimens (Figure 2) 
(Cancer Genome Atlas, 2013). 
 
 

 
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Figure 2: a) Institutional data from the MSKCC and b) data from the endometrial 
TCGA detailing ARID1A mutation rates in various cohorts 
 
 
 
ARID1A and EZH2 
 
Given the prevalence of ARID1A mutations in endometrioid and clear cell ovarian cancer, and 
its implications in carcinogenesis, a therapeutic approach to targeting cancers with such 
mutations has been explored.  Novel treatment strategies targeting enhancer of EZH2 in 
ARID1A mutated cancers have been recently reported (Ayhan et al, 2012). Enhancer of zeste 
homolog 2 (EZH2) is a histone methyltransferase that mediates gene silencing by catalyzing 
trimethylation on lysine 27 of histone H3 (H3K27Me3) (Bitler et al, 2016).  It is a member of 
the polycomb group of genes (PcG), and has been implicated in nucleosome modification, 
chromatin remodeling, and interaction with various transcription factors (Simon and Tamjun, 
2002) (Eskander et al, 2013).  In a series of eloquent experiments, Bitler et al. were able to 
show that inhibition of EZH2 methyltransferase activity using GSK126 (a small molecule 
highly selective inhibitor of EZH2), acts in a synthetic lethal manner in ARID1A mutated 
ovarian cancer cell lines, and that ARID1A mutational status correlated with response to the 
EZH2 inhibitor (Bitler et al, 2015).  The authors identified PIK3IP1 (PI3K interacting protein 
1) as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and 
contributes to the observed synthetic lethality via the inhibition of PI3K-AKT signaling.  
Furthermore, EZH2 inhibition resulted in the regression of ARID1A mutated ovarian cancers 
in vivo, and decreased the number of disseminated tumor nodules in xenograft models (Bitler 
et al, 2015).  In this context, ARID1A mutation status could serve as a biomarker to predict 
efficacy of EZH2 inhibition in ARID1A mutated, recurrent, endometrioid and clear cell 
ovarian cancer, an area of high unmet clinical need. 
 
ARID1A and Endometrial Cancer 
As previously discussed, ARID1A mutations have been identified in up to 47% of low grade 
endometrioid endometrial carcinomas, 60% of high grade endometrioid adenocarcinomas, 
11% of serous adenocarcinomas and up to 24% of carcinosarcomas (Takeda et al, 2016). An 
association between loss of ARID1A protein expression and activation of the PI3K/AKT 
b) TCGA 
a) MSKCC  
Possiblymisclassifiedandtruly
loweruterinesegment
endometrialcancer
N=26
N=4
N=118
N=2
N=9
N=78
N=4
TotalN=360

 
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pathway has also been detailed.  Mutations of PTEN and PIK3CA frequently occur in 
endometrial carcinomas with ARID1A mutation, and it is hypothesized that these ARID1A 
mutations induce aberrant activation of the PI3K pathway (Takeda et al, 2016).  Additionally, 
investigators have explored the possibility that ARID1A mutation may result in defective 
mismatch repair, resulting in microsatellite instability and a greater tumor mutational burden.  
A strong association between ARID1A loss and sporadic microsatellite instability (MSI) is 
thought to result from epigenetic silencing of MLH1 (Bosse et al, 2013).  Furthermore, EZH2 
overexpression has been described in both endometrial and ovarian cancer, with an impact on 
resultant downstream genes (DK3, SFRP1, E-cadherin) (Eskander et al, 2013). 
The frequency and identification of ARID1A mutations in EAOC and endometrioid 
endometrial adenocarcinoma, as well as the clinical availability of a therapeutic agent 
capitalizing on ARID1A loss, advocates for the development of a clinical trial examining 
EZH2 inhibitors in this patient population.  Given the data outlined above, we propose to 
explore the efficacy of single agent tazemetostat in patients with recurrent or persistent (1) 
endometrioid and clear cell ovarian or primary peritoneal cancer and (2) endometrioid 
endometrial adenocarcinoma. 
2.1 
Background on tazemetostat 
 
Tazemetostat (EPZ-6438) is a selective, reversible, S-adenosyl methionine (SAM)-
competitive small molecule inhibitor of the EZH2 histone methyl transferase enzymatic 
activity.  As outlined above, genetic alterations in proteins of the SWI/SNF complex 
(including ARID1A) result in an oncogenic dependency on EZH2 activity, lending these solid 
tumor susceptible to EZH2 inhibition.  Tazemetostat inhibits both wild-type EZH2 and 
mutated EZH2 residues Y641, A677G and A687 with half maximal inhibitory concentrations 
(Ic50) ranging from 2-38 nmol/L.  The compound has 35-fold selectivity over the most 
closely related HMT, EZH1, and a greater than 4500-fold selectivity over other HMTs.  The 
drug selectively inhibits intracellular H3K27 methylation in a concentration- and time-
dependent manner, leading to selective cell killing of cell lines that depend on EZH2 activity.   
 
 

 
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Figure 3: Chemical structure of tazemetostat (EPZ-6438) 
 
 
 
 
 
 
Epizyme is currently evaluating the efficacy of tazemetostat in ongoing clinical trials in adult 
subjects.  The studies focus on subjects with hematologic malignancies (NHL (DLBCL and 
FL)), solid tumors and mesothelioma. In 2016, at the ASH Lymphoma Biology meeting, data 
regarding preliminary safety and activity of tazemetostat in patients with relapsed or 
refractory NHL and advanced solid tumors was presented.   Within the cohort of 55 subjects a 
total of 3, grade 3 or greater treatment-related AEs were reported (1 each of: 
thrombocytopenia, neutropenia, hypertension).  Additional preliminary data evaluating the 
efficacy of tazemetostat in patients with INI1-negative and SMARCA4-negative rhabdoid 
tumors and sarcomas (n=11), showed both complete and partial responses, with some subjects 
experiencing stable disease lasting greater than 6 months.  Importantly, INI1 and SMARCA4 
are subunits of the SWI/SNF complex, in addition to ARID1A. 
Tazemetostat nonclinical pharmacokinetics 
The plasma pharmacokinetics of tazemetostat in rats and monkeys was characterized by high-
to-moderate clearance, moderate-to-large volume of distribution, and a short half-life of 0.4 to 
1.6 hours.  Low-to-moderate accumulation of tazemetostat in plasma was observed after 
repeated doses in male rats.  In contrast, there was a 3- to 5-fold decrease in systemic 
exposure between day 1 and day 28 in monkeys. In vitro, cytochrome P450 (CYP)3A4 is the 
predominant enzyme responsible for the hepatic metabolism of tazemetostat.  The desethyl 
metabolite, EPZ-6930, was the major metabolite formed in vitro in all species and no 
metabolite unique to humans was observed.   
Tazemetostat clinical pharmacokinetics 
Tazemetostat was administered orally at doses of 100, 200, 400, 800, and 1600 mg twice daily 
(BID) in subjects with advanced solid tumors or with B-cell lymphomas.  The drug was 
rapidly absorbed, with time to maximal plasma concentration (Tmax) of approximately 1-2 
hours after administration, and a mean terminal half-life of 3-5 hours.  Relative to single day 
dosing, BID dosing resulted in a decrease in systemic exposure on day 15.  Systemic exposure 
at steady state did not change after day 15. Administration of tazemetostat with food 
decreased the rate of oral absorption with no relevant effect on total systemic exposure when 

 
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compared to drug administration in the fasting state.  Drug studies conducted with midazolam 
suggest that tazemetostat is a weak inducer of CYP3A4/5 mediated metabolism.  Thus, 
potential interactions with concomitantly administered medications that are substrates for 
CYP3A4/5 will be mild.  
 
Treatment-Related Treatment-Emergent Adverse Events Occurring in ≥ 5% of Patients (taken 
from Table 12 of p 72 of Epizyme’s IB for tazemetostat)  
The following side effects or risks have been identified, requiring additional monitoring, or 
tests, to potentially minimize the occurrence of these events: T-cell lymphoblastic lymphoma 
or T-cell acute lymphoblastic leukemia (T-LBL/T-ALL): 
• A 9-year-old subject treated with tazemetostat in a study being conducted in children 
developed a type of non-Hodgkin lymphoma, which is also called T-cell 
lymphoblastic lymphoma (T-LBL) after receiving tazemetostat for 14 months. 
During pre-clinical animal testing, T-LBL, including lymphoid hyperplasia in the thymus, was 
observed in one model, rats, but not in other animal models.  It was noted by the company that 
in rats, these events were observed at the highest doses, doses higher than have been used in 
humans. 

 
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The risk for T-LBL/T-ALL occurring in patients treated with tazemetostat is thought to be 
greater in children but is unknown in adults.  The incidence of T-LBL/T-ALL in adults treated 
with tazemetostat is expected to be uncommon.  As of 1 May 2018, this is the only case of T-
cell lymphoma that has occurred out of a total of 79 children enrolled in tazemetostat clinical 
trials.  In addition, there have been no cases of T-LBL/T-ALL in the 702 adult patients treated 
across multiple studies conducted in different types of cancer.  The company will continue to 
monitor all patients treated with tazemetostat very carefully for the development of secondary 
malignancies. 
2.2 
Translational Science Background 
The Memorial Sloan Kettering Cancer Center has extensive clinical experience surrounding 
ARID1A assessment as part of GOG protocol 0283. Dr. Hyman, the principal investigator of 
GOG-0283 completed ARID1A gene sequencing and established a validated, NIH Biomarker 
Review Committee-approved IHC assay for BAF250a expression. The IHC assay was found 
to have excellent concordance with ARID1A mutational status as detailed in Figure 4 below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4: Monograph illustrating BAF250a IHC as well as correlation between ARID1A 
mutation status and BAF250a expression (courtesy of Dr. Hyman) 
 
2.3   
Stage 1 data informing protocol modification for patients enrolled after 20-OCT-2021 
version date 
 
 
Between March 2019 and August 2019, a total of 38 patients were enrolled onto stage 1 of 
NRG GY014 (n=19 in each cohort).  All eligible and evaluable patients in the endometrial 
cancer cohort were endometrioid histology.  Seven of 17 patients (41%) with endometrial 
cancer were identified as having an ARID1A mutation by NGS.  Of the 16 patients with 
BAF250a IHC, absent IHC expression was noted in 2 patients with endometrial cancer, with 
ARID1 A mutant 
ARID1 A wild type 

 
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variable expression in the remaining 14 patients.  Importantly, there were no objective 
responses identified in the endometrial cancer cohort, irrespective of ARID1A mutation 
status. 
 
All patients enrolled in the ovarian cancer cohort had clear cell histology.  Of the 15 patients 
in the cohort who were eligible, evaluable, and examined for mutation status, 9 were 
identified as having an ARID1A mutation by NGS (60%).  Of the 13 patients with BAF250a 
IHC, absent IHC expression was noted in 1 patient with ovarian clear cell carcinoma, with 
variable expression in the remaining 12 patients.  There were 2 confirmed objective responses 
(1 complete response (CR) and 1 partial response (PR)) and one unconfirmed PR in the 
ovarian clear cell carcinoma cohort (ORR 33%).  All 3 patients were identified to have 
ARID1A mutation by NGS.  Furthermore, ARID1A mutation by NGS appeared to be 
associated with response to single agent tazemetostat in the ovarian cancer cohort.  Lastly, an 
additional 4 patients harboring ARID1A mutations exhibited stable disease > 6 months, 
resulting in a 6-onth clinical benefit rate of 77.8%. These results prompted revision of the 
protocol to enroll patients with clear cell ovarian cancer and ARID1A mutations in a 
prospective manner. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the NRG Oncology Statistics 
and Data Management Center-Pittsburgh Office (see protocol cover page).  
 
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 Patients must have the psychological ability and general health that permits completion of the 
study requirements and required follow up. 
 
  
3.1.2 Submission of tumor tissue is required for all patients. Investigators should check with their 
pathology department regarding release of tissue biospecimens before approaching patients 
about participation in the trial. (See Section 10 for details.) 
 
3.2 
Eligibility Criteria (09-DEC-2021) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
3.2.1 Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent 
ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid 
endometrial adenocarcinoma.  Patients with recurrent endometrial cancer must have MMR 
immunohistochemistry completed. If they are found to be mismatch repair deficient, they 
should be offered treatment with immune checkpoint inhibition before consideration for 

 
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treatment on trial. 
 
Primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have 
histologically documented recurrence with at least 50% endometrioid or clear cell 
morphology.  Institutional pathology reports must be provided indicating at least 50% 
endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions). 
   
3.2.1.1 As of protocol version date 20-OCT-2021, only patients with recurrent or persistent 
ovarian clear cell carcinoma (OCCC) with ARID1A pathologic variant or likely 
pathologic variant mutations per NGS are eligible for entry. (20-OCT-2021) 
 
Institutional pathology reports indicating at least 50% clear cell morphology for ovarian 
tumors (primary or recurrent lesions) and NGS report must be available for Step 1 
registration. (20-OCT-2021) (09-DEC-2021) 
 
All other eligibility criteria (Secs 3.2.2-3.2.14) and ineligibility criteria (Secs 3.31-3.38) 
must be met for Step 2 registration. (20-OCT-2021) (09-DEC-2021) 
 
3.2.2 All patients must have measurable disease as defined by RECIST v 1.1. Measurable disease is 
defined as at least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded).  Each lesion must be ≥ 10 mm when measured by CT, MRI 
or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph 
nodes must be ≥15 mm in short axis when measured by CT or MRI. Refer to Section 13.1.2 
for details if in site of previous radiation.  
 
3.2.3 Patients must have had at least one, but no more than 3, prior cytotoxic regimens for 
management of primary disease.  Unlimited prior hormonal therapy, targeted therapy 
(including immunotherapy) or antiangiogenic therapy will be permitted. 
 
3.2.4 Patients must have completed prior therapy as detailed below: 
 
Prior Therapy 
Time from Last Prior Therapy Regimen, if applicable (08/13/2019) 
Chemotherapy: 
cytotoxic 
At least 28 days since last dose of chemotherapy prior to Step 2 
registration. 
Chemotherapy: 
nitrosoureas 
At least 6 weeks since last dose of chemotherapy prior to Step 2 
registration. 
Chemotherapy: non-
cytotoxic (e.g. small 
molecule inhibitor) 
At least 28 days since last dose of chemotherapy prior to Step 2 
registration. 
Monoclonal 
antibody(ies) 
At least 28 days since last dose of monoclonal antibody prior to Step 2 
registration. 
Immunotherapy 
At least 28 days since last dose of immunotherapy prior to Step 2 
registration. 
Radiotherapy (RT) 
At least 14 days from last local site RT prior to Step 2 registration. 
 
At least 21 days from stereotactic radiosurgery prior to Step 2 

 
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registration. 
 
At least 12 weeks from craniospinal, ≥50% radiation of pelvis or total 
body irradiation prior to Step 2 registration. 
 
Patients with CNS disease should demonstrate evidence of stabilization 
after the 28-day time point after definitive treatment. 
 
Full recovery of radiation related side effects prior to Step 2 
registration.  
 
All subjects must have evidence of measurable disease outside of the 
radiation field at the time of Step 2 registration. 
 
3.2.5 Appropriate stage for study entry based on the following diagnostic workup: 
• History/physical examination within 14 days prior to Step 2 registration; 
• Imaging of the chest, abdomen and pelvis within 28 days prior to Step 2 registration (See 
Section 4.1) 
 
3.2.6 Age ≥ 18 
 
3.2.7 ECOG Performance Status of 0, 1 or 2 within 14 days prior to Step 2 registration. 
 
3.2.8 Adequate hematologic function within 14 days prior to Step 2 registration defined as follows: 
(08/13/2019) 
• Platelets ≥ 100,000/mcl 
• ANC ≥ 1,500/mcl 
• Hemoglobin ≥8 g/dL 
• Differential with no clinically significant morphologic abnormalities on complete blood 
count (CBC) testing. Manual differential is encouraged, if clinically indicated, and in 
cases where an automated differential is abnormal. 
 
3.2.9 Adequate renal function within 14 days prior to Step 2 registration defined as follows: 
(08/13/2019) 
•  Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN) 
 
3.2.10 Adequate hepatic function within 14 days prior to Step 2 registration defined as follows: 
• AST and ALT ≤ 3 x ULN 
• Total serum bilirubin level ≤ 1.5 x ULN; Direct bilirubin ≤ ULN for subjects with total 
bilirubin > 1.5 x ULN (patients with isolated indirect bilirubin elevations and a history of 
Gilbert’s Syndrome are eligible) 
 
3.2.11 Patients must be able to swallow and retain oral medications and not have gastrointestinal 
illnesses that would preclude absorption of tazemetostat as judged by the treating physician. 
(20-OCT-2021) 
 

 
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3.2.12 Women of childbearing potential must be willing and able to use adequate contraception 
(hormonal and barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and for 6 months after the last dose of study agent.  Should a 
woman become pregnant or suspect she is pregnant while she is participating in this study, she 
should inform her treating physician immediately. Theoretically, CYP3A induction with 
tazemetostat use may result in the loss of efficacy in hormonal contraceptives, thus a barrier 
method of contraception must be used in addition to hormonal contraceptives due to the 
potential drug-drug interaction with tazemetostat. (20-OCT-2021)   
 
3.2.13 The patient or a legally authorized representative must provide study-specific informed 
consent and authorization permitting release of personal health information prior to study 
entry. 
 
3.2.14 Patients with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial. (08/13/2019) 
 
3.3 
Ineligibility Criteria (09-DEC-2021) 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.3.1 Prior treatment with an investigational EZH2 inhibitor. 
 
3.3.2 Patients who have: (08/13/2019) 
• A prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). 
• Abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and 
myeloproliferative neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing 
and DNA sequencing. 
• A prior history of T-LBL/T-ALL. 
 
3.3.3 Patients who have had therapeutic paracentesis or thoracentesis within 8 weeks prior to Step 2 
registration. (20-OCT-2021) 
 
3.3.4 Patients with clinical or radiographic evidence of bowel obstruction. (20-OCT-2021) 
 
3.3.5 Severe, active co-morbidity per the treating investigator’s discretion. 
 
3.3.6 Pregnant or lactating patients. 
 
3.3.7 Known HIV positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with tazemetostat.  In addition, treatments 
involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in 
this patient population. 
 
3.3.8 Treatment with strong and moderate inhibitors or inducers of CYP3A within 14 days of Step 2 
registration and during the study treatment (See Section 5.8.2). (20-OCT-2021) 
 
 

 
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4 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
4.1 
PRE-TREATMENT ASSESSMENTS (08/13/2019) (20-OCT-2021) (06-APR-2022) 
  
 
* Prior to Step 2 Registration Assessments should be used for Pre Cycle 1, Day 1 as long 
as they are within the stated Cycle 1, Day 1 window.   
 
** Radiographic tumor measurements should be obtained via imaging of the chest, abdomen 
and pelvis to establish the location and extent of disease. See RECIST 1.1 for allowable 
imaging modalities used to assess disease at baseline (and subsequent assessments). Contrast 
CT is the preferred modality. PET-CT is not permitted for any disease assessment or 
reassessment. 
 
Assessments 
Prior to Step 1 
Registration 
Prior to Step 2 
Registration 
 (calendar days)* 
Prior to Treatment 
(calendar days) 
(Cycle 1, Day 1)* 
Pathology report from primary 
surgery/diagnosis 
X 
 
 
Pathology report from specimen 
used for NGS (if different from 
above pathology report) 
X 
 
 
Submission of NGS report 
showing ARID1A pathologic 
variant or likely pathologic 
variant mutation 
X 
 
 
History and Physical 
 
≤ 14 days 
≤ 14 days 
Concomitant Medications 
 
≤ 14 days 
≤ 14 days 
Vital Signs (blood pressure, 
height, weight, pulse, temperature, 
respiratory rate) 
 
≤ 14 days 
≤ 14 days 
Performance Status 
 
≤ 14 days 
≤ 14 days 
Toxicity Assessment 
 
≤ 14 days 
≤ 14 days 
CBC with differential/Platelets 
 
≤ 14 days 
≤ 14 days 
Sodium, Potassium, Chloride, 
CO2, Magnesium, BUN, 
Creatinine, Calcium, Bilirubin, 
AST/SGOT, ALT/SGPT, Alkaline 
Phosphatase 
 
≤ 14 days 
≤ 14 days 
Urine Pregnancy Test (if 
childbearing potential exists) 
 
≤ 14 days 
≤ 72 hours 
ECG (if clinically indicated) 
 
≤ 28 days 
≤ 28 days 
Radiographic Tumor 
Measurement** 
 
≤ 28 days 
≤ 28 days 

 
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4.2 
ASSESSMENTS DURING TREATMENT * (08/13/2019) 
Assessments 
Prior to Each Treatment 
Cycle, Day 1 (after Cycle 1, 
Day 1)* 
Timed (Treatment Cycle 
Independent) 
History and Physical 
X 
 
Concomitant Medications 
X 
 
Vital Signs (blood pressure, 
height, weight, pulse,  
temperature, respiratory rate) 
X 
 
Performance Status 
X 
 
Toxicity Assessment 
X 
 
CBC with differential, 
platelets 
X** 
 
Sodium, Potassium, 
Chloride, CO2, Magnesium, 
BUN, creatinine, Calcium, 
bilirubin, AST/SGOT, 
ALT/SGPT, alkaline 
phosphatase  
X 
 
Patient Medication Calendar 
(see Appendix V) 
X 
 
Radiographic Tumor 
Measurement 
 
X*** 
 
 
 
*  
Each cycle will be defined as a 28 day period. Visit assessment windows of +/- 3 days 
will be permitted. Delays of up to 7 days will be allowed and will not be considered a 
protocol violation for major life events (e.g., serious illness in a family member, major 
holiday, vacation which is unable to be rescheduled). Documentation to justify this 
decision should be provided. 
 
** Every 2 weeks during the first two cycles and then once per cycle (monthly) thereafter 
with more frequent CBCs as clinically indicated.   
 
 
 
*** Every 8 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and /or changes in 
treatment schedule) for the first 12 months; then every 12 weeks (+/- 7 days) thereafter.  
Radiographic tumor measurements are obtained until disease progression is confirmed; at 
the investigator’s discretion they can be repeated any other time if clinically indicated 
based on symptoms of physical signs suggestive of new or progressive disease.  A tool is 
provided on the CTSU website to calculate dates of re-imaging.  Utilize same imaging 
modality of abdomen, pelvis and chest (see footnote under Pre-Treatment Assessments) 
as for pre-cycle 1 baseline assessment.   
 

 
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4.3 
ASSESSMENTS IN FOLLOW UP 
Assessments 
Timed (after progression or 
discontinuation of treatment) 
Vital Status 
1 
Toxicity Assessment 
2 
Radiographic tumor measurement 
3 
 
1 Every 3 months for 2 years and then every 6 months for 3 years. Follow-up Forms are 
collected until study termination.  
2 Patients who discontinue treatment for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. For reporting of delayed toxicity, see 
Section 7. 
3  In the case that protocol directed therapy is discontinued for reasons other than disease 
progression, follow radiographic tumor measurement schedule as defined under 
Assessments During Treatment (until disease progression documented by RECIST 1.1 or 
until patient initiates a subsequent cancer therapy). 
 
Definition of Disease Assessments 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
5.  
TREATMENT PLAN/REGIMEN DESCRIPTION 
 
 
TREATMENT SHOULD BEGIN WITHIN 14 DAYS OF REGISTRATION in order to avoid 
having to repeat the pre-treatment assessments as outlined in Section 4.1. 
 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy  
5.1.1 Tazemetostat 800 mg BID administered orally in continuous 28-day cycles until disease 
progression or unacceptable toxicity.  
 
Tazemetostat can be taken with or without food. Tablets should be taken whole and not 
chewed or crushed.  Doses must be taken twice per day with no less than 8 hours between 
each dose. If a dose is missed or vomited, skip the dose and take the next scheduled dose. (09-
DEC-2021). 
 
No grapefruit juice, Seville oranges, or grapefruit can be consumed while on tazemetostat. 
 
See Sections 9.1.10, 9.1.11  and Appendix IV 
 
5.2 
Radiation Therapy 
 
Not Applicable. 
5.3 
Surgery  
Not Applicable. 

 
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5.4 
Device  
 
Not Applicable. 
5.5 
Imaging 
 
Not Applicable. 
5.6 
Integral Biomarker Assay 
Not applicable. 
  
5.7 
Intervention Not Otherwise Categorized 
Not applicable. 
 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
 
5.8.1 Permitted Supportive/Ancillary Care and Concomitant Medications (20-OCT-2021) 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication.  
 
• Strong and moderate CYP3A4 inhibitors or inducers are prohibited from 14 days prior 
to Step 2 registration to the end of the study.   
 
CYP3A induction with tazemetostat use may result in the loss of efficacy in hormonal 
contraceptives. 
 
Permitted medication(s), include: 
• Supportive care measures and symptomatic treatment for any treatment-related 
toxicity, including short course of glucocorticoids (< 4 weeks), if clinically indicated 
• Non-enzyme inducing anti-epileptic drugs 
• Prophylactic use of standard antiemetics 
Medication(s) to be used with caution: 
• In vitro, tazemetostat inhibits MATE1 and MATE2K. Tazemetostat does not inhibit 
CYP1A2, 2B6, 2C9, 2D6, P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, 
OAT3, or BSEP at clinically relevant concentrations. Tazemetostat also induces 
CYP3A4. Medications that are substrates of CYP3A or P-gp with a narrow therapeutic 
index and substrates of MATE1 and MATE2K should be used with caution. 
 
Substrates of P- gp, CYP3A, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 with 
narrow therapeutic index 
Digoxin 
Phenytoin 
Tacrolimus 
Warfarin 
Carbamazepine 
Quinidine  
Cyclosporine  

 
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Midazolam 
Triazolam 
Lansoprazole 
Omeprazole 
Tolbutamide 
Tizanidine 
Dextromethorphan 
Nebivolol 
 
 
The study team should check a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of.   
 
Appendix IV (Clinical Trial Wallet Card) should be provided to patients. 
 
5.8.2 Prohibited Therapies (20-OCT-2021) (09-DEC-2021) 
 
Prohibited medication(s) 
• Antineoplastic therapy or other investigational therapy for the treatment of cancer 
• Prophylactic use of hematopoietic colony stimulating factors 
• In vitro, tazemetostat is metabolized primarily by CYP3A and to a lesser extent by 
CYP2C8 and CYP2D6.  It is a P-gp substrate but not a substrate of BCRP, OAT1B1, 
OAT1B3, OAT3, OCT2, and MATE1.  Therefore, treatment with strong and moderate 
inhibitors or inducers of CYP3A should be avoided from 14 days prior to the first dose 
of tazemetostat to the end of the study. Strong inhibitors and inducers of CYP2C8, 
2D6, and P-gp should be used with caution. 
 
Strong CYP3A4 inhibitors 
Strong CYP3A4 inducers 
Indinavir 
Nelfinavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Saquinavir 
Suboxone 
Telithromycin  
Boceprevir 
Cobicistat 
Danoprevir 
Ritonavir 
Grapefruit Jiuce 
Posaconazole 
Telaprevir 
Troleandomycin 
Voriconazole 
Nevirapine 
Barbiturates 
Carbamazepine 
Enzalutamide 
Oxcarbazepine 
Modafinil 
Phenytoin 
Rifampin 
 
Rifabutin  
Apalutamide 
Mitotane 
St. John’s wort 
Moderate CYP3A4 inhibitors 
Moderate CYP3A4 inducers 

 
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Aprepitant 
Ciprofloxacin 
Conivaptan 
Crizotinib 
Cyclosporine 
Diltiazem 
Dronedarone 
Erythromycin 
Fluconazole 
Fluvoxamine 
Imatinib 
Tofisopam 
Verapamil 
Bosentan 
Efavirenz 
Etravirine 
Phenobarbital 
Primidone 
 
• Non-approved herbal medications or supplements 
 
The study team should check a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of. 
 
Appendix IV (Clinical Trial Wallet Card) should be provided to patients. 
 
5.9 
Duration of Therapy (20-OCT-2021)  
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression 
▪ 
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 for 
further treatment in the judgment of the investigator, including non-compliance taking the 
study drug. 
 
Note: 
▪ Patient has the right to refuse further treatment, but that does not necessitate 
withdrawing consent for participation in the study (e.g. follow-up) (See Section 
8.3.1 re study consent withdrawal) 
▪ If all protocol treatment is discontinued, follow-up and data collection will 
continue as specified in the protocol. 
 
 

 
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6.  
TREATMENT MODIFICATIONS/MANAGEMENT 
 
 
 
 
No modification of dose is required for the following grade 3 or greater non-hematologic 
toxicities: 
• 
Transient fatigue or asthenia (return to grade 1 within 7 days) 
• 
Transient myalgia or arthralgia (return to grade 1 within 7 days) 
• 
Nausea that resolves to < grade 2 within 7 days (with or without anti-emetics) 
• 
Vomiting that resolves to < grade 2 within 48 hours (with or without anti-emetics) 
• 
Diarrhea that resolves to < grade 2 within 48 hours (with or without anti-diarrheal 
medications) 
 
Other toxicities that, in the opinion of the Investigator are possibly, probably, or definitely 
related to the study treatment, should be managed per Table 1 below.  Toxicities that are felt 
by the Investigator to be unrelated to tazemetostat but clinically significant should be 
discussed with the study PI.  In the event of an urgent unrelated toxicity, study treatment 
should be interrupted per Table 1.  Dose re-escalation is not permitted. 
 
Table 1: Dose modifications for treatment related toxicities 
Toxicitya 
During Therapy 
Approximate Dose Adjustmentb 
Grade 1 
All occurrences 
Continue study treatment 
Maintain dose level 
Grade 2c 
All occurrences 
Continue study treatment 
Maintain dose level 
Grade 3d (not including neutropenia) 
1st occurrence 
Interrupt study treatment until 
resolved to Grade ≤ 1 or baselineb 
Restart at 600 mg BID 
2nd occurrence 
Restart at 400 mg BID 
3rd occurrence 
Discontinue study treatment 
Not applicable 
Grade 3d neutropenia (ANC <1000-500/mcl) (XX-APR-2022)  
1st occurrence 
Interrupt study treatment until 
resolved to ANC ≥ 1,500/mcl 
Maintain dose level 
2nd occurrence 
Restart at 600 mg BID 
3rd occurrence 
Restart at 400 mg BID 
4th occurrence 
Discontinue study treatment 
Not applicable 
Grade 3 Thrombocytopenia with bleeding and Grade 4 Thrombocytopenia (Platelets 
<25,000-50,000) 
1st occurrence 
Interrupt study treatment until 
resolved to ≥75,000/mcl 
Restart at 600 mg BID 
2nd occurrence 
Restart at 400 mg BID 
3rd occurrence 
Restart at 400 mg BID 
4th occurrence 
Discontinue study treatment 
Not applicable 
Grade 4 
All occurrences 
Interrupt study treatment until 
resolved to Grade ≤ 1 or baseline 
and discuss with study chair 
Pending discussion with study 
chair 
Agent 
Starting Dose 
Dose -1 
Dose -2 
Tazemetostat 
800 mg BID 
600 mg BID 
400 mg BID 

 
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ANC = absolute neutrophil count; BID = twice daily 
a. Excluding alopecia, nausea, vomiting or diarrhea not receiving adequate treatment 
b. A delay of tazemetostat for more than 14 days due to any toxicity requires discontinuation of 
study treatment.  
c. Any case of grade 2 toxicity where investigator believes that an interruption or dose 
modification is warranted should be discussed with study chair. 
d. Excludes Grade 3 anemia: Subjects are allowed to continue tazemetostat at the current dose 
level with transfusions per investigator discretion. 
 
• If a new case of T-LBL/T-ALL occurs in patients then the patient will be discontinued from 
treatment, a case assessment will be conducted to better understand the event, and enrollment 
will be suspended. 
o Patients on study who continue to derive clinical benefit will be maintained on therapy. 
• For any MDS/AML or other myeloid malignancies like MPN: 
The patient will be discontinued from treatment, and a case assessment will be conducted 
to better understand the event. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   
Protocol Agents 
Investigational Agents 
The investigational agent administered in NRG-GY014, tazemetostat, is being made available 
under an IND sponsored by DCTD, NCI.  For patients receiving tazemetostat, determination 
of whether an adverse event meets expedited reporting criteria, see the reporting table in 
section 7.4.2 of the protocol. 
7.2  
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 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 5.0. 
 
7.2.2 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 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. 

 
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7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Tazemetostat 
(NSC 791066) (07-JUL-2020) (20-OCT-2021) (11-JAN-2023) 
 
 
 
The Comprehensive Adverse Events 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 (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 941 patients. Below is the CAEPR for 
Tazemetostat. 
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, November 16, 20221 
 
 Adverse Events with Possible  
 Relationship to Tazemetostat (EPZ-6438) 
 (CTCAE 5.0 Term) 
[n= 941] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Bronchial infection 
 
  
 
Upper respiratory infection 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
  
 
Creatinine increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count 
decreased (Gr 2) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 
2) 
 
Weight loss 
 
  

 
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 Adverse Events with Possible  
 Relationship to Tazemetostat (EPZ-6438) 
 (CTCAE 5.0 Term) 
[n= 941] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
White blood cell decreased 
 
 White blood cell decreased 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
  
Hyperglycemia 
 
  
 
Hypertriglyceridemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
 
 
Treatment related secondary 
malignancy2 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Cough 
 Cough (Gr 2) 
 
 
Dyspnea 
 Dyspnea (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
  
 
 
Photosensitivity 
  
 
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.  
 
2Treatment related secondary malignancies includes Peripheral T-cell lymphoma (PTCL), T-cell lymphoblastic 
lymphoma (T-LBL), and B-cell acute lymphoblastic leukemia (B-ALL). It may be worth noting that the adult 
patient observed with B-ALL may be due to an underlying Diffuse large B-cell lymphoma (DLBCL). 
 
 
Adverse events reported on Tazemetostat trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that Tazemetostat caused the adverse event: 
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Chest pain - cardiac; Left ventricular systolic dysfunction 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Dry eye; Periorbital edema; Vision decreased; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Dyspepsia; Dysphagia; Flatulence; 
Gastric perforation; Gastrointestinal disorders - Other (defecation urgency); Hemorrhoids; Mucositis oral; 
Rectal hemorrhage; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Flu like 
symptoms; General disorders and administration site conditions - Other (early satiety); General disorders and 

 
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administration site conditions - Other (general physical health deterioration); Localized edema; Malaise; Non-
cardiac chest pain 
HEPATOBILIARY DISORDERS - Gallbladder obstruction; Hepatobiliary disorders - Other (hepatocellular 
injury) 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Device related infection; Esophageal infection; Infections 
and infestations - Other (lower respiratory tract infection); Lung infection; Pharyngitis; Sepsis; Sinusitis; Skin 
infection; Soft tissue infection; Thrush; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CPK 
increased; Electrocardiogram QT corrected interval prolonged; Investigations - Other (c-reactive protein 
increased); Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperkalemia; Hyperlipidemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Metabolism and nutrition disorders - Other 
(diabetic metabolic decompensation); Metabolism and nutrition disorders - Other (polydipsia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Muscle cramp; 
Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Dysphasia; Hydrocephalus; 
Lethargy; Memory impairment; Nervous system disorders - Other (vocal cord paralysis); Paresthesia; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Radiculitis; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Depression; Hallucinations; Insomnia; Psychiatric disorders - Other 
(mood swings) 
RENAL AND URINARY DISORDERS - Proteinuria; Renal and urinary disorders - Other (polyuria); Urinary 
frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(vulvovaginal rash) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Epistaxis; 
Hypoxia; Nasal congestion; Oropharyngeal pain; Pleural effusion; Pulmonary edema; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (tachypnea) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Hair color changes; Hair texture 
abnormal; Hirsutism; Hyperhidrosis; Hypertrichosis; Nail ridging; Pruritus; Purpura; Rash acneiform; Rash 
maculo-papular; Skin and subcutaneous tissue disorders - Other (HSV oral infection); Skin and subcutaneous 
tissue disorders - Other (psoriasis); Skin hyperpigmentation; Urticaria 
VASCULAR DISORDERS - Hot flashes; Hypertension; Superior vena cava syndrome; Thromboembolic event; 
Vascular disorders - Other (peripheral venous disease) 
 
Note: Tazemetostat (EPZ-6438) 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.  
 
Note: AESI:  Based on preclinical findings in toxicology studies, FDA has requested the following Adverse 
Events of Special Interest (AESI) to be reported in an expedited manner: 1) T-cell lymphoma; and 2) abnormal 
bone growth. It should be noted that abnormal bone growth has not been observed in clinical trials of 
tazemetostat (EPZ-6438). 
7.4 
Expedited Reporting of Adverse Events (06-APR-2022) 
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 https://ctepcore.nci.nih.gov/ctepaers/security/login  
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 

 
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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. 
 
7.4.1 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.  Supporting source 
documentation should 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 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.  
•  
7.4.2 Expedited Reporting Requirements for Adverse Events (06-APR-2022) 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under a CTEP IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 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 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar Days 

 
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Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
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; 3 Calendar Days” - The AE must initially be reported via electronic submission within 24 
hours of learning of the AE, followed by a complete expedited report within 3 calendar days of the 
initial 24-hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
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 3 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
      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. 
 
7.4.3 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. 
 
7.4.4 Secondary Malignancies  
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. 

 
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Please see Section 7.3 for reporting of AESIs. 
 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (08/13/2019) (07-JUL-2020) 
 
8.1 
CTEP Registration Procedures  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.   
RCR utilizes five person registration types. 
• IVR – MD, DO, or international equivalent; 
• NPIVR – advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• AP – clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
(such as the Roster Update Management System [RUMS], OPEN, Rave, acting as the 
primary site contact, or with consenting privileges; 
• Associate (A) – other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) – individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 

 
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Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs 
and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the 
FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval.  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.    
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.2 
CTSU Registration Procedures (06-APR-2022) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
8.2.1 IRB Approval:   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI 
CIRB review to activate new studies at the site after March 1, 2019. Local IRB review will 
continue to be accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue to submit 
Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-
specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the CTSU 

 
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website.  Acceptable documentation of local IRB/REB approval includes: 
 
• Local IRB documentation 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB 
approval record to be completed: 
• Holds an active CTEP status; 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); 
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
8.2.2 Downloading Site Registration Documents:   
• Download the site registration forms from the NRG-GY014 page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and its associated investigators and staff on a 
participating roster.  To review/download site registration forms:Log in to the CTSU 
members’ website (https://www.ctsu.org) using your CTEP-IAM username and 
password; 
• Click on Protocols in the upper left of the screen: 
o Enter the protocol # NRG-GY014 in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select NRG, and 
protocol # NRG-GY014. 
▪ Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided.  (Note: For 
sites under the CIRB, IRB data will load automatically to the CTSU.) 

 
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8.2.3 Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission.  
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU 
(2878), or CTSURegHelp@coccg.org in order to receive further instruction and support. 
8.2.4 Checking Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
 
o Click on Regulatory at the top of the screen; 
o Click on Site Registration; and 
o Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol Status 
and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s status 
with NCI or their affiliated networks. 
 
8.3 
Patient Enrollment (20-OCT-2021) (09-DEC-2021) (06-APR-2022) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with 
the LPOs registration/randomization systems or the Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment. OPEN will 
populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type. 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 

 
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approval on their Form FDA 1572 in RCR.  
 
Prior to accessing OPEN for Step 1 registration, site staff should verify the following: 
 
• All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
• All eligibility criteria, as determined by pre-screening and patients’ medical 
history/pathology report, must be met prior to Step 1 registration (See Sec 4.1). 
 
Sites will be notified via email to proceed with Step 2 registration after study chair review of 
the submitted pathology and NGS reports. Please make sure to supply the email for the 
individual who should be notified of the approval to proceed to Step 2 registration as 
requested in OPEN.  
 
Prior to accessing OPEN for Step 2 registration, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes. 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
8.3.1    Patient-Initiated Consent Withdrawal from the Study (20-OCT-2021) 
If a patient chooses to have no further interaction regarding the study (i.e., allow no future 
follow up data to be submitted to NRG Oncology), the study applicable form should be 
completed in Medidata Rave to report the patient’s consent withdrawal.  
NOTE: This should not be done if the patient has only chosen to stop protocol treatment and 
is willing to still be followed. (See Section 5.9) 
 
8.4 
Data Submission / Data Reporting (20-OCT-2021) (06-APR-2022) 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
 
Requirements to access Rave via iMedidata: 
 
• A valid CTEP-IAM account; and 
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 

 
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• Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• Rave Read Only role must have at a minimum  an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-
mail from iMedidata.  To accept the invitation, site staff must click on the link in the email or 
log in to iMedidata via the CTSU members’ website under Data Management > Rave Home 
and click to accept the invitation in the Tasks pane located in the upper right corner of the 
iMedidata screen.  Site staff will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (eLearnings) and can be accessed by clicking on the eLearning link in the 
Tasks pane located in the upper right corner of the iMedidata screen. If an eLearning is 
required for a study and has not yet been taken, the link to the eLearning will appear under the 
study name in the Studies pane located in the center of the iMedidata screen once the 
successful completion of the eLearning has been recorded, access to the study in Rave will be 
granted, and a Rave EDC link will replace the eLearning link under the study name. 
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by email at ctsucontact@westat.com.   
 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total Delinquencies 
and Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, forms with current status and timeliness reports. Review the 
DQP modules on a regular basis to manage specified queries and delinquent forms. 
 

 
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The DQP is accessible by site staff that are rostered to a site and have access to the 
CTSU website. Staff that have Rave study access can access the Rave study data using 
a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries,  DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
9.0 
DRUG INFORMATION  
 
9.1 
Tazemetostat (EPZ-6438, E7438), NSC #791066 (06-APR-2022) 
 
9.1.1 
Chemical Name or Amino Acid Sequence: N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-
yl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(morpholin-4-
ylmethyl)biphenyl-3-carboxamide hydrobromide 
 
 
Classification: Enhancer of zeste homolog 2 (EZH2) Inhibitor 
 
CAS Registry Number: 1467052-75-0 
 
 
Molecular  
 
Formula:  C34H45BrN4O4 (Hydrobromide salt)     M.W.: 653.65 (Hydrobromide salt)  
 
C34H44N4O4 (Free base)  
 
572.74 (Free base) 
 
9.1.2 
Approximate Solubility: Soluble in 0.1 N hydrochloride (HCl) solution, very slightly soluble 
in water and ethanol, and practically insoluble in phosphate buffered saline (PBS, pH 7.4). 
 
9.1.3 
Mode of Action: Tazemetostat is a selective, reversible, S-adenosylmethionine (SAM)-
competitive small molecule inhibitor of the enhancer of zeste homolog 2 (EZH2), a histone 
methyltransferase (HMT). Tazemetostat selectively inhibits intracellular H3K27 methylation.  
 
9.1.4 
Description: The tazemetostat HBr salt form is a white powder. 
 
9.1.5 
How Supplied: Epizyme supplies and PMB, CTEP, DCTD, NCI distributes tazemetostat as 
film-coated tablets. 
  
Film-coated tablets are red, round, and biconvex with a diameter of approximately 10 mm 
containing 200 mg of drug substance (as free base). Tablets are supplied in 240-count white 
HDPE bottles with desiccants and child resistant, tamper-evident polypropylene screw caps. 
The excipients are lactose monohydrate, low-substituted hydroxypropyl cellulose, 
hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate, hypromellose, talc, 
polyethylene glycol, titanium dioxide, and ferric oxide (red).  
 
9.1.6 
Storage: Film-coated tablets: Do not store above 25°C (77°F). Brief excursion (less than 4 
hours) up to 30°C is allowable. Store in the original package and protect from moisture.   
 

 
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If a storage temperature excursion is identified, promptly return tazemetostat tablets to below 
25°C (77°F) 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. 
 
9.1.7 
Stability:  Stability studies are ongoing. Dispense tablets in the original manufacturer’s 
container. If tablets are transferred to a pharmacy vial, they should be assigned a 30-day 
expiration.  
 
9.1.8 
Route of Administration: Oral without regard to meals. Doses must be taken twice per day with 
no less than 8 hours between each dose. If a dose is missed or vomited, skip the dose and take the 
next scheduled dose. (20-OCT-2021) 
 
9.1.9 
Method of Administration: The tablets should be taken whole and not cut, crushed or chewed.  
 
9.1.10 Potential Drug Interactions: (20-OCT-2021) In vitro, tazemetostat is metabolized primarily 
by CYP3A and to a lesser extent by CYP2C8 and CYP2D6.  It is a P-gp substrate but not a 
substrate of BCRP, OAT1B1, OAT1B3, OAT3, OCT2, and MATE1.  Therefore, treatment 
with strong and moderate inhibitors or inducers of CYP3A should be avoided from 14 days 
prior to the first dose of tazemetostat to the end of the study. Strong inhibitors and inducers of 
CYP2C8, 2D6, and P-gp should be used with caution. 
 
In vitro, tazemetostat inhibits MATE1 and MATE2K. Tazemetostat does not inhibit CYP1A2, 
2B6, 2C9, 2D6, P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, or BSEP 
at clinically relevant concentrations. Tazemetostat also induces CYP3A4. Medications that are 
substrates of CYP3A or P-gp with a narrow therapeutic index and substrates of MATE1 and 
MATE2K should be used with caution. 
 
9.1.11 Special Handling: Adequate precautions must be taken to avoid direct contact of tazemetostat 
powder to skin/mucous membranes. 
 
9.1.12 Patient Care Implications: 
 
Prolonged exposure to sunlight should be avoided during treatment with tazemetostat.  
Patients should wear protective clothing, sunscreen, and avoid tanning beds. 
 
Females of childbearing potential should agree to remain abstinent (refrain from heterosexual 
intercourse) or use adequate contraceptive methods while receiving tazemetostat and for 6 
months after the last dose of tazemetostat.  Female subjects that use hormonal contraceptives 
should also use an additional barrier method. Women should not breastfeed during treatment 
and for 1 week after the last dose of tazemetostat. 
 
9.1.13 Adverse Events 
 
Please see Section 7.3. for the Tazemetostat CAEPR. 
 
 

 
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9.1.14 Agent Ordering 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD through an 
annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, 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 participating investigator at that institution.  
 
 
Sites may order initial agent supplies after a subject has been enrolled onto the study. Please 
provide the subject ID number in the comment box of the order. 
 
 
Submit agent requests 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, a “current” password, and 
active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management. 
 
9.1.15 Agent Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB 
using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) 
available on the CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
9.1.16 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email. 
9.1.17  Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  

 
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• 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) 
 
10. 
 PATHOLOGY/BIOSPECIMEN (20-OCT-2021) 
 
10.1 
Central Pathology Review 
 
Not Applicable. 
 
10.2 
Biospecimen Selection for Integral Biomarker Testing (20-OCT-2021) 
As outlined in section 2.3 above, analysis of data obtained from stage 1 of the study resulted 
in protocol modification.  As of version date 20-OCT-2021, all patients with clear cell ovarian 
cancer enrolled on trial will be required to have a document ARID1A pathologic variant or 
likely pathologic variant mutation based on NGS assessment. 
 
10.3 
Biospecimen Selection for Integrated Biomarker Testing (20-OCT-2021) 
NOTE: As of version date 20-OCT-2021, Sections 10.3.1-10.3.5 are no longer applicable. 
 
10.3.1 Integrated Biomarker to be Tested (08/13/2019) 
BAF250a expression will be evaluated by immunohistochemistry (IHC) as an indicator of 
ARID1A mutation status and correlated with clinical response to study drug. 
 
ARID1A mutation analysis will be evaluated by MSK-IMPACT. 
 
 
10.3.2 Integrated Biomarker Testing Requirements and Reporting (08/13/2019) 
Formalin-fixed, paraffin-embedded (FFPE) tumor tissue and DNA extracted from whole 
blood will be used for BAF250A IHC and ARID1A mutation analysis (i.e., MSK-IMPACT). 
See Mandatory Biospecimen Submission Table (Section 10.4.1) for details. 
 
IHC test results will be considered positive (RETAINED) if any of the tumor nuclei are 
immunoreactive and negative (LOSS) if all tumor nuclei show no staining. The result will be 
interpreted as a technical failure and subsequently repeated on an additional slide if all nuclei 
on the slide show no immunoreactivity. 
 
10.3.3 Method of Integrated Biomarker Testing (08/13/2019) 
Only one tumor type will be tested. If more than one tumor type is submitted, the more 
advanced and most recently obtained tumor type will be tested (e.g., a metastatic lesion rather 
than a primary; recurrent or persistent tumor rather than a primary or metastatic tumor from a 
previously untreated patient). 
 
IHC will be used to measure BAF250a expression. One slide will be stained for BAF250a 
(Sigma, Catalog  # HPA005456) and one with hematoxylin and eosin (H&E). The H&E will 
confirm there is normal tissue present on the slide to serve as a normal control. All stained 
slides will be reviewed by a gynecologic pathologist. 
 
MSK-IMPACT (Cheng, 2015; FDA DEN170058) will be used to determine ARID1A 

 
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mutation status. This next generation sequencing (NGS) assay is comprised of 467 genes 
including alternate components of the SWI/SNF pathway (e.g., ARID1B, ARID2, SMARCA4, 
SMARCB1, SMARCD1, and PBRM1). 
 
10.3.4 Location of Integrated Biomarker Testing 
Integrated biomarker testing will be done by Dr. David Hyman at Memorial Sloan Kettering 
Cancer Center. 
 
10.3.5 Biospecimen Submission for Integrated Biomarker Testing (08/13/2019) 
Four unstained sections (charged, 5μm) of FFPE tumor tissue are needed for IHC; additional 
unstained sections and DNA isolated from whole blood will be used for MSK-IMPACT. 
Clear cell or endometrioid carcinoma AND normal tissue must be present in the tissue 
section placed on each slide. See Mandatory Biospecimen Submission Table (Section 10.4.1) 
for details.  
 
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 VI. 
 
10.4.1 Mandatory Biospecimen Submissions (08/13/2019) (20-OCT-2021) 
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 Specimen (Specimen Code) 
Collection Time Point 
Sites Ship 
Specimens To 
FFPE TUMOR – Submit one of the following 
FFPE Primary Tumor (FP01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
Archival tumor collected prior to 
the patient receiving any treatment 
 
Submit one - Primary preferred; 
submit metastatic if primary not 
available 
NRG BB-Columbus 
within 8 weeks of 
registration3 
FFPE Metastatic Tumor (FM01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
FFPE Primary Neoadjuvant Tumor 
(FPT01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
Archival tumor collected after the 
patient received neoadjuvant 
treatment, but prior to the patient 
receiving study treatment 
 
Submit one if tumor collected 
prior to the patient receiving any 
treatment is not available 
FFPE Metastatic Neoadjuvant Tumor 
(FMT01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
FFPE Recurrent Primary Tumor (FRP01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
Archival tumor collected prior to 
the patient receiving study 
treatment 
 

 
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FFPE Recurrent Metastatic Tumor 
(FRM01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
Submit one if tumor collected 
prior to the patient receiving any 
treatment or tumor collected after 
the patient received neoadjuvant 
is not available 
FFPE Persistent Primary Tumor (FPP01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
FFPE Persistent Metastatic Tumor 
(FPM01)1,2 
1st Choice: block 
2nd Choice: 20 unstained consecutive slides 
(charged, 5µm) 
BLOOD 
Whole Blood (WB01) 
7-10mL drawn into purple top (K2EDTA) 
tube(s) 
Prior to or after starting study 
treatment 
NRG BB-Columbus 
the day the specimen 
is collected3 
 
 
 
1 A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the NRG BB-
Columbus. 
2 Clear cell AND normal tissue must be present in the FFPE submitted for biomarker testing  
. 
3 NRG BB-Columbus / Protocol NRG-GY014, 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 Testing (08/13/2019) 
10.5.1  SWI/SNF Pathway Mutation Analysis (08/13/2019) (20-OCT-2021) 
DNA isolated from FFPE and whole blood will be used to identify potential mutations 
predictive of response, with preserved BAF250a expression (for patients enrolled prior to 
the 20-OCT-2021 version date). The next generation sequencing (NGS) assay to be used, 
MSK-IMPACT, comprises n467 other genes including alternate components of the 
SWI/SNF pathway (e.g., ARID1B, ARID2, SMARCA4, SMARCB1, SMARCD1, and PBRM1). 
 
10.6 
Banking Biospecimens for Future Research 
Details regarding the banking and use of biospecimens for future research can be found in 
Appendix VI. 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
 
Not Applicable. 
 
12. 
MODALITY REVIEWS 
Not Applicable. 
 
13. 
ASSESSMENT OF EFFECT  
13.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (uni-dimensional 

 
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measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
   
13.1.1 Definitions 
 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment on study. 
 
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
 
13.1.2 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, as ≥20 
mm by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
  
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
  
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal/pelvic 
masses (identified by physical exam and not CT or MRI), are considered as non-measurable.  
 
Notes:  
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered as measurable lesions if 
the soft tissue component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 

 
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Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.  
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, and in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.  
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up. 
 
13.1.3 Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
  

 
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Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline, and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, subsequent 
image acquisitions should use the same type of scanner and follow the baseline imaging 
protocol as closely as possible. If possible, body scans should be performed with breath-hold 
scanning techniques. 
 
NRG Oncology will not allow PET-CT use for RECIST 1.1 response criteria.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 

 
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FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT  scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR due 
to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
13.1.4 Response Criteria  
 
13.1.4.1  Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters (i.e. the nadir) while on 
study.  
 
13.1.4.2  Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (<10 mm short axis).  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  
 

 
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Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase.  
 
Although a clear progression of only “non-target” lesions is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator).  
 
13.1.4.3 
Evaluation of Best Overall (unconfirmed) Response  
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest sum recorded since the treatment started. The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria  
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
 
 
 
 
Time Point Response for Patients with only Non-Measurable Disease (i.e., Non-
Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 

 
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*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
13.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
date of study entry, including the baseline measurements. 
 
13.1.6 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time of 
progression or death, whichever occurs first. 
 
13.1.7 Survival 
Survival is defined as the duration of time from study entry to time of death or the date of last 
contact. 
 
14. 
DATA AND RECORDS 
14.1 
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 

 
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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. 
14.2 
NRG Data Management Forms 
Refer to the CTSU member website for the table of Required Form and Materials. 
14.3 
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 more timely monitoring of patient safety and 
care. See Section 7.4 for information about expedited and routine reporting.   
14.4 
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.  Instructions for submitting data using the 
CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
15. 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design (-20-OCT-2021) 
 
The data showed promise of activity in Cohort A among the patients with ARID1A mutated 
clear cell ovarian cancer, so the study will examine this population with more patients. 
 
The original study involved two distinct cohorts to be examined separately and independently. 
Cohort A included patients with clear cell or endometrioid histology who had recurrent or 
persistent ovarian or peritoneal cancer (measurable disease by RECIST v1.1). Cohort B 
included patients who had recurrent or persistent endometrioid endometrial adenocarcinoma 
(measurable disease by RECIST v1.1). Each cohort included unselected subsets of ARID1A 
mutation positive patients and ARID1A wild types. These patients could have been accrued in 
two stages. The first stage targeted a sample size of 16 patients but allowed between 12 and 19 
patients to enroll. If 1 or fewer patients out of 12 to 14 patients responded (objective complete 
or partial responses), or if 2 or fewer patients out of 15 to 19 responded, then the drug was 
considered clinically uninteresting in that cohort and stopped early for futility. Otherwise the 
study was designed to continue with the cohort assuming medical judgment indicated. If the 
study proceeded, then a cumulative sample size of 40 patients would have been targeted but 
allowed to deviate from 36 to 43 patients. If 6 or fewer patients responded out of 36 to 39 
patients, or 7 patients or fewer responded out of 40 to 43, then the drug would have been 
deemed clinically uninteresting and not worthy of further investigation. Otherwise, the drug 
could have been deemed clinically interesting with medical judgment indicating and considered 
for further study with that cohort. 
 
The study is not randomized so there were no stratification factors. 
 

 
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There is no robust historical data available on what the anticipated response probability will be 
in this patient population, so we tested whether the proportion responding was indicative of 
treatment activity for the agent in the patient population based on a wider group of recurrent 
patients. The null hypothesis for both cohorts was that the probability of a patient responding to 
treatment is 10% or less (i.e. Ho: p ≤ 0.10). The alternative hypothesis was that the probability 
of response is 30% or more (i.e. Ha: p ≥ 0.30). Using the decision rules listed above, the study 
had a 71% chance of stopping early when the treatment is not active (i.e. p=0.10). The overall 
probability of a type I error (alpha) is 5% for each cohort. On the other hand, if the drug is active 
with p=0.30, then the decision rules had a 90% chance of correctly declaring the regimen 
interesting and worthy of further investigation. 
 
Design for the Cohort of Patients with Ovarian Clear Cell Carcinoma (OCCC) ARID1A 
pathologic variant or likely pathologic variant Mutation: 
 
A cumulative sample size of 40 patients with ovarian clear cell carcinoma is targeted as the 
second stage of the trial for Cohort A. To be eligible for the second stage, patients must be 
ARID1A mutant. The population being targeted is different from the original population. 
Following the rules of the original design, accrual is allowed to deviate from 36 to 43 patients. If 
6 or fewer patients responded out of 36 to 39 patients, or 7 patients or fewer responded out of 40 
to 43, then the drug would have been deemed clinically uninteresting and not worthy of further 
investigation. Otherwise, the drug will be deemed clinically interesting with medical judgment 
indicating and considered for further study with that cohort. 
 
It is difficult to assess the operating characteristics of the design because the populations in each 
stage are different. For simplicity, let’s assume the Ho: 𝑝1 ≤0.10, 𝑝2 ≤0.10 where p1 and p2 
are the probabilities of response for ARID1A mutant and wild type patients, respectively, under 
the hypothesis that the drug is not active in either population. In addition, we will assume that 
Ha: 𝑝1 ≥0.30, 𝑝2 ≤0.10 under the alternative hypothesis. This hypothesis implies that the 
drug is active for ARID1A mutant patients but not for ARID1A wild type. Lastly, let’s assume 
that 19 patients were enrolled in Stage 1 with 10 patients who were wild types and that 21 are 
enrolled in Stage 2. The first stage decision rules were not necessarily followed, so a simplifying 
assumption will be that the number of responses among the ARID1A mutant patients is 
𝑋1~𝐵𝑖𝑛(𝑛= 9 + 21, 𝑝1) and the number of responses among the ARID1A wild type patients 
is 𝑋2~𝐵𝑖𝑛(𝑛= 10, 𝑝2). Let 𝑇= 𝑋1 + 𝑋2, the total number of responses. The distribution of 
the total number of responses is given by: 
 
𝑓𝑇(𝑡) = ∑
𝑓𝑥1(𝑡−𝑥2) ∙𝑓𝑥2(𝑥2)
𝑚𝑖𝑛(𝑛2,𝑡)
𝑥2=𝑚𝑎𝑥(0,𝑡−𝑛1)
  
 
When Ho is true, 𝑃(𝑇≤7) = 0.958, which leads to acceptance of the null hypothesis. The 
probability of a type I error is 0.042. When Ha is true, 𝑃(𝑇≤7) = 0.177, which would lead to 
rejection of Ha. The power of the study is 0.823. 
 
15.2 
Study Endpoints  
 
15.2.1 Primary Endpoint (20-OCT-2021 
 

 
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Tumor response as defined by RECIST v 1.1. If the patient fails to respond (including stable 
disease), she will be classified as a non-responder for the purposes of the decision rule.  
 
15.2.2 Secondary Endpoints (20-OCT-2021) 
Tumor response in patients with ARID1A mutations using tumor response as defined by 
RECIST v 1.1 (including stable disease). If the patient fails to respond, she will be classified 
as a non-responder for the purposes of the study. NOTE: This is not a secondary endpoint 
as of version date 20-OCT-2021. 
 
6-month progression free survival (clinical benefit rate) 
 
Adverse events according to grade of toxicity by organ or organ system. 
 
Progression-free survival. 
 
Overall survival. 
 
15.2.3 Translational Research Endpoints (08/13/2019) (20-OCT-2021) 
 
Integrated Endpoint: ARID1A mutational status. 
 
BAF250a expression by IHC. 
 
NOTE: This is not a translational research endpoint as of version date  20-OCT-2021 
 
15.3 
Sample Size and Power Calculations (20-OCT-2021) 
 
The sample size and power justification for the original design was provided in the paper by 
Chen and Ng (1998). The revised power calculations use elementary probability. 
 
15.4 
Study Monitoring of Primary Objectives 20-OCT-2021) 
The objective of the original interim analysis was treatment/study futility. The subsequent 
study is the second stage evaluation. 
 
The study will be monitored on a quarterly basis by the Early Phase Monitoring Committee 
(EPTOC). 
 
Interim Analysis for the DMC NOTE: this does not apply to the study after version date 
20 OCT, 2021 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a year 
with respect to patient accrual and morbidity. The DMC also will review the study on an “as 
needed” basis. 
 
Since this is not a randomized study, it will be monitored according to the SOP involving 
single arm studies. 
 

 
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15.5 
Accrual/Study Duration Considerations (20-OCT-2021) 
 
 
The original study was open from 3/29/2019 to 8/2/2019, a duration of 126 days. During this 
time, 9 patients with ovarian cancer had ARID1A mutations. Based on this result, we 
anticipate a monthly accrual rate of 2.17 patients per month. 
 
For the original study, the anticipated period of active accrual for Cohort A is 8 months and 
12 months respectively for the first and second stage of accrual. The anticipated period of 
active accrual for Cohort B is 5.3 months and 8 months respectively for the first and second 
stage of accrual. 
 
For the ARID1A mutated cohort, the anticipated period of active accrual is approximately 10 
months. 
 
15.6 
Secondary, Translational Research, or Exploratory Endpoints (including correlative 
science aims) (08/13/2019) 
 
See section 15.2. 
 
15.6.1 Translational Research Integrated Hypotheses and Endpoints: (08/13/2019) (20-OCT-
2021) 
 
The null and alternative hypotheses for patients with ARID1A are that the probability of 
response is 10% or less (Ho: p≤0.10) and 30% or more (Ha: p≥0.30), respectively. The 
endpoints are whether or not the patient has an objective tumor response. 
 
The integrated biomarker in the original study is now the integral biomarker. 
 
15.6.2 Definitions of Integrated TR Endpoints and How These Will Be Analyzed (08/13/2019) 
(20-OCT-2021) 
 
For the definition of the TR endpoints, see section 15.2. 
 
The following points were considered in the original study: The number of patients who are 
ARID1A mutant was not fixed in the original trial. If 16 patients are accrued and the 
probability of a patient being mutant is 50%, then the chances that the number of people with 
ARID1A mutations being between 4 and 11 is 95%. Within this subset of patients, 90% 1-
sided CIs (i.e. CIs of the form [0, pU]) will be constructed for the probability of response. If 
this CI contains the value of 30% or higher, then the study could be amended to screen 
patients for ARID1A mutations. If the total number of patients with ARID1A mutations is 6 or 
less, then the study will reopen for patients with ARID1A mutations. The chances of obtaining 
6 or fewer patients with ARID1A mutations within a sample of 16 are 23%. The sample size is 
essentially too small to exclude the possibility of a 30% response rate, regardless of the 
number of observed responses. If 7 to 11 patients are accrued with ARID1A mutations, then 1 
or more responses are necessary within this subset before consideration is given to amending 
the study. If 12 to 15 patients have ARID1A mutations, then 2 or more responses are necessary 

 
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before consideration is given to amending the study. If 16 patients have ARID1A mutations, 
then 3 or more responses are necessary before consideration is given to amending the study. 
In this setting, the study has about a 67.6% probability of being amended when the true 
probability of response is 10% within this subset, and a 95.9% probability of being amended 
when the true probability of response is 30%. 
 
For the analysis of the ARID1A mutated cohort, the biomarker is now integral so that all 
additional patients are required to be ARID1A mutated. We anticipate 28 to 32 cases. 
 
For Secondary Endpoints 
Adverse events will be tabulated by organ or organ system and grade of toxicity. Comparisons 
between cohorts may be conducted while emphasizing that the study is not randomized. 
 
Progression-free survival (PFS) and overall survival (OS) will be characterized by quartiles 
and the median of the distribution with confidence intervals. Kaplan-Meier plots will show an 
estimate of the survival function for these populations. 
 
An analysis of strictly the ARID1A mutated patients in the second stage will be conducted. If 
5 or more out of 21 patients are observed with responses, this analysis will deem the regimen 
interesting and worthy of further investigation. If the number of evaluable patients deviates 
from 21, then the 1-sided test will be conducted at the 10% level of significance. This analysis 
will be a secondary analysis. This study has about 80% power when the probability of 
response is 30%. 
 
TR Endpoints 
Associations between BAF250a and ARID1A mutations may be examined with contingency 
table analysis (e.g. potentially including Chi-square analyses or Spearman’s correlation). 
Tables may be created to examine response by type of ARID1A mutation among those tumors 
that express BAF250a to identify potential mutations predictive of response in patients with 
preserved BAF250a expression. 
 
 

 
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15.7 
Gender/Ethnicity/Race Distribution 
 
15.7.1 Endometrial Patients (20-OCT-2021) 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
0 
0 
0 
3 
White  
16 
0 
1 
0 
16 
More Than One Race 
0 
0 
0 
0 
0 
Total 
19 
0 
0 
0 
19 
 
 
15.7.2 Ovarian Cancer Patients  
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
0 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
0 
0 
0 
2 
White  
40 
0 
0 
0 
40 
More Than One Race 
0 
0 
0 
0 
0 
Total 
43 
0 
0 
0 
43 
 
 
 

 
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Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, Irie-Kunitomi H, et al. ARID1A gene 
mutation in ovarian and endometrial cancers (Review). Oncol Rep 2016 Feb;35(2):607-13. 
 
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr., Kinzler KW. Cancer 
genome landscapes. Science 2013 Mar 29;339(6127):1546-58. 
 
Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in 
endometriosis-associated ovarian carcinomas. N Engl J Med 2010 Oct 14;363(16):1532-43. 
 
 
 

 
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APPENDIX I FIGO OVARIAN CANCER STAGING 2014  
 
STAGE I: Tumor confined to ovaries  
 
IA Tumor limited to 1 ovary, capsule intact, no rumor on surface, negative washings. 
 
IB Tumor involves both ovaries otherwise like 1A. 
 
IC Tumor limited to 1 or both ovaries 
 
IC1 
Surgical spill 
IC2 
Capsule rupture before surgery or tumor on ovarian surface 
IC3 
Malignant cells in the ascites or peritoneal washings 
 
STAGE II: 
Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) 
 
or primary peritoneal cancer  
 
IIA Extension and/or implant on uterus and/or Fallopian tubes 
 
IIB Extension to other pelvic intraperitoneal tissues 
 
STAGE III: 
Tumor involves 1 or both ovaries with cytologically or histologically 
 
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the 
 
retroperitoneal lymph nodes  
 
IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the 
pelvis 
 
 
IIIA1 Positive retroperitoneal lymph nodes only 
IIIA1(i)  
Metastasis ≤ 10 mm 
IIIA1(ii) 
Metastasis > 10mm 
 
 
IIIA2 
Microscopic, extrapelvic (above the brim) peritoneal involvement ± 
positive retroperitoneal lymph nodes 
 
IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
STAGE IV: Distant metastasis excluding peritoneal metastasis 
 
IVA 
Pleural effusion with positive cytology 
 

 
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IVB 
Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal 
organs (including inguinal lymph nodes and lymph nodes outside of the abdominal 
cavity). 
Other major recommendations are as follows: 
• Histologic type including grading should be designated at staging 
• Primary site (ovary, Fallopian tube or peritoneum) should be designated where possible 
• Tumors that may otherwise qualify for stage I but involved with dense adhesions justify 
upgrading to stage II if tumor cells are histologically proven to be present in the adhesions 
 
 
 

 
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APPENDIX II FIGO STAGING OF ENDOMETRIAL CARCINOMA 2009 
 
 
Stage I* Tumor confined to the corpus uteri.  
 
 
IA* No or less than half myometrial invasion  
 
 
IB* Invasion equal to or more than half of the myometrium  
  
Stage II* Tumor invades cervical stroma, but does not extend beyond the uterus**  
 
Stage III* Local and/or regional spread of the tumor  
IIIA* Tumor invades the serosa of the corpus uteri and/or adnexae#  
  
IIIB* Vaginal and/or parametrial involvement#  
  
IIIC* Metastases to pelvic and/or para-aortic lymph nodes#  
  
 
 
IIIC1* Positive pelvic nodes 
  
IIIC2* Positive para-aortic lymph nodes with or without positive pelvic lymph nodes  
Stage IV* Tumor invades bladder and/or bowel mucosa, and/or distant metastases  
IVA* Tumor invasion of bladder and/or bowel mucosa  
 
IVB Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes   
*Either G1, G2, or G3.  
**Endocervical glandular involvement only should be considered as Stage I and no longer as Stage 
II.  
#Positive cytology has to be reported separately without changing the stage.  

 
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APPENDIX III 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 IV CLINICAL TRIAL WALLET CARD  (20-OCT-2021) 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
 
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
 
 
 

 
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APPENDIX V- PATIENT MEDICATION CALENDAR – TAZEMETOSTAT (20-OCT-2021) 
(09-DEC-2021) (06-APR-2022) 
 
This is a calendar on which you are to record the number of tazemetostat tablets you take each day.  
The instructions on how to take the tazemetostat are below.  
 
Use the calendar to record date, time and number of tazemetostat tablets taken each day.  You will 
start by taking 800 mg (four 200 mg tablets) of tazemetostat twice each day for 28 days. This 28-day 
time period is called a cycle. It is possible your doctor may reduce the amount of tazemetostat you 
take while participating in this study.  Your doctor will discuss the new treatment plan with you at 
that time. Medication should be taken as instructed without skipping any medications.  If you have 
missed a dose please mark down as “0” in the # slot for that day.  If your doctor changes the amount 
of tazemetostat you take, please be sure to write down the correct number of pills and correct amount 
taken in the columns below. 
 
Tazemetostat can be taken with or without a meal, but there must be at least 8 hours between 
doses. Tablets must be swallowed whole and must not be cut, crushed or chewed.  
 
If a dose is missed or vomited, skip the dose and take the next scheduled dose. 
You should not take CYP3A inhibitors or inducers while on this study. You will be given a clinical 
trial wallet card to share with any of your healthcare providers, 
 
You should not drink or eat grapefruit juice, Seville oranges or grapefruit while on this study. 
 
 
Note to staff:  Please give patient a drug log at initial enrollment and every week 4 visit.  Instruct 
patient how to complete the diary log.  If they are taking the first dose at a visit complete the log with 
them.  Remind them they must bring the log back at each visit along with pill bottles, empties 
included. 
 
 
Please note: Medication Calendar should be brought to each appointment along 
with medication bottles (empty included). 
 
 

 
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NRG-GY014 PATIENT MEDICATION CALENDAR-TAZEMETOSTAT 
 
Patient Name_______________________________  Patient Study ID____________ 
 
Instructions: Take  ___  tablets 2 times a day (at least 8 hours apart) 
Day 
Date 
First Dose 
Time 
# of 200mg 
tablets 
Second Dose 
Time 
# of 
200mg 
tablets 
Comments 
1  
 
 
 
 
 
 
2  
 
 
 
 
 
 
3  
 
 
 
 
 
 
4  
 
 
 
 
 
 
5  
 
 
 
 
 
 
6  
 
 
 
 
 
 
7 
 
 
 
 
 
 
8  
 
 
 
 
 
 
9 
 
 
 
 
 
 
10  
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14  
 
 
 
 
 
 
15 
 
 
 
 
 
 
16  
 
 
 
 
 
 
17 
 
 
 
 
 
 
18  
 
 
 
 
 
 
19 
 
 
 
 
 
 
20  
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Patient Signature ___________________________________   Date _________________ 
 
 
 
Physician’s Office will complete this section:  
1. Date patient started protocol treatment____________________________________________________ 
2. Date patient started this cycle _________________         This is cycle #__________ 
3. Patient’s planned total daily dose for this cycle_____________________  
4. Total number of tablets taken this month__________________________________________________ 
5. Number or pills returned/unused this month ________________________________________________ 
6. Physician/Nurse/Data Manager’s Signature_________________________________________________ 

 
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APPENDIX VI – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (20-OCT-
2021) (09-DEC-2021) 
 
I. Obtaining a Bank ID for Translational Science Biospecimens 
One Bank ID (N# # # # # # # # #) is assigned per patient per study. 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.  
 
Please contact User Support (support@nrgoncology.org) if you need assistance. 
 
II. Requesting Translational Science Biospecimen Kits 
Kits are not provided for this protocol. A pre-paid FedEx air bill is provided for the submission of 
whole blood via the online Kit Management system (https://kits.bpc-apps.nchri.org/). 
 
III. FFPE Tissue Shipped to the NRG BB-Columbus 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the specimen 
type (e.g., primary, metastatic, recurrent, persistent). 
 
• Archival primary (FP01) and metastatic (FM01) tumor should be collected prior to the patient 
receiving any treatment. 
 
• Primary neoadjuvant (FPT01) and metastatic neoadjuvant (FMT01) tumor should be 
collected after the patient received neoadjuvant treatment, but prior to the patient receiving study 
treatment. 
 
• Recurrent and persistent tumor should be collected prior to the patient receiving any study 
treatment. Recurrent or persistent tumor collected from the site of primary disease should be 
labeled recurrent primary (FRP01) or persistent primary (FPP01), respectively. Recurrent or 
persistent tumor collected from a site other than the site of primary disease (e.g., lymph node) 
should be labeled recurrent metastatic (FRM01) or persistent metastatic (FPM01), 
respectively.  
 
Only one block may be submitted per tissue type. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
Mandatory FFPE Biospecimen Requirement (08/13/2019) 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided on a 
permanent basis, then 20 unstained slides (charged, 5µm) should be submitted. All tissue sections 
must be cut sequentially from one block. 
 
Note: Clear cell AND normal tissue must be present in the FFPE tissue submitted for 
biomarker testing.  
Completing Form TR for FFPE Biospecimens 

 
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The type of biospecimen (block or slides) should be specified on Form TR. If submitting slides, the 
slide type, thickness, and count should also be specified. 
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational science 
tissue biospecimen with: 
 
Bank ID (N# # # # # # # # #)* 
Patient ID (e.g., AB###-GY014-#####) 
specimen code (see section 10.4.1) 
collection date (mm/dd/yyyy) 
surgical pathology accession number 
block number 
 
*Leading zeros may be omitted when labeling biospecimens with the Bank ID.  For example, 
N00000010 may be written as N10. 
 
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. Whole Blood Shipped to the NRG BB-Columbus 
1.  Label the lavender/purple top (EDTA) collection tube(s) as described below. Multiple tubes may 
be used to collect the required amount. 
2. Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL is 
needed for processing. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Ship whole blood to the NRG BB-Columbus the day the biospecimen is collected. If the whole 
blood absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated (4°C) 
shipped within 24 hours. Do not collect whole blood the day before a holiday. 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label should be used to label each translational science 
whole blood biospecimen with: 
 
Bank ID (N # # # # # # # # # # )* 
Patient ID (e.g., AB###-GY014-#####) 
specimen code (WB # #) 
collection date (mm/dd/yyyy) 
 
*Leading zeros may be omitted when labeling biospecimens with the Bank ID.  For example, 
N00000010 may be written as N10. 
 
V. Submitting Form TR 
A specimen transmittal form (i.e., Form TR) for each biospecimen will be available in the 
Translational Research Folder in Rave, once the Specimen Consent (located in the Baseline 

 
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Folder) has been completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each biospecimen 
shipped to the NRG BB-Columbus (or alternate laboratory). Handwritten forms will not be 
accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus (or alternate laboratory) if 
biospecimens are not collected. 
 
Form TR must 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.  
 
Note: Biospecimens will not be marked as received in Rave without receipt of a corresponding 
electronically completed Form TR. Incomplete forms or those containing incorrect information 
will not be processed. 
  
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.  
 
All translational science biospecimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG-GY014 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
A. FFPE Tissue Shipped to the NRG BB-Columbus 
FFPE tissue and a copy of the corresponding pathology report should be shipped using your own 
container at your own expense to the NRG BB-Columbus at the address above.  
 
Do not ship FFPE tissue for Saturday delivery. 
 

 
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B. Whole Blood Shipped to the NRG BB-Columbus 
Whole blood biospecimens should be shipped to the NRG BB-Columbus at the address above. 
 
Whole blood biospecimens can be shipped to the NRG BB-Columbus Monday through Friday for 
Tuesday through Saturday delivery. Do not ship whole blood the day before a holiday. Use your 
own shipping container to ship biospecimens via FedEx priority overnight. 
 
When shipping whole blood biospecimens, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the NRG BB-Columbus at 
BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  
 
To ship whole blood biospecimens you will need (1) a sturdy shipping container (e.g., a cardboard or 
styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a puncture and 
pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, and (5) a 
pre-paid FedEx air bill. 
 
*If you will be shipping whole blood biospecimens from more than one patient, please put each 
biospecimen in a separate plastic zip-lock bag before placing the biospecimens in the shipping bag. 
You may include up to four different blood biospecimens in one biohazard envelope. 
 
If you do not have these materials available at your site, you may order them from any supplier (e.g., 
Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
Shipping Whole Blood Using Your Own Shipping Container 
1. Place the whole blood biospecimen in a biohazard envelope containing absorbent material. Expel 
as much air as possible before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing the 
envelope. 
4. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
5. Insert a copy of Form TR for each biospecimen.  
6. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
7. Print a pre-paid FedEx air bill using the Kit Management link (https://kits.bpc-apps.nchri.org/). 
Attach the air bill. 
8. Make arrangements 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 
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. 
 

 
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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. 
 
 

 
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APPENDIX VII – 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.