A Phase III Randomized, Placebo-Controlled Study of Pembrolizumab (MK-3475, NSC #776864) in Addition to Paclitaxel and Carboplatin for Measurable Stage III or IVA, Stage IVB or Recurrent Endometrial Cancer
Phase: PHASE3
Conditions: Endometrial Clear Cell Adenocarcinoma, Endometrial Dedifferentiated Carcinoma, Endometrial Endometrioid Adenocarcinoma, Endometrial Mixed Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Endometrial Undifferentiated Carcinoma, Recurrent Endometrial Adenocarcinoma, Recurrent Endometrial Carcinoma, Recurrent Endometrial Clear Cell Adenocarcinoma, Recurrent Endometrial Dedifferentiated Carcinoma, Recurrent Endometrial Endometrioid Adenocarcinoma, Recurrent Endometrial Mixed Cell Adenocarcinoma, Recurrent Endometrial Serous Adenocarcinoma, Recurrent Endometrial Undifferentiated Carcinoma, Stage III Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8, Stage IV Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8
Sponsor: National Cancer Institute (NCI)

 
NRG-GY018 
i 
NCI Version Date: February 24, 2023 
For Protocol Amendment #12 to: NRG-GY018 
 
NCI Protocol #: NRG-GY018 
Local Protocol #: NRG-GY018 
 
NCI Version Date: February 24, 2023 
 
This amendment is being submitted in response to an RRA from Dr. Elad Sharon 
(sharone@mail.nih.gov): 
 
 
Section 
Comments 
Title Pages 
NCI Version Date is now February 24, 2023. 
 
6.2 
NCI has updated the dose modification guidelines for pembrolizumab. 
6.2.3, 6.2.4 
The tables in 6.2.3 and 6.2.4 were replaced with updated dose modification 
guidelines for pembrolizumab. 
6.2.5 
This section, neurological toxicities, was added and the remaining section 
was renumbered. 
7.3 
The CAEPR for pembrolizumab has been updated to Version 2.7, 
December 13, 2022: 
 
• Added New Risk: 
• Rare but Serious: Endocrine disorders - Other 
(hypoparathyroidism); Nervous system disorders - Other 
(optic neuritis)  
 
• Decrease in Risk Attribution: 
• Changed to Also Reported on Pembrolizumab (MK-3475) 
Trials But With Insufficient Evidence for Attribution from 
Less Likely: CPK increased; Joint effusion; Pleuritic pain 
 
• Deleted: 
• Less Likely: Avascular necrosis; Immune system disorders - 
Other (pseudoprogression/tumor inflammation); Infection; 
Musculoskeletal and connective tissue disorder - Other 
(tenosynovitis) 
• Footnote #4 “Infection includes all 75 sites of infection 
under the INFECTIONS AND INFESTATIONS SOC.” is 
deleted. 
ICD 
Please see the ICD for additional changes. 
 
 
 

 
NRG-GY018 
ii 
NCI Version Date: February 24, 2023 
In addition, the following changes were made: 
 
Section 
Comments 
Title Page 
• The date of closure to accrual was added. 
• CTSU Logistical language was updated. 
Schema 
“On February 6, 2023, all patient treatment assignments were unblinded and 
made available through Medidata Rave.  Patients randomized to Arm 1 will not 
receive additional placebo infusions.  All other study related treatments and 
evaluations will proceed per protocol.  Patients on Arm 2 will continue all study 
related treatments and evaluation” was added. 
5. 
“On February 6, 2023, all patient treatment assignments were unblinded and 
made available through Medidata Rave. Patients randomized to Arm 1 will not 
receive additional placebo infusions.  All other study related treatments and 
evaluations will proceed per protocol.  Patients on Arm 2 will continue all study 
related treatments and evaluations” was added. 
5.2 
“Effective February 06, 2023, all patients have been unblinded.  Patients 
randomized to Arm 1 will not receive additional placebo infusions.  All other 
study related treatments and evaluations will proceed per protocol. Patients on 
Arm 2 will continue all study related treatments and evaluations” was added.  
8.1 
CTSU Logistical language was updated. 
8.2 
CTSU Logistical language was updated. 
8.2 
The Delegation of Tasks Log section was updated to reflect the unblinding of all 
patients as of February 6, 2023. A new DTL (without the Unblinded Study 
Personnel task) is available on the CTSU website and must be completed and 
signed by the site CI.   
8.3/8.3.1 
CTSU Logistical language was updated. 
8.4 
• CTSU Logistical language was updated. 
• Central Monitoring Section was added. 
8.5, 8.5.1, 
8.5.2  
• References to Unblinded Study Personnel were removed. 
• OAOP has been replaced with AURORA. 
8.5.3 
Agent Accountability information was updated. 
8.5.4 
OAOP has been replaced with AURORA. 
9.1.4 
This section was updated. 
9.1.5 
This section was updated. 
9.1.6 
This section was updated. 
9.2.2 
This section was updated due to the unblinding of all patients as of February 6, 
2023. 

 
NRG-GY018 
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NCI Version Date: February 24, 2023 
9.2.3 
This section was updated. 
9.2.4 
• The drug order timeline/shipment chart was updated. 
• OAOP was replaced with AURORA. 
• References to Unblinded Study Personnel were removed. 
• Vial transfer information was updated. 
• Drug Return information was updated. 
13.1 
This section was removed as it was duplicative with information in Section 8.4.  
Remaining sections were renumbered. 
Appendix 
VII 
• In the Approximate scan collection per subject section, #2 was revised 
and #3 was deleted for better consistency with Section 4.2. 
• CTSU Logistical language for TRIAD was updated. 
Appendix 
IX 
• “On February 6, 2023, all patient treatment assignments were unblinded.  
Submission and maintenance of a Pharmacy Agreement for unblinded 
site personnel is no longer required. . .” was added.  A new DTL (without 
the Unblinded Study Personnel task) is available on the CTSU website 
and must be completed and signed by the site CI. 
• “As of the unblinding of all patients on February 6, 2023, this Pharmacy 
Agreement no longer applies” was added to the top of the Agreement. 
Appendix 
XIV 
“Effective February 06, 2023, all patients were unblinded.  Patients randomized 
to placebo (Arm 1) will not receive additional placebo infusions.  All other study 
related treatments and evaluations will proceed per protocol” was added to the 
end of the appendix. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
NRG-GY018 
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NCI Version Date: February 24, 2023 
NRG ONCOLOGY 
 
NRG-GY018  
(ClinicalTrials.gov NCT # 03914612) (09/24/2019) 
A PHASE III RANDOMIZED, PLACEBO-CONTROLLED STUDY OF PEMBROLIZUMAB 
(MK-3475, NSC #776864) IN ADDITION TO PACLITAXEL AND CARBOPLATIN FOR 
MEASURABLE STAGE III OR IVA, STAGE IVB OR RECURRENT ENDOMETRIAL CANCER 
 
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; SWOG; and the Canadian Cancer Trials Group (CCTG). 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (07/03/2019) (14-OCT-2020) 
Principal Investigator/Gyn Oncology 
Gyn Oncology Co-Chair 
Ramez N. Eskander, M.D. 
Amanda N. Fader, M.D. 
UC San Diego Moores Cancer Center 
The Kelly Gynecologic Oncology Service 
3855 Health Sciences Drive 
600 N. Wolfe Street, Phipps 287 
La Jolla, CA 92093-0987 
Baltimore, MD 21287 
858-822-6199/ FAX: 858-822-6319 
410-955-8240/ FAX: 
reskander@health.ucsd.edu 
AFader1@jhmi.edu   
 
 
Statistician 
CCTG Study Co-Chair 
Michael Sill, Ph.D. 
Stephen Welch, M.D. 
NRG Oncology Biostatistical Center-Buffalo 
London Regional Cancer Program 
Elm and Carlton Streets 
790 Commissioners Road East 
Buffalo, NY 10065 
London, ON Canada N6A 4L6 
716-845-5702/FAX: 716-845-8393 
519-685-8640 
sillm@nrgoncology.org  
Stephen.welch@lhsc.on.ca  
 
 
Patient Reported Outcomes Co-Chair 
Translational Scientist 
Lari Wenzel, Ph.D. 
Heather A Lankes, Ph.D., M.P.H 
UC Irvine Health 
NRG Oncology 
Chao Family Comprehensive Cancer Center 
Four Penn Ctr, 1600 JFK Blvd., Ste 1020 
100 Theory Street, Suite 110 
Philadelphia, PA 19103 
Irvine, CA 92697 
lankesh@nrgoncology.org  
lwenzel@uci.edu  
 

 
NRG-GY018 
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Research Nurse (14-OCT-2020) 
Data Manager 
Vania Hom 
Ashley Badders 
Memorial Sloan Kettering Cancer Ctr 
NRG Oncology SDMC-Pittsburgh 
1275 York Ave 
201 N. Craig St., Suite 500 
New York, NY 10065 
Pittsburgh, PA 15213 
646-888-4227 
412-624-5532/FAX: 412-624-1082 
homv@mskcc.org  
baddersa@nrgoncology.org  
 
 
Protocol Coordinator 
 
Meg Colahan, M.A. 
 
NRG Oncology 
 
Four Penn Ctr, 1600 JFK Blvd., Ste 1020 
 
Philadelphia, PA 19103 
 
267-295-9476/FAX: 215-854-0716 
 
colahanm@nrgoncology.org  
 
 
 
 
 
 
NRG Oncology Contact Information (07/03/2019) (21-MAY-2021) 
Data Management 
For questions concerning data 
submission 
Ashley Badders 
NRG Oncology Statistics and Data Management Center- 
Pittsburgh  
201 N. Craig St., Suite 500 
Pittsburgh, PA 15213 
412-624-5532/FAX 412-624-1082 
baddersa@nrgoncology.org   
Protocol Development 
For questions concerning protocol 
and informed consent versions and 
amendments 
Protocol Coordinator  
Meg Colahan, M.A. 
NRG Oncology-Philadelphia East 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Philadelphia, PA 19103 
267-295-9476 
colahanm@nrgoncology.org  
Regulatory 
NRG-GY-Regulatory@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 
 
 
The following NCTN Group Study Champion has been added to this trial: 
CCTG: Stephen Welsh, M.D., London Regional Cancer Program, Stephen.welch@lhsc.on.ca  

 
NRG-GY018 
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NCI Version Date: February 24, 2023 
Gynecologic Oncology 
Committee Chair 
Carol Aghajanian, M.D. 
Memorial Sloan Kettering Cancer Center 
Department of Medicine 
1275 York Avenue 
New York, NY 10065 
(646) 888-4217 
aghajanc@mskcc.org  
 
 
Protocol Agents (09/24/2019) 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Pembrolizumab (MK-3475) 
CTEP 
776864 
 
DCTD, NCI 
Carboplatin 
Commercial 
241240 
N/A 
N/A 
Paclitaxel 
Commercial 
673089 
N/A 
N/A 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version Date 
Amendment 12 
February 24, 2023 
Closed to Accrual 
December 06, 2022 
Amendment 11 
September 30, 2022 
Amendment 10 
May 19, 2022 
Amendment 9 
March 9, 2022 
Amendment 8 
October 6, 2021 
Amendment 7 
May 21, 2021 
Amendment 6 
December 08, 2020 
Amendment 5 
October 14, 2020 
Amendment 4 
February 27, 2020 
Amendment 3 
February 07, 2020 
Amendment 2 
09/24/2019 
Amendment 1 
07/03/2019 
Initial 
06/14/2019 
 
 
 
 
  
 
 
 
 
 
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. 

 
NRG-GY018 
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NCI Version Date: February 24, 2023 
NRG ONCOLOGY 
 
NRG-GY018 
 
A PHASE III RANDOMIZED, PLACEBO-CONTROLLED STUDY OF 
PEMBROLIZUMAB (MK-3475, NSC #776864) IN ADDITION TO PACLITAXEL AND 
CARBOPLATIN FOR MEASURABLE STAGE III OR IVA, STAGE IVB OR RECURRENT 
ENDOMETRIAL CANCER 
 
CONTACT INFORMATION (14-OCT-2020) (21-MAY-2021) (09-MAR-2022) (24-FEB-2023) 
 
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), or 
CTSURegHelp@coccg.org 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 logging in with a CTEP-IAM username and 
password or linked ID.me account (ID.me accounts are required for all newly created CTEP0-IAM accounts 
and by July 1, 2023 for all users).  
 
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 Roster Maintenance application and in most cases viewable 
and manageable via the Roster Update Management System (RUMS) on the CTSU members’ website.   
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the Lead 
Protocol Organization. 

 
NRG-GY018 
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NCI Version Date: February 24, 2023 
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.  
For imaging submission questions, contact IROCPHILA-DI@acr.org. 
 
 
 

 
NRG-GY018 
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TABLE OF CONTENTS 
1. 
OBJECTIVES .................................................................................................................. - 12 - 
1.1 
Primary Objective ............................................................................................. - 12 - 
1.2 
Secondary Objectives (07/03/2019) .................................................................. - 12 - 
1.3 
Exploratory objectives ...................................................................................... - 12 - 
2. 
BACKGROUND (07/03/2019) (14-OCT-2020) ............................................................. - 13 - 
2.1 
Immunotherapy in endometrial cancer ............................................................. - 14 - 
2.2 
Combining cytotoxic chemotherapy with immune checkpoint inhibitors: 
safety and efficacy ............................................................................................ - 15 - 
2.3 
Pembrolizumab (MK-3475) .............................................................................. - 19 - 
2.4 
Incorporation of maintenance pembrolizumab (MK-3475)/placebo (14-OCT-
2020) (08-DEC-2020) ....................................................................................... - 22 - 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA .............. - 24 - 
3.1 
Patient Selection Guidelines ............................................................................. - 24 - 
3.2 
Eligibility Criteria (07-FEB-2020) (21-MAY-2021) (09-MAR-2022) ............ - 24 - 
3.3 
Ineligibility Criteria .......................................................................................... - 27 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ........ - 29 - 
4.1 
PRE-TREATMENT ASSESSMENTS (09/24/2019) (07-FEB-2020) (14-
OCT-2020) (08-DEC-2020) (09-MAR-2022) .................................................. - 29 - 
4.2 
ASSESSMENTS DURING TREATMENT (09/24/2019) (14-OCT-2020) ..... - 30 - 
4.3 
ASSESSMENTS IN FOLLOW UP .................................................................. - 31 - 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION ........................................................ - 31 - 
5.1 
Treatment  (14-OCT-2020) (08-DEC-2020) (19-MAY-2022) ......................... - 32 - 
5.2 
Unblinding Procedures (14-OCT-2020) (08-DEC-2020) (09-MAR-2022) (24-
FEB-2023)......................................................................................................... - 34 - 
5.3 
Radiation Therapy ............................................................................................. - 35 - 
5.4 
Surgery .............................................................................................................. - 35 - 
5.5 
Device ............................................................................................................... - 35 - 
5.6 
Imaging ............................................................................................................. - 35 - 
5.7 
Integral Biomarker Assay (09-MAR-2022) ...................................................... - 35 - 
5.8 
General Concomitant Medication and Supportive Care Guidelines ................. - 35 - 
5.9 
Duration of Therapy (14-OCT-2020) (08-DEC-2020) (09-MAR-2022).......... - 37 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT (14-OCT-2020) (21-MAY-2021)- 38 - 
6.1 
Paclitaxel and Carboplatin Dose Modification and Supportive Care Guidelines 
for Drug-Related Adverse Events (07-FEB-2020) (21-MAY-2021) ................ - 38 - 
6.2 
Pembrolizumab (MK-3475)/Placebo Dose Modification and Supportive Care 
Guidelines for Drug-Related Adverse Events (24-FEB-2023) ......................... - 40 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................... - 54 - 
7.1 
Protocol Agents ................................................................................................. - 54 - 
7.2 
Adverse Events and Serious Adverse Events ................................................... - 54 - 

 
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7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) for MK-3475 
(pembrolizumab, NSC 776864) (27-FEB-2020) (06-OCT-2021) (24-FEB-
2023) ................................................................................................................. - 55 - 
7.4 
Adverse Events for Commercial Study Agents ................................................ - 59 - 
7.5 
Expedited Reporting of Adverse Events (09-MAR-2022) ............................... - 59 - 
7.6 
Routine Reporting Requirements for Adverse Events (14-OCT-2020) ........... - 61 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (07/03/2019) (14-OCT-2020)- 61 
- 
8.1 
Investigator and Research Associate Registration with CTEP (24-FEB-2023) - 61 - 
8.2 
Cancer Trials Support Unit Registration Procedures (09-MAR-2022) (24-
FEB-2023)......................................................................................................... - 63 - 
8.3 
Patient Enrollment (24-FEB-2023) ................................................................... - 66 - 
8.4 
Data Submission / Data Reporting (09/24/2019) (09-MAR-2022) (24-FEB-
2023) ................................................................................................................. - 69 - 
8.5 
Agent Ordering and Agent Accountability (09-MAR-2022) (24-FEB-2023) .. - 72 - 
8.6 
ePRO Registration Process (07/03/2019) ......................................................... - 73 - 
9. 
DRUG INFORMATION ................................................................................................. - 75 - 
9.1 
Investigational Study Agent: pembrolizumab (MK-3475) (NSC# 776864) 
/CTEP-supplied placebo (14-OCT-2020) (09-MAR-2022).............................. - 75 - 
9.2 
Provision of  Pembrolizumab (MK-3475) and Placebo (09-MAR-2022) ........ - 76 - 
9.3 
Commercial Agent: Carboplatin ....................................................................... - 80 - 
9.4 
Commercial Agent: Paclitaxel .......................................................................... - 80 - 
10. 
PATHOLOGY/BIOSPECIMEN ..................................................................................... - 81 - 
10.1 
Central Pathology Review Guidelines .............................................................. - 81 - 
10.2 
Biospecimen Selection for Integral Biomarker Testing (09/24/2019) (21-
MAY-2021) (19-MAY-2022) ........................................................................... - 81 - 
10.3 
Biospecimen Selection for Integrated Biomarker Testing ................................ - 83 - 
10.4 
Biospecimen Submission Tables ...................................................................... - 83 - 
10.5 
Biospecimen Selection for Exploratory Biomarker Testing (09/24/2019) (21-
MAY-2021) (09-MAR-2022) (19-MAY-2022) ............................................... - 84 - 
10.6 
Banking Biospecimens for Future Research ..................................................... - 86 - 
11. 
SPECIAL STUDIES (Non-Tissue) .................................................................................. - 87 - 
11.1 
Patient Reported Outcomes (PROs) in the pMMR population ......................... - 87 - 
12. 
ASSESSMENT OF EFFECT .......................................................................................... - 89 - 
12.1 
Antitumor Effect – Solid Tumors ..................................................................... - 89 - 
12.2 
Response Criteria (07/03/2019) ........................................................................ - 92 - 
12.3 
Duration of Response ........................................................................................ - 95 - 
12.4 
Progression-Free Survival ................................................................................. - 96 - 
12.5 
Survival ............................................................................................................. - 96 - 
13. 
DATA AND RECORDS (24-FEB-2023) ........................................................................ - 96 - 
13.1 
NRG Data Management Forms ........................................................................ - 96 - 

 
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13.2 
Summary of Data Submission .......................................................................... - 96 - 
13.3 
Enhanced Centralized Monitoring .................................................................... - 96 - 
13.4 
Enhanced Auditing (21-MAY-2021) ................................................................ - 97 - 
13.5 
Global Reporting/Monitoring (09/24/2019) ..................................................... - 97 - 
14. 
STATISTICAL CONSIDERATIONS............................................................................. - 98 - 
14.1 
Study Design (07/03/2019) (09/24/2019) (19-MAY-2022) (30-SEP-2022) .... - 98 - 
14.2 
Study Endpoints ................................................................................................ - 99 - 
14.3 
Primary Objectives Study Design ................................................................... - 100 - 
14.4 
Study Monitoring of Primary Objectives (09/24/2019) (19-MAY-2022) (30-
SEP-2022) ....................................................................................................... - 102 - 
14.5 
Accrual/Study Duration Considerations ......................................................... - 103 - 
14.6 
Secondary or Exploratory Endpoints (including correlative science aims) 
(07/03/2019) (09-MAR-2022) ........................................................................ - 104 - 
14.7 
Exploratory Hypothesis and Endpoints (07/03/2019) ..................................... - 107 - 
14.8 
Gender/Ethnicity/Race Distribution (21-MAY-2021) .................................... - 107 - 
15. 
REFERENCES .............................................................................................................. - 108 - 
APPENDIX I - CARCINOMA OF THE ENDOMETRIUM FIGO CLASSIFICATION 2009- 112 - 
APPENDIX II – PERFORMANCE STATUS CRITERIA ....................................................... - 113 - 
APPENDIX III- CARBOPLATIN DOSE CALCULATION INSTRUCTIONS (09/24/2019) (07-
FEB-2020) (21-MAY-2021) .......................................................................................... - 114 - 
APPENDIX IV – GENERAL TREATMENT GUIDELINES (14-OCT-2020) (21-MAY-2021)- 116 
- 
APPENDIX V - CTEP COLLABORATIVE AGREEMENTS LANGUAGE ......................... - 117 - 
APPENDIX VI - TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (21-MAY-2021) 
(09-MAR-2022) ............................................................................................................. - 119 - 
APPENDIX VII:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (07/03/2019) (14-OCT-
2020) (09-MAR-2022) (24-FEB-2023) ......................................................................... - 124 - 
APPENDIX VIII –CENTRALIZED MMR IHC TESTING LABORATORY MANUAL (07-FEB-
2020) (21-MAY-2021) (09-MAR-2022) (19-MAY-2022) ........................................... - 125 - 
APPENDIX IX - NRG-GY018 PHARMACY AGREEMENT (07/03/2019) (09/24/2019) (07-FEB-
2020) (09-MAR-2022) (24-FEB-2023) ......................................................................... - 129 - 
APPENDIX X - BIOSPECIMEN BANK-COLUMBUS FFPE MATERIALS VERIFICATION 
FORM ............................................................................................................................ - 133 - 
APPENDIX XI – PPD LABORATORY MANUAL (07/03/2019) (09/24/2019) (09-MAR-2022) 
(19-MAY-2022) ............................................................................................................. - 134 - 

 
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APPENDIX XII - MEDIDATA PATIENT CLOUD ePRO OPERATIONAL PROCEDURES 
(07/03/2019) (08-DEC-2020) ........................................................................................ - 135 - 
APPENDIX XIII – TREATMENT CONSIDERATIONS IN THE CONTEXT OF THE COVID-19 
PANDEMIC AND PLACEBO DESIGN ...................................................................... - 141 - 
Appendix XIV: COUNTRY-SPECIFIC APPENDIX – JAPAN (09-MAR-2022) (19-MAY-2022) 
(24-FEB-2023) ............................................................................................................... - 143 - 
 
 
 

 
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NRG-GY018 SCHEMA (09/24/2019) (07-FEB-2020) (14-OCT-2020) (21-MAY-2021) (09-
MAR-2022) (30-SEP-2022) (24-FEB-2023) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Abbreviations: (07/03/2019) 
 
 
 
On February 6, 2023, all patient treatment assignments were unblinded and made available through 
Medidata Rave.  Patients randomized to Arm 1 will not receive additional placebo infusions.  All 
other study related treatments and evaluations will proceed per protocol.  Patients on Arm 2 will 
continue all study related treatments and evaluations. 
ENDOMETRIAL CANCER 
• 
Measurable stage III 
• 
Measurable stage IVA 
• 
Measurable OR Non-Measurable stage IVB 
• 
Measurable OR Non-Measurable Recurrent 
Submission of slides for Centralized MMR testing* 
(See Section 10.2 and Appendix VIII) 
*slides for PD-L1 testing should be submitted simultaneously 
REGISTRATION/STRATIFICATION – STEP 2  
• 
MMR Status based on local testing 
Mismatch repair deficient (dMMR) (yes/no)  
As of August 17, 2022, the dMMR cohort is Closed 
• 
Performance Status (0 or 1 vs 2) 
• 
Prior chemotherapy (yes/no) 
RANDOMIZATION 
Arm 1 
Combination Phase: 
Placebo 200 mg IV Day 1 
Paclitaxel 175mg/m2 IV over 3 hours Day 1 
Carboplatin AUC 5 IV Day 1 
Every 3 weeks x 6 cycles 
Maintenance Phase: 
Placebo 400 mg IV Day 1  
Every 6 weeks x up to 14 cycles 
  
One cycle= 3 weeks for the combination phase 
 One cycle = 6 weeks for maintenance phase 
 
Maximum number of placebo cycles (combination 
phase + maintenance phase) = 20 
Arm 2 
Combination Phase: 
Pembrolizumab (MK-3475) 200 mg IV Day 1 
Paclitaxel 175mg/m2 IV over 3 hours Day 1 
Carboplatin AUC 5 IV Day 1 
Every 3 weeks x 6 cycles 
Maintenance Phase: 
Pembrolizumab (MK-3475) 400 mg IV Day 1  
Every 6 weeks x up to 14 cycles 
 
One cycle= 3 weeks for the combination phase 
 One cycle = 6 weeks for maintenance phase 
 
Maximum number of pembrolizumab (MK-3475) cycles 
(combination phase + maintenance phase) = 20 

 
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Abbreviations: (07/03/2019) 
 
dMMR 
 
Mismatch repair deficient 
pMMR 
 
Mismatch repair proficient  
IHC 
 
Immunohistochemistry 
MMR 
 
Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) 
MSI 
 
Microsatellite instability 
MSI-H 
 
Microsatellite instability – high 
MSS 
 
Microsatellite stable 
PCR 
 
Polymerase chain reaction 
PD-1 
 
Programmed cell death protein 1 
PD-L1 
 
Programmed death-ligand 1 
 

 
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1. 
OBJECTIVES 
1.1 
Primary Objective 
1.1.1 To evaluate the efficacy of pembrolizumab (MK-3475) in combination with paclitaxel and 
carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and 
recurrent endometrial cancer.  Efficacy will be determined via investigator assessed 
progression free survival (PFS) as assessed by RECIST 1.1 in two distinct populations 
referred to as proficient and deficient mismatch repair (pMMR and dMMR). (07/03/2019) 
 
1.2 
Secondary Objectives (07/03/2019) 
1.2.1 To determine the nature, frequency and degree of toxicity as assessed by CTCAE for each 
treatment arm. 
1.2.2 To evaluate BICR assessed or investigator assessed objective response rate (ORR) as 
assessed by RECIST 1.1 by treatment arm and by MMR IHC status in patients who enter the 
study with measurable disease. (09-MAR-2022) 
1.2.3 To evaluate BICR assessed or investigator assessed duration of response (DOR) by treatment 
arm and by MMR IHC status in patients who enter the study with measurable disease. (09-
MAR-2022) 
1.2.4 To evaluate the effect of pembrolizumab (MK-3475) on OS in patients with pMMR or 
dMMR. 
1.2.5 To determine whether the addition of pembrolizumab (MK-3475) to standard combination 
chemotherapy is associated with improved patient reported physical function as measured 
with the PROMIS-physical function scale (short form), quality of life as measured with the 
FACT-En TOI and worsened fatigue as measured with the PROMIS-Fatigue scale (short 
form) in the pMMR patients. 
1.2.6 To determine concordance between institutional MMR IHC testing and centralized MMR 
IHC. 
 
1.3 
Exploratory objectives 
1.3.1 To explore the correlation between patient-reported physical function as measured with the 
PROMIS-physical function scale (short form) and quality of life as measure with the FACT-
En TOI. 
1.3.2 To explore whether the addition of pembrolizumab (MK-3475) to standard combination 
chemotherapy is associated with self-reported neurotoxicity as measured with the 
FACT/GOG-Ntx subscale (short) and the extent to which patients differ on their self-reported 
bother from side effects of cancer therapy in the pMMR patients. 
1.3.3 To evaluate the efficacy of pembrolizumab (MK-3475) in combination with paclitaxel and 
carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and 
recurrent endometrial cancer by PD-L1 IHC (positive vs negative).  Efficacy will be 
determined via investigator assessed progression free survival (PFS) and overall survival 
(OS) in two distinct populations referred to as proficient and deficient mismatch repair 
(pMMR and dMMR). 
1.3.4 To assess the association between PD-L1 IHC (positive vs negative) and mismatch repair 
status (pMMR and dMMR). 
 
 

 
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2. 
BACKGROUND (07/03/2019) (14-OCT-2020) 
 
Endometrial cancer (EC) continues to be the most common gynecologic malignancy in the 
United States and is the only cancer of the female genital tract with a rising incidence and 
mortality (Evans, 2011).  In 2017 there were an estimated 61,380 new cases and 10,920 
deaths (Siegel, 2017).  Despite the excellent prognosis in patients with early stage disease, 
those with advanced stage, metastatic or recurrent EC have limited therapeutic options with 
long-term survival approaching 15%, representing an area of unmet clinical need.  Since 
the completion of Gynecologic Oncology Group (GOG) protocol 177, which explored the 
triplet regimen of paclitaxel, doxorubicin, and cisplatin (TAP) in patients with advanced 
stage and recurrent EC, there have been limited therapeutic advancements (Fleming, 2004).  
GOG 209 was a phase 3 clinical trial comparing the combination regimen of paclitaxel and 
carboplatin to TAP.  This study enrolled over 1300 subjects and demonstrated less toxicity 
and a non-inferior PFS and OS with the doublet regimen, rendering paclitaxel and 
carboplatin the backbone for future clinical trials (Miller, 2012).  Second line chemotherapy 
options for endometrial cancer are notably less effective, with megestrol acetate being the 
only FDA approved agent in this setting.  A phase III randomized trial of second line 
ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer did 
not meet its primary objective of improving OS in the ixabepilone arm compared to the 
control chemotherapy arm (McMeekin, 2015).  OS, PFS and ORR were similar in both arms, 
with control chemotherapy showing median OS of 12.3 months, median PFS of 4 months and 
ORR of 15.7% (all partial responses). 
Immunotherapy has emerged as a therapeutic strategy in patients with advanced stage or 
recurrent EC (Vanderstraeten, 2014, Coosemans, 2014).  The clinical relevance of 
immunotherapy in the treatment of solid malignancies is well established, with checkpoint 
inhibitors approved for the treatment of several solid malignancies: melanoma, renal cell 
carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, and non small cell 
lung cancer.  Most recently, the anti-PD-1 antibody pembrolizumab (MK-3475, Keytruda®) 
was granted FDA approval as monotherapy in patients with mismatch repair deficient 
(dMMR) or microsatellite instability-high (MSI-H) solid tumors, whose disease has 
progressed following prior therapy, and who have no satisfactory alternative treatment 
options (including endometrial carcinoma).  This approval was partially based on the 
promising results reported with single agent checkpoint inhibition in patients with heavily 
pretreated, dMMR or MSI-H endometrial cancer.  In an effort to improve response rates, and 
oncologic outcomes in this patient population, we propose a randomized, placebo-controlled 
phase III study examining paclitaxel and carboplatin combination chemotherapy with the 
checkpoint inhibitor, pembrolizumab (MK-3475) or placebo in patients with advanced stage 
or recurrent endometrial cancer.   
Identifying a more effective treatment strategy in this vulnerable population that translates 
into an improvement in outcomes, would represent a significant oncologic achievement.  
Furthermore, understanding the role of checkpoint inhibition in endometrial cancer, for both 
the mismatch repair deficient and microsatellite stable populations, may inform future studies 
and allow for the inclusion of immunotherapeutic treatment paradigms in clinical trial 
designs targeting earlier stage disease.  Ultimately, the goal would be to improve the quality 
of life and outcomes for women affected by these aggressive cancers. 
Disease progression in patients with recurrent endometrial cancer can present clinically, 

 
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requiring history and physical examination to guide identification and inform 
treatment/patient counseling.  In context of the above, it is recommended that patients be 
seen and examined with appropriate interval history and physical examination as part of 
routine care and on clinical trial.  Assessment intervals of 6-weeks will allow for patient 
evaluation and is a reasonable examination schedule.  Thus, because it is appropriate to see 
patients every 6 weeks for health monitoring, it is reasonable to incorporate every 6-week 
placebo/pembrolizumab administration schedule into the study protocol as outlined in section 
4.2. 
 
2.1 
Immunotherapy in endometrial cancer 
Immunohistochemical studies on EC specimens have detailed PD-1 and PD-L1 expression 
levels surpassing those seen in ovarian and cervical carcinoma (Vanderstraeten, 2014,  
Herzog, 2015)(Table 1) (Brahmer, 2012). 
 
Table 1: PD-1 and PD-L1 expression levels in uterine cancer (450 specimens) (Herzog, 
2015)  
Histology 
PD-1 
PD-L1 
 
% Expression based on IHC staining* 
Endometrioid 
77.9 
39.7 
Serous 
Carcinoma 
68.2 
10.2 
Carcinosarcoma 
80.0 
22.2 
Clear Cell 
Carcinoma 
69.2 
23.1 
* IHC antibody = Spring Bioscience (Rabbit anti-Human IgG) 
 
A compelling argument for the use of immune checkpoint inhibitors in EC was put forth by a 
phase 2 trial of pembrolizumab (MK-3475), in patients with mismatch repair deficient 
(dMMR) or microsatellite instability-high (MSI-H), progressive metastatic carcinoma (Le, 
2015).  This trial was designed to test the hypothesis that dMMR or MSI-H, tumors are more 
responsive to PD-1 blockade than microsatellite stable (MSS) tumors, due to the high 
somatic mutational load, resulting in neo-antigen formation and a more prominent 
lymphocytic infiltrate.  As predicted, the two cohorts with dMMR or MSI-H cancers (one 
with colorectal cancer patients and the other with non-colorectal cancer patients, including 2 
patients with recurrent, previously treated endometrial cancer) had significantly higher 
objective response rates by immune-related response criteria and by Response Evaluation 
Criteria in Solid Tumors (RECIST).  The MSI-H cohorts also experienced a significantly 
better immune-related PFS and disease control rate at 20 weeks by RECIST.  Building upon 
this, A.N. Fader et al. presented an expanded cohort of dMMR, recurrent or persistent, 
endometrial cancer patients treated with single agent pembrolizumab (MK-3475) (An, 2016).  
All 10 patients received at least 1 prior line of systemic chemotherapy, and up to 4 previous 
regimens.  The authors reported an overall response rate of 70% (95% CI 21%–86%, n = 7), 
with 2 complete responses (CR) and 5 partial responses (PR).  The disease control rate, or 
“clinical benefit” rate (CR + PR + stable disease), was 80% (n = 8).  The 12-month overall 
survival (OS) rate was 89%, and the median OS was not yet reached.  Importantly, MSI 

 
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status was determined using standard of care MMR IHC testing for MLH1, MSH2, MSH6, 
and PMS2.  Patients lacking expression of DNA mismatch repair proteins were classified as 
dMMR or MSI-H, consistent with prior studies reporting concordance rates great than 90% 
between MMR IHC and MSI PCR.  
 
Most recently, following review of pooled data from five uncontrolled, open-label, multi-
cohort, multi-center, single arm trials, single agent pembrolizumab (MK-3474) was approved 
for the treatment of dMMR or MSI-H solid tumors that progressed following prior therapy, 
with no alternative treatment options.  This disease site agnostic approval, issued by the FDA 
on 5-23-17, was the first of its kind, reflecting the clinical relevance of checkpoint inhibition 
in patients with limited therapeutic options.  Across all 5 trials, the efficacy analysis showed 
an ORR of 39.6% (95% CI 31.7-47.9) with a complete response rate of 7.4% and a partial 
response rate of 32.2%.  At the time of data cutoff, median duration of response had not yet 
been reached (range 1.6+ to 22.7+ months), with 78% of responding patients having 
responses of six months or longer.  Of the 149 subjects in the pooled analysis, 14 had 
recurrent endometrial cancer, with a reported ORR of 36% (DOR range 4.2+, 17.3+), 
surpassing historical controls in this pretreated patient population.   
 
Goodfellow et al. additionally confirmed MSI-H status in 28.4% (296 of 1043 EC 
specimens) of EC tumors examined as part of NRG/GOG-0210 (Goodfellow, 2015).  
Expanding on this assessment McMeekin et al. examined the clinicopathologic significance 
of MMR defects in a cohort of endometrioid endometrial cancers (NRG/GOG0210).  Within 
this population, MMR defects were identified in 71 (42%) of 168 subjects with stage 3 or 4 
disease.  The frequency of MMR deficiency in the recurrent population was confirmed in an 
unpublished analysis of patients treated on GOG 86P, with nearly 40% of subjects with 
recurrent grade 2 or 3 endometrioid adenocarcinoma having absent PMS2 or MSH6 
expression (data courtesy of Dr. Aghajanian). 
 
Howitt et al examined the hypothesis that microsatellite unstable endometrial cancers would 
exhibit more tumor specific neo-antigens, resulting in increased tumor infiltrating 
lymphocytes and a compensatory up-regulation of immune checkpoints (Howitt, 2015).  
Microsatellite unstable tumors exhibited higher numbers of CD3+ and CD8+ tumor 
infiltrating lymphocytes.  Furthermore, PD-1 was overexpressed in tumor infiltrating 
lymphocytes, and peri-tumoral lymphocytes of microsatellite unstable tumors.  This 
combination of increased mutational load, tumor infiltrating lymphocytes, and high PD-
1/PD-L1 expression makes endometrial cancer an ideal target for immunotherapeutic 
interventions. 
  
These studies provide clinical evidence that immune checkpoint inhibitors may be effective 
in the treatment of endometrial cancer, and trials exploring this novel therapy in the front-line 
setting are both feasible and urgently needed. 
 
2.2 
Combining cytotoxic chemotherapy with immune checkpoint inhibitors: safety and 
efficacy 
 
In order to improve on the number of patients responding to checkpoint inhibitors, 

 
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investigators are assessing combination regimens involving cytotoxic chemotherapy and PD-
1/PD-L1 inhibition.  Although no randomized controlled trials exist comparing single agent 
checkpoint inhibition to combination regimens with cytotoxic agents, preclinical data may 
support such an approach (Postow, 2015). 
 
Several preclinical studies have indicated that cytotoxic chemotherapy may result in robust 
immune stimulation (Zitvogel, 2011).  Platinum agents, including oxaliplatin, have been 
shown to result in immunogenic cell death (ICD), producing a favorable milieu for immune 
activations within tumor tissues (Ingeborg, 2016).  Furthermore, taxanes, including docetaxel 
and paclitaxel, are known to modulate the anti-tumor immune response.  As an example, 
concurrent paclitaxel therapy was shown to significantly enhance radiation-induced ICD in 
breast cancer cell lines (Golden, 2014). The anti-tumor effects of cytotoxic chemotherapy 
may additionally be immunologic, with a reduction in regulatory T-cell activity and an 
enhanced presentation of tumor cell specific antigens (Zitvogel, 2011, Galluzzi, 2015, 
Apetoh, 2015).  Cytotoxic agents also appear to directly influence immune checkpoint 
expression.  The in vitro treatment of dendritic cells (DCs) with platinum-based compounds 
strongly enhanced their potential to activate T-cells, via the downregulation of PD-L2 in DCs 
(Lesterhuis, 2011).  This effect was the result of STAT6 inactivation, the transcriptional 
regulator of PD-L2, also occurring on tumor tissue, resulting in enhanced T cell recognition.  
Additionally, chemotherapy has been shown to induce PD-L1 expression on cancer cells 
(Peng, 2015).  Thus, combining chemotherapy and immunotherapy may lead to enhanced 
anti-tumor effects. 
 
Additional data supporting the investigation of a combinatorial approach comes from the 
phase I, CheckMate 012, multi cohort study reported by Rizvi et al (Rizvi, 2016).  This study 
was conducted to explore the safety and efficacy of the anti-PD-1 immune checkpoint 
inhibitor, nivolumab, in combination with current standard therapies in first-line advanced 
non-small cell lung cancer (NSCLC).  A total of 56 patients received nivolumab plus 
platinum-based doublet chemotherapy concurrently every 3 weeks for four cycles followed 
by nivolumab alone until disease progression or unacceptable toxicity.  Regimens included 
nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (non-
squamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies).  The 
primary objective was to assess safety and tolerability.  Secondary objectives included 
objective response rate and 24-week progression-free survival rate.  Thirty of the 56 patients 
(54%) enrolled on study were female, and 38% received prior radiation therapy.  
 
Importantly, no dose-limiting toxicities occurred during the first 6 weeks of treatment, and 
the most common toxicities reported for the combination were those anticipated with 
platinum doublet therapy alone.  Furthermore, fewer than 10% of patients experienced 
treatment-related grade 3 or 4 leukopenia and anemia.  Overall, 21% of patients discontinued 
therapy as a result of treatment-related AEs, although nearly all (10 of 12 patients (83%)) 
discontinued during the nivolumab monotherapy maintenance period.  In the Nivolumab 10 
mg/kg plus paclitaxel-carboplatin arm, the discontinuation rate was 13% (2 of 15 patients).  
Grade 3 or 4 treatment related AEs led to discontinuation in 14% of patients, most commonly 
as a result of pneumonitis and acute renal failure (5% [n=2] each).  All discontinuations as a 
result of treatment related pneumonitis occurred during nivolumab monotherapy.  The 

 
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paclitaxel + carboplatin + nivolumab regimen was associated with a favorable toxicity 
profile, and median OS was not reached during follow up (range 8.8 to 30.1+ months) (Rizvi, 
2016).   
 
Furthermore, the results of the phase 2 cohort of the open-label Keynote-021 study were 
recently published (Langer, 2016).  Researchers enrolled a total of 123 patients with stage 
3B/4 chemotherapy-naïve, nonsquamous, non-small cell lung cancer, to receive 4 cycles of 
carboplatin and pemetrexed (500mg/m2 every 3 weeks), with or without 24 months of 
treatment with pembrolizumab (MK-3475) (200 mg every 3 weeks).  After a median follow 
up of 10.6 months, patients receiving pembrolizumab (MK-3475) + chemotherapy exhibited 
a significantly greater objective response rate (55% vs. 29%, p = 0.0016) and an improved 
PFS (13 vs. 8.9 months; HR 0.53; 95% CI 0.31-0.91).  Importantly, the entire study cohort 
was 61% female, with 38 of 60 patients (63%) in the pembrolizumab (MK-3475) plus 
chemotherapy cohort being women.   
 
With respect to safety, the incidence of grade 3 or worse treatment-related adverse events 
was similar between groups (39% pembrolizumab (MK-3475) + chemotherapy vs. 26% 
chemotherapy alone), in the context of a 1.6-times longer exposure to treatment in the 
pembrolizumab (MK-3475) containing arm.  The most common treatment related adverse 
events of any grade were fatigue (64% pembrolizumab (MK-3475) + chemotherapy vs 40% 
chemotherapy alone), nausea (58% vs. 44%), and anemia (32% vs. 53%).  The most common 
grade 3 or worse treatment-related adverse events in the pembrolizumab (MK-3475) plus 
chemotherapy group were anemia (12%), neutropenia (3%), and acute kidney injury (3%) 
(Langer, 2016).  In the chemotherapy alone group, the most common grade 3 or worse events 
were anemia (15%), neutropenia (3%), pancytopenia (3%), and thrombocytopenia (3%) 
(Langer, 2016).  Six (10%) of 59 patients in the pembrolizumab (MK-3475) plus 
chemotherapy group and eight (13%) of 62 treated patients in the chemotherapy alone arm 
discontinued study treatment because of treatment related events.  There was only one 
treatment related death in the pembrolizumab (MK-3475) arm of the study (1%, sepsis), 
compared to two in the chemotherapy alone group (3%, sepsis and pancytopenia).  The most 
common immune-mediated adverse events of any grade in the pembrolizumab (MK-3475) 
plus chemotherapy group were hypothyroidism (15%), hyperthyroidism (8%), and 
pneumonitis (5%).  Perhaps most strikingly, the incidence of potentially immune mediated 
adverse events in the pembrolizumab (MK-3475) plus chemotherapy group of the as-treated 
population (22%), was similar to that seen with pembrolizumab (MK-3475) monotherapy in 
KEYNOTE-010 (20% in the 2 mg/kg cohort; 19% in the 10 mg/kg cohort). 
 
In Keynote 189 (Gandhi, 2018), a double-blind, randomized (2:1) phase 3 trial, 616 patients 
with NSCLC were randomized to receive platinum-chemotherapy and pemetrexed with 
pembrolizumab (MK-3475) or placebo and up 2 years of pemetrexed maintenance with 
pembrolizumab (MK-3475) or placebo. At a median follow up of 10.5 months, the objective 
response rate (47.6%, 95% CI, 42.6 to 52.5 vs 18.9% 95% CI, 13.8 to 25.0; P<0.001), 
progression-free survival (HR 0.52; 95% CI, 0.43 to 0.64; P<0.001) and overall survival (HR 
0.49; 95% CI, 0.38 to 0.64; P<0.001) favored the pembrolizumab (MK-3475) arm. The grade 
3 or worse adverse event rate was similar in the pembrolizumab (MK-3475)-containing arm 
vs the placebo containing arm (67.2% vs 65.8%).  Furthermore, in the neoadjuvant treatment 

 
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of breast cancer, pembrolizumab (MK-3475) has also demonstrated preliminary evidence of 
activity in combination with chemotherapy (Schmid, 2017). Patients received chemotherapy 
in 2 different cohorts: Cohort A received single-dose pembrolizumab (MK-3475) followed 
by 4 cycles of pembrolizumab (MK-3475) Q3W + nab-paclitaxel weekly followed by 4 
cycles of pembrolizumab (MK-3474) + doxorubicin + cyclophosphamide Q3W. Cohort B 
treatment was the same as in A but with carboplatin Q3W added to pembrolizumab (MK-
3475) + nab-paclitaxel. The ORR (CR+PR) before surgery was 80% (90% CI, 49-96) with a 
pathologic complete response rate of 70% (90% CI, 39-91) in cohort A. The ORR (CR+PR) 
before surgery was 100% (90% CI, 74-100) with a pathologic complete response rate of 90% 
(90% CI, 61-100) in cohort B. 
 
These data are further supported by the I-SPY2 trial, which evaluated pembrolizumab (MK-
3475) in combination with 12- weekly cycles of paclitaxel followed by 4 cycles of 
adriamycin and cyclophosphamide prior to surgery for high-risk, locally advanced breast 
cancer (Nanda, 2017).  The pathologic complete response rate was tripled with chemotherapy 
in combination with pembrolizumab (MK-3475) (60%) in triple-negative breast cancer 
versus chemotherapy without pembrolizumab (MK-3475). 
 
Taken together, these preclinical and clinical observations in other tumor types support the 
safety and efficacy of checkpoint inhibitors in combination with a cytotoxic chemotherapy 
backbone (paclitaxel and carboplatin) in patients with advanced stage or recurrent 
endometrial cancer. 
The efficacy of immune checkpoint inhibition in the treatment of solid malignancies is well 
established, with United States Food and Drug Administration (FDA) approval in multiple 
disease sites.  Furthermore, the clinical utility of checkpoint inhibition in patients with 
dMMR or MSI-H solid tumors has been documented, with the first ever disease site agnostic 
FDA approval of pembrolizumab (MK-3475) in patients with unresectable or recurrent 
tumors progressing after prior therapy who harbor this biomarker.  Given the above, we aim 
to explore whether pembrolizumab (MK-3475) is broadly useful as an immune-oncologic 
agent for all women with endometrial cancer or more efficacious in the dMMR/MSI-H 
population.  Thus, we will conduct a randomized, placebo-controlled phase III trial, designed 
to assess the efficacy and safety of pembrolizumab (MK-3475) in combination with 
paclitaxel and carboplatin versus placebo plus paclitaxel and carboplatin in women with 
measurable stage III or IVA, stage IVB or recurrent endometrial cancer. 
 
We predict that the addition of pembrolizumab (MK-3475) will improve the efficacy of 
paclitaxel and carboplatin in advanced stage and recurrent endometrial cancer patients with 
acceptable toxicity and an associated improvement in quality of life.  The primary end point 
of the randomized phase III trial is progression free survival (PFS).  MMR status, for the 
purpose of stratification, will be determined via centralized tissue testing, and this data will 
be used to examine the correlation between institutional and central MMR results. The trial 
will be stratified by dMMR/MSI-H versus MSS/MMR proficient (based on centralized MMR 
IHC), performance status (0 or 1 versus 2) and receipt of prior adjuvant chemotherapy.   
 
 

 
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2.3 
Pembrolizumab (MK-3475) 
 
Pembrolizumab (MK-3475) has high affinity and potent receptor-blocking activity for the 
programmed cell death 1 (PD-1) receptor, based on preclinical in vitro data (Investigator’s 
Brochure, 2018).  Pembrolizumab (MK-3475) has an acceptable preclinical safety profile and 
is being advanced for clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. 
 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis et al., 2010).  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  
Tumor-infiltrating lymphocytes can be expanded ex vivo and re-infused, inducing durable 
objective tumor responses in cancers such as melanoma (Dudley et al., 2005; Hunder et al., 
2008).   
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T 
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (programmed cell death ligand 1 
[PD-L1] and/or programmed cell death ligand 2 [PD-L2]) (Greenwald et al., 2005; Okazaki 
et al., 2001).   
 
The structure of murine PD-1 has been resolved (Zhang et al., 2004).  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-
based switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, 
SHP 1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade (Chemnitz et al., 2004; Sheppard et al., 2004; 
and Riley, 2009).  The mechanism by which PD-1 down modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping 
set of signaling proteins (Parry et al., 2005; Francisco, 2010).  As a consequence, the PD-
1/PD-L1 pathway is an attractive target for therapeutic intervention in endometrial cancer. 
 
 
 

 
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2.3.1 Pembrolizumab (MK-3475) Background and Clinical Trials 
Pembrolizumab (MK-3475), a humanized monoclonal antibody against the PD-1 protein, has 
been developed by Merck & Co. for the treatment of cancer.  Pembrolizumab (MK-3475) is 
approved for treatment of melanoma in several countries; in the United States (US) and 
European Union it is approved for the treatment of advanced (unresectable or metastatic) 
melanoma in adults.  Pembrolizumab (MK-3475) has also been approved for treatment of 
NSCLC in several countries; in the US it is indicated for use: 1) in combination with 
pemetrexed and platinum chemotherapy, as  first-line treatment of patients with metastatic 
nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations; 2) in combination 
with carboplatin and either paclitaxel or nab- paclitaxel, as first-line treatment of patients 
with metastatic squamous NSCLC; 3) as a single agent for the first-line treatment of patients 
with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score 
(TPS) ≥50%] as determined by an FDA- approved test, with no EGFR or ALK genomic 
tumor aberrations; and 4) as a single agent for the treatment of patients with metastatic 
NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, 
with disease progression on or after platinum-containing chemotherapy. Patients with EGFR 
or ALK genomic tumor aberrations should have disease progression on FDA-approved 
therapy for these aberrations prior to receiving pembrolizumab (MK-3475). 
Pembrolizumab (MK-3475) is approved in the US for the treatment of patients with recurrent 
or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on 
or after platinum-containing chemotherapy, as well as classical Hodgkin Lymphoma (cHL), 
Primary Mediastinal Large B-Cell Lymphoma (PMBCL), urothelial carcinoma, gastric 
cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), and 
microsatellite instability-high cancer (treatment of adult and pediatric patients with 
unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair 
deficient solid tumors that have progressed following prior treatment and who have no 
satisfactory alternative treatment options, or colorectal cancer that has progressed following 
treatment  
Ongoing clinical trials are being conducted in a number of other advanced solid tumor 
indications and hematologic malignancies.  For study details please refer to the Investigator’s 
Brochure (2018). 
 
2.3.2 Rationale for Pembrolizumab (MK-3475) Dose Selection (14-OCT-2020) 
 
The dose of pembrolizumab (MK-3475) planned to be studied in this trial is 200 mg 
administered every 3 weeks (Q3W) in the combination phase of the clinical trial, and 400 mg 
administered every 6 weeks (Q6W) in the maintenance setting.  The maintenance dose is 
based on pharmacokinetic modeling and exposure-response analyses that compared the 
predicted exposure of pembrolizumab 400 mg every six weeks to observed exposures of 
pembrolizumab in patients who received pembrolizumab at 2 mg/kg every three weeks, 200 
mg every three weeks, and 10 mg/kg administered every two weeks. The pharmacokinetic 
modeling were supported by additional exposure-response analyses across the 
pembrolizumab development program and an interim analysis of pharmacokinetics and 

 
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overall response rate (ORR) in a cohort of patients (Cohort B) enrolled in Study KEYNOTE-
555 (NCT03665597). Cohort B of Study KEYNOTE-555 was an international, single-arm, 
multi-center study that enrolled 101 patients with advanced or metastatic melanoma who had 
not received prior PD-1, PD-L1, or CTLA-4 inhibitors (other than CTLA-4 inhibitors in the 
adjuvant setting). The ORR was 39% (95% CI: 24, 55) in the first 44 patients enrolled in 
KEYNOTE-555 (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-
new-dosing-regimen-pembrolizumab). 
 
The initial phase 1 study of pembrolizumab (MK-3475), KN001, evaluated 5 dose levels (1 
mg/kg every 2 weeks [Q2W], 3 mg/kg Q2W, 10 mg/kg Q2W, 2 mg/kg Q3W, and 10 mg/kg 
Q3W) in patients with advanced solid tumors.  All 5 dose levels were well tolerated and no 
dose-limiting toxicities (DLTs) were observed.  Pembrolizumab (MK-3475) showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg, and 10 mg/kg Q2W).  No maximum tolerated dose (MTD) has 
been identified to date.  In addition, 2 randomized cohort evaluations of melanoma patients 
receiving pembrolizumab (MK-3475) 2 mg/kg or 10 mg/kg Q3W have been completed, and 
1 randomized cohort evaluating 10 mg/kg Q3W or 10 mg/kg Q2W has also been completed.  
The clinical efficacy and safety data demonstrate a lack of any important differences in 
efficacy or safety profile across doses. 
 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab (MK-3475) exposure-response relationship for efficacy and safety has been 
found in patients with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  
Exposures for 200 mg Q3W are expected to lie within this range and will be close to those 
obtained with 2 mg/kg Q3W dose. 
 
The PK profile of pembrolizumab (MK-3475) is consistent with that of other humanized 
monoclonal antibodies, which typically have a low clearance and a limited volume of 
distribution.  A population PK model, which characterized the influence of body weight and 
other patient covariates on exposure, has been developed.  The distribution of exposures from 
the 200 mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg 
dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  The PK properties of 
pembrolizumab (MK-3475), specifically the weight-dependency in clearance and volume of 
distribution, are consistent with no meaningful advantage to weight-based dosing relative to 
fixed dosing. 
 
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in patients with melanoma can be expected.  As the antitumor 
effect of pembrolizumab (MK-3475) is driven through immune system activation rather than 
through a direct interaction with tumor cells, it is rendered independent of the specific tumor 
type.  In addition, available PK results in patients with melanoma, NSCLC, and other tumor 
types support a lack of meaningful difference in PK exposures obtained at tested doses across 
tumor types.  Thus, the 200 mg Q3W fixed-dose regimen is considered an appropriate fixed 
dose during the combination phase of the study. 

 
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A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed-dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.   
 
2.4 
Incorporation of maintenance pembrolizumab (MK-3475)/placebo (14-OCT-2020) (08-
DEC-2020) 
The proposed study will incorporate maintenance pembrolizumab (MK-3475)/placebo for up 
to 24 months of therapy.  The rational for maintenance is based on prior studies conducted in 
patients with solid malignancies.  CheckMate 012, Keynotes 021 and 189 were designed with 
maintenance checkpoint inhibitor until disease progression or unacceptable toxicity, or up to 
24 months of therapy.  Furthermore, Keynote 045 (NCT02256436), and Keynote 028 
(NCT02054806) were designed to treat with single agent pembrolizumab (MK-3475) until 
disease progression, toxicity, or until the patient/investigator elected to stop treatment.  
With respect to front line studies in combination with chemotherapy, Keynote 189 
(NCT02578680) and Keynote 407 (NCT02775435) examined pembrolizumab (MK-3475) + 
chemotherapy, followed by pembrolizumab (MK-3475) maintenance.  Specifically, in 
Keynote 407, subjects will receive up to 35 cycles of pembrolizumab (MK-3475).  Based on 
the above trial designs, the rational exists to adopt an analogous schema in this front-line 
endometrial cancer study, in an effort to improve clinical response and prolong survival. 
A one year period of treatment has been evaluated in adjuvant therapy trials in melanoma and 
lung cancer.  Keynote 054 – resected stage III melanoma 
(https://www.nejm.org/doi/full/10.1056/NEJMoa1802357) and Checkmate 238 – resected 
stage III or IV melanoma (https://www.nejm.org/doi/full/10.1056/NEJMoa1709030); showed 
recurrence free survival benefit (it is unclear as to whether these results will translated into a 
survival benefit).  In stage III lung cancer, adjuvant durvalumab for 1 year after 
chemoradiation improved overall survival 
(https://www.nejm.org/doi/full/10.1056/NEJMoa1809697). 
The NRG Oncology GY018 study is a trial of advanced/recurrent or metastatic disease and 
excludes the adjuvant stage III/IVA population (chemotherapy naïve). We therefore chose 
the up to approximately 24 months of therapy used in comparable patient populations. 
NRG Oncology GY018 was amended to incorporate Q6 week pembrolizumab dosing in the 
maintenance phase as outlined in section 2.3.2 above. This has the advantage of 1) reducing 
the number of visits required to the infusion center by half for both study arms and 2) 
reflecting an up to date usual care option that may be employed at the time of trial 
completion and reporting of results. 
Management of potential subject crossover and inclusion of saline placebo (07/03/2019) 
With FDA approval of single agent pembrolizumab (MK-3475) in dMMR or MSI-H and 
FDA accelerated approval of pembrolizumab (MK-3475) plus lenvatinib in patients with 
pMMR recurrent endometrial cancer, we anticipate the potential for crossover at the time of 
disease progression for patients randomized to the placebo arm of the trial (details of 
unblinding are outlined in section 5.2).  The use of a saline placebo in combination with 
standard chemotherapy will help ensure the objectivity of investigator-assessed progression 
as well as any decisions to interrupt/discontinue therapy, thus preserving the integrity of the 

 
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trial and the primary end point of progression free survival (PFS).  The timing of scans will 
be carefully specified and continue after the patient goes off of therapy or until disease 
progression.  Furthermore, disease progression will be assessed using blinded independent 
central radiology review per RECIST 1.1.  Post progression therapy will be monitored for all 
subjects on study. 
The feasibility of a saline placebo in this setting has been established in the recently 
published, analogously designed, Keynote 189 trial.  In this prospective, randomized, double-
blind phase 3 clinical trial, patients with metastatic nonsquamous NSCLC received 
pemetrexed and a platinum-based drug plus either pembrolizumab (MK-3475) or placebo 
every 3 weeks for 4 cycles, followed by pembrolizumab (MK-3475) or placebo for a total of 
35 cycles.  Saline placebo was administered as a 30-minute IV infusion every 3 weeks.  
The subjects, the investigators and the sponsor personnel or delegate(s) who are involved in 
the treatment administration or clinical evaluation of the subjects will be unaware of the 
group assignments.  The chemotherapy agents will be open-label.  The sponsor, investigator 
and subject will not know whether the treatment administered contains pembrolizumab (MK-
3475) or saline placebo.  Each study site will have an unblinded pharmacist that will obtain 
each subject’s study identification number, and drug assignment and then prepare the 
solutions for infusion.  The unblinded pharmacist will provide the investigative staff with the 
ready-to-use blinded pembrolizumab (MK-3475)/saline infusion solutions, packaged 
identically in order to maintain the blinding, for administration at scheduled infusion visits.   
 
Inclusion of MMR-proficient and non-endometrioid histologies 
 
Based on historical data abstracted from prior NRG/GOG clinical trials in this setting, we 
predict that enrollment on study will consist of: 1/3 grade 1 or 2 endometrioid, 1/3 grade 3 
endometrioid and 1/3 serous histologies, with a small proportion of clear cell carcinomas.  It 
is anticipated that robust responses will be identified in the dMMR or MSI-H cohort with the 
addition of pembrolizumab (MK-3475) to standard chemotherapy.  Given that ~ 70% of 
patients will be microsatellite stable (MSS), we feel that it is important and timely to explore 
the therapeutic implications of combination checkpoint inhibition + cytotoxic chemotherapy 
in these patients, irrespective of histology (endometrioid, serous and clear cell).  Based on 
unpublished data from GOG 86P, we anticipate that approximately 40% of patients with 
recurrent endometrioid adenocarcinoma will be MMR deficient.  Conversely, in the serous 
and clear cell population, MMR deficiency was identified in less than 5% of subjects. 
 
The state-of-the-science argues for such an approach, with 5 current randomized phase III 
clinical trials exploring chemotherapy +/- checkpoint inhibition in serous histology 
gynecologic cancers.  Furthermore, the recent accelerated approval of pembrolizumab (MK-
3475) + chemotherapy as a frontline treatment for patients with metastatic or advanced 
NSCLC, regardless of PD-L1 expression, supports the assessment of this regimen in patients 
with recurrent endometrial cancer, where there are limited therapeutic options.  As previously 
published, cytotoxic chemotherapy is immunogenic, and our intent is to determine if 
pembrolizumab (MK-3475) + chemotherapy results in improved PFS in these patient cohorts 
(MSS).  Furthermore, the potential role of the immune micro environment on endometrial 
cancer outcomes has been reported, with high numbers of CD8+ T-lymphocytes, and a high 
CD8+/FoxP3+ ratio being associated with favorable prognostic parameters, and oncologic 

 
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outcome across endometrial cancer histotypes. 
 
Assessment of MMR status (03-MAR-2022) 
 
Subject stratification, on trial, will require MMR IHC testing (known stratification factor).  
With the recent FDA approval of pembrolizumab (MK-3475) in dMMR or MSI-H solid 
tumors (based on either IHC or PCR), we will look to explore the clinical relevance and 
reliability of local/institutional testing in this patient population. Therefore, a retrospective, 
centralized assessment of subjects will be conducted comparing centralized MMR IHC to 
local MMR IHC.  This planned central assessment will be conducted to assess concordance 
between institutional and centralized determination of MMR IHC status.  
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
 
 
Notes: 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).  
 
Inclusion of Women and Minorities (09/24/2019) 
NIH policy requires that women and members of minority groups and their subpopulations 
be included in all NIH-supported biomedical and behavioral research projects involving 
NIH-defined clinical research unless a clear and compelling rationale and justification 
establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is 
not an acceptable reason for exclusion except when the study would duplicate data from 
other sources.  Women of childbearing potential should not be routinely excluded from 
participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf  
 
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 Sections 5.7 and 10 for details.) 
 
3.2 
Eligibility Criteria (07-FEB-2020) (21-MAY-2021) (09-MAR-2022) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 

 
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This is a 2-step registration trial.  Consent must be signed BEFORE Step 1 Registration 
and submitting tissue for centralized MMR IHC testing (see Appendix VIII).   
 
Patients must start treatment within 14 days of randomization. 
 
Drug shipment times must be considered when scheduling a patient for initial treatment 
(See Section 9.2.4).  
 
3.2.1 Measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) 
or recurrent (with or without measurable disease) endometrial cancer.  
 
Pathology report showing results of institutional MMR IHC testing. (Sites in Japan—see 
Appendix XIV.) (08-DEC-2020) (09-MAR-2022) 
 
 
Histologic confirmation of the original primary tumor is required (submission of pathology 
report(s) is required).  Patients with the following histologic types are eligible:  Endometrioid 
adenocarcinoma, serous adenocarcinoma, dedifferentiated/undifferentiated carcinoma, clear 
cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified 
(N.O.S.). (07/03/2019) 
 
Submission of tumor specimens for centralized MMR IHC testing is required after Step 1 and 
before Step 2 registration. (See Section 5.7 and 10.2 for details.) 
 
3.2.2 In patients with measurable disease, lesions will be defined and monitored 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 or MRI. Lymph nodes must be ≥ 15 mm in short axis when measured by CT 
or MRI. (21-MAY-2021) 
 
3.2.3 Prior Therapy: (09/24/2019) (07-FEB-2020) (09-MAR-2022) 
• Patients may have received 
➢ NO prior chemotherapy for treatment of endometrial cancer OR 
➢ Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component 
of concurrent chemotherapy and radiation therapy [with or without cisplatin]) 
provided adjuvant chemotherapy was completed ≥ 12 months prior to STEP 2 
registration. 
• Patients may have received prior radiation therapy for treatment of endometrial cancer.  
Prior radiation therapy may have included pelvic radiation therapy, extended field 
pelvic/para aortic radiation therapy, intravaginal brachytherapy, and/or palliative 
radiation therapy.  All radiation therapy must be completed at least 4 weeks prior to 
STEP 2 registration. 
• Patients may have received prior hormonal therapy for treatment of endometrial cancer.  
All hormonal therapy must be discontinued at least three weeks prior to STEP 2 
registration. 

 
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• Interval or cytoreductive surgery, after start of treatment on this trial, and prior to 
documentation of disease progression, is NOT permitted. 
3.2.4 Age ≥ 18 
3.2.5 Performance Status of 0, 1 or 2 (see Appendix II) (07/03/2019) 
3.2.6 Adequate hematologic function defined as follows: 
• Platelets ≥ 100,000/mcl 
• Absolute neutrophil count (ANC) ≥ 1,500/mcl 
3.2.7 Adequate renal function defined as follows: (07/03/2019) 
Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN). 
3.2.8 Adequate hepatic function defined as follows: 
• Total serum bilirubin level ≤ 1.5 x ULN (patients with known Gilbert’s disease who have 
bilirubin level ≤ 3 x ULN may be enrolled) 
• AST and ALT ≤ 3 x ULN  
3.2.9 TSH within normal limits. If TSH is not within normal range despite no symptoms of thyroid 
dysfunction, normal Free T4 level is required.  (09-MAR-2022) 
3.2.10 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 
6 months of Step 2 registration are eligible for this trial. 
3.2.11 For patients of child bearing potential: negative urine or serum pregnancy test.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test is required. (07-
FEB-2020) 
3.2.12 Administration of study drugs (pembrolizumab [MK-3475], paclitaxel, carboplatin) may 
have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-
lethality. Women of childbearing potential (WOCBP) must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) from at least 14 days 
prior to Step 2 registration (for oral contraceptives), during treatment, and for 120 days after 
the last dose of study medication.  Should a woman become pregnant or suspect she is 
pregnant while she is participating in this study, she should inform her treating physician 
immediately.  Patients will be considered of nonreproductive potential if they are either: 
 
1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age, a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient); OR 
 
2) Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2 registration; OR 
 
3) Have a congenital or acquired condition that prevents childbearing. (07/03/2019) 
3.2.1.3 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. (07/03/2019) 
3.2.14 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry and, for patients treated in the U.S., authorization permitting 
release of personal health information. 
 
 

 
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3.3 
Ineligibility Criteria 
Patients with any of the following conditions are NOT eligible for this study.  
3.3.1 Patients with prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeutic 
antibody or other similar agents. 
3.3.2 Patients who have a history of a severe hypersensitivity reaction to monoclonal antibody or 
pembrolizumab (MK-3475) and/or its excipients; and/or a severe hypersensitivity reaction to 
paclitaxel and/or carboplatin. (07/03/2019) (21-MAY-2021) 
3.3.3 Patients who are currently participating and receiving cancer-directed study therapy or have 
participated in a study of an investigational agent and received cancer-directed study therapy 
within 4 weeks prior to Step 2 registration. (07-FEB-2020) 
3.3.4 Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to Step 2 registration 
(07-FEB-2020) 
• Patients who have received steroids as CT scan contrast premedication may be enrolled. 
• The use of inhaled or topical corticosteroids is allowed. 
• The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed. 
• The use of physiologic doses of corticosteroids may be approved after consultation with 
the study chair. 
3.3.5 Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-
directed therapy shows no evidence of progression, and they have been off steroids for at 
least 4 weeks prior to Step 2 registration and remain clinically stable. (07-FEB-2020) 
3.3.6 Patients with active autoimmune disease or history of autoimmune disease that might recur, 
which may affect vital organ function or require immune suppressive treatment including 
systemic corticosteroids. This includes, but is not limited to, patients with a history of 
immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating)  
neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such 
as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), 
Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis 
(TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of 
recurrence or exacerbation of disease. 
Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis 
managed with replacement hormones including physiologic corticosteroids are eligible. 
Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome and psoriasis 
controlled with topical medication and patients with positive serology, such as antinuclear 
antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target 
organ involvement and potential need for systemic treatment but should otherwise be 
eligible. 
3.3.7 Patients who have a history of (non-infectious) pneumonitis that required steroids, or current 
pneumonitis. 
3.3.8 Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection 
(except for uncomplicated urinary tract infection), interstitial lung disease or active, non-
infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, 

 
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cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. (09/24/2019) 
3.3.9 Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; 
and cirrhosis. 
 
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load 
must be undetectable on suppressive therapy, if indicated. 
 
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. 
For patients with HCV infection who are currently on treatment, they are eligible if they have 
an undetectable HCV viral load. 
3.3.10 Pregnant or lactating patients (See Section 3.2.12 for information on contraception and 
pregnancy). 
 
 

 
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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PRE-TREATMENT ASSESSMENTS (09/24/2019) (07-FEB-2020) (14-OCT-2020) (08-
DEC-2020) (09-MAR-2022) 
 
Assessments 
(See Section 10.4.1 for Mandatory 
Biospecimen Submission Information) 
Prior to Step 1 
Registration 
Prior to Step 2 
Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
(Cycle 1, Day 1) 
Pathology report confirming endometrial 
cancer 
X 
 
- 
Pathology report with institutional 
mismatch repair protein 
immunohistochemistry results (MLH1, 
MSH2, MSH6, PMS2) 
As of August 17, 2022, the dMMR cohort 
is Closed (30-SEP-2022) 
 
X  
(not required for 
sites in Japan; Sites 
in Japan, see 
Appendix XIV) 
- 
SLIDE SUBMISSION FOR 
Centralized mismatch repair protein 
immunohistochemistry (IHC) (MLH1, 
MSH2, MSH6, PMS2) and PD-L1 IHC 
(See Sections 5.7 and 10.2) 
 
X1 
- 
History and Physical 
 
≤ 14 days 
≤ 14 days 
Concomitant Medications 
 
≤ 14 days 
≤ 14 days 
Vital Signs 
 
≤ 14 days 
≤ 14 days 
Performance Status 
 
≤ 14 days 
≤ 14 days 
Toxicity Assessment 
 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
 
≤ 14 days 
≤ 14 days 
Chemistries* 
 
≤ 14 days 
≤ 14 days 
TFTs (TSH and Free T4**) 
 
≤ 28 days 
≤ 28 days 
Hepatitis B Surface Antigen 
 
≤ 28 days 
≤ 28 days 
Hepatitis B Core Antibody, Total 
 
≤ 28 days 
≤ 28 days 
Hepatitis C Antibody 
 
≤ 28 days 
≤ 28 days 
Pregnancy Test (if childbearing potential 
exists) 
 
≤ 14 days 
≤ 72 hours 
ECG 
 
≤ 3 months 
≤ 3 months 
Radiographic Tumor Measurement*** 
 
≤ 28 days 
≤ 28 days 
Patient Reported Outcomes (PRO) for 
pMMR patients only 
 
 
Baseline – prior to 
any premedication 
or treatment 
administration 
 
1 Submission of slides to NeoGenomics AFTER Step 1 registration is completed—see Sections 5.7, 
10.2 and Appendix VIII. 
 *   Chemistries:  BUN/UREA, creatinine, sodium, potassium, chloride, CO2, calcium, glucose, total 
bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT (21-MAY-2021) 
** Free T4 can be omitted if TSH normal 

 
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***  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 to be used for any disease assessment or reassessment. 
Images from radiographic studies should be uploaded for independent radiologic review via 
TRIAD Digital Image Submission as detailed in Appendix VII. 
   
4.2 
ASSESSMENTS DURING TREATMENT (09/24/2019) (14-OCT-2020) 
Assessments 
Prior to Each 
Cycle, Day 1 
(after Cycle 1, 
Day 1) 
Prior to every 
other cycle (prior 
to cycle 3, 5, 7, etc) 
Timed (Treatment 
Cycle 
Independent) 
History and Physical5 
≤ 3 days 
(07/03/2019) 
 
 
Concomitant Medications 
≤ 3 days  
 
 
Vital Signs 
≤ 1 day 
 
 
Performance Status 
≤ 3 day 
 
 
Toxicity Assessment 
≤ 1 days 
 
 
CBC/Differential/Platelets 
≤ 3 days 
 
 
Chemistries1 
≤ 3 days 
 
 
TFTs (TSH and Free T42) 
 
≤ 3 days 
 
Radiographic Tumor 
Measurement 
 
 
X3 
Patient Reported Outcomes 
(PRO) for pMMR patients 
 
 
X4 
1 
Chemistries:  BUN/UREA, creatinine, sodium, potassium, chloride, CO2, calcium, glucose, total 
bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT (21-MAY-2021) 
2 
Free T4 can be omitted if TSH normal 
3 
Every 9 weeks (+/- 7 days) from cycle 1, day 1 (regardless of delays and/or changes in treatment 
schedule) for the first 9 months; then every 12 weeks (+/- 14 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.  Utilize same imaging modality of 
abdomen, pelvis and chest (see footnote under Pre-Treatment Assessments) as for pre-cycle 1 
baseline assessment. PET/CT is NOT to be used for any disease assessment or reassessment.  
Images from radiographic studies should be uploaded for independent radiologic review via 
TRIAD Digital Image Submission as detailed in Appendix VII.  An excel tool is available on the 
CTSU website to calculate dates of re-imaging. 
4 
PROs assessment intervals to occur Week 0, Week 6, Week 18, Week 30, Week 54 (See Section 
11.1 Assessment Intervals). PRO assessments are required, even after a patient has been removed 
from treatment.  See Section 11.1. 
5 
While on maintenance therapy with placebo or pembrolizumab, patients should be seen every 6 
weeks for history and physical exam.  During combination treatment (chemotherapy + 
placebo/pembrolizumab) patients should be seen prior to each cycle of treatment. 
 

 
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4.3 
ASSESSMENTS IN FOLLOW UP 
Assessments 
Timed 
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 for the 5-year follow-up period or until study termination, whichever occurs first. 
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 
Randomization will be stratified within the following groups: 
1. Mismatch repair deficient (dMMR) (yes/no) As of August 17, 2022, the dMMR cohort is 
Closed (30-SEP-2022) 
2. Performance Status (0 or 1 vs 2) 
3. Prior chemotherapy (yes/no) 
 
Treatment must begin within 14 days of Step 2 randomization. (07-FEB-2020) 
 
On February 6, 2023, all patient treatment assignments were unblinded and made available through 
Medidata Rave. Patients randomized to Arm 1 will not receive additional placebo infusions.  All 
other study related treatments and evaluations will proceed per protocol.  Patients on Arm 2 will 
continue all study related treatments and evaluations. (24-FEB-2023) 
 
 

 
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5.1 
Treatment  (14-OCT-2020) (08-DEC-2020) (19-MAY-2022) 
See Appendix III – Carboplatin dose calculation instructions 
See Appendix IV – General treatment guidelines 
 
 
Order of drug administration:  pembrolizumab (MK-3475)/placebo, paclitaxel, carboplatin 
 
Arm 1: 
Combination Phase: 
Placebo over 30 minutes (-5min/+10 min) IV Day 1 
Paclitaxel 175 mg/m2 IV over approximately 3 hours Day 1 
Carboplatin AUC 5 IV over approximately 30-60 minutes Day 1 (07-FEB-2020) 
Carboplatin, Paclitaxel and Placebo will be administered every 3 weeks for a total of 6 cycles 
in the combination phase 
One cycle = 3 weeks 
 
Maintenance Phase: 
Placebo IV over 30 minutes (-5min/+10 min) Day 1  
Every 6 weeks for up to 14 cycles 
One cycle = 6 weeks 
Maximum number of placebo cycles (combination phase + maintenance phase) = 20 
 
Arm 2: 
Combination Phase: 
Pembrolizumab (MK-3475) 200 mg flat dose IV over 30 minutes (-5min/+10 min) Day 1 
Paclitaxel 175mg/m2 IV over approximately 3 hours Day 1 
Carboplatin AUC 5 IV over approximately 30-60 minutes Day 1 (07-FEB-2020) 
Carboplatin, Paclitaxel and Pembrolizumab will be administered every 3 weeks for a total of 
6 cycles in the combination phase. 
One cycle = 3 weeks  
 
Maintenance Phase (to begin 3 weeks after last chemotherapy cycle): 
Pembrolizumab (MK-3475) 400 mg flat dose IV over 30 minutes (-5 min/+10 min) Day 1  
Every 6 weeks for up to 14 cycles 
One cycle = 6 weeks 
Maximum number of pembrolizumab (MK-3475) cycles (combination phase + maintenance 
phase) = 20 
 
Any patient who is currently receiving Q3 week pembrolizumab in the maintenance 
phase should be transitioned to a Q6 week pembrolizumab schedule after discussion 
with the patient and follow assessment intervals as outlined in the protocol document.  
Please contact study chair and data manager to confirm treatment schedule and total 
number of cycles for these patients (as it will vary depending on when in the treatment 
course the transition is made).  
 
 

 
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Cycle # 
1 
2 
3 
4 
5 
6 
7 
Start 
Maintenance 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Week # 
0 
3 
6 
9 
12 
15 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
96 
 
 
NOTE: Patients with SD or PR who still have measurable disease at the completion of cycle 
6 may continue to receive paclitaxel and carboplatin (with pembrolizumab (MK-3475) or 
normal saline) up to a total of 10 cycles (if deemed necessary by the treating investigator).  
Patients who continue with cycles 7-10 will continue with all study assessments as described 
for Prior to each cycle (cycles 1-6). 
 
For patients receiving 7 cycles of chemotherapy: 
 
Cycle # 
1 
2 
3 
4 
5 
6 
7 
 
8 
Start Maintenance 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Week # 
0 
3 
6 
9 
12 
15 
18 
21 
27 
33 
39 
45 
51 
57 
63 
69 
75 
81 
87 
93 
 
For patients receiving 8 cycles of chemotherapy: 
 
Cycle # 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
Start Maintenance 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Week # 
0 
3 
6 
9 
12 
15 
18 
21 
24 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 
90 
 
For patients receiving 9 cycles of chemotherapy: 
 
Cycle # 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
Start Maintenance 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Week # 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
33 
39 
45 
51 
57 
63 
69 
75 
81 
87 
 
For patients receiving 10 cycles of chemotherapy: 
 
Cycle # 
1 
2 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
Start Maintenance 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Week # 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
36 
42 
48 
54 
60 
66 
72 
78 
84 

 
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Treatment Up to 20 total cycles (or approximately 24 months) 
Treatment with pembrolizumab (MK-3475)/placebo will continue for up to 20 total cycles 
(or approximately 24 months), or until documented disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the patient, patient withdraws consent, pregnancy of the 
patient, noncompliance with trial treatment or procedure requirements, administrative 
reasons, or unblinded patients receiving placebo during maintenance. 
 
5.2 
Unblinding Procedures (14-OCT-2020) (08-DEC-2020) (09-MAR-2022) (24-FEB-2023) 
 
Effective February 06, 2023, all patients have been unblinded.  Patients randomized to Arm 1 
will not receive additional placebo infusions.  All other study related treatments and 
evaluations will proceed per protocol. Patients on Arm 2 will continue all study related 
treatments and evaluations.  
 
Emergency Unblinding: 
The decision to break the unblinding code based on a serious adverse event must be 
unexpected for the study drug and related to the study drug or extraordinary clinical 
circumstance for which knowledge of drug assignment will affect clinical judgment.  
 
Unblinding for subsequent treatment planning upon progression of disease:  
Commercial pembrolizumab in combination with commercial lenvatinib is available for 
second-line therapy for women with MMR proficient disease (pMMR/MSS).  Commercial 
pembrolizumab is available for second-line therapy for women with MMR deficient disease 
(dMMR/MSI-H).  Patients and their physicians may request unblinding at the time of 
progression to determine if they received pembrolizumab in order to guide subsequent 
treatment decisions. Study-provided pembrolizumab and/or lenvatinib is not available for 
subsequent treatments. 
 
Unblinding related to COVID-19 safety concerns for patients in maintenance phase or 
about to enter maintenance phase:   
Unblinding can be requested by the patient and/or the patient’s treating physician because of 
safety concerns related to the COVID-19 pandemic.  The patient or treating physician can 
determine that safety of the patient is potentially compromised by COVID-19 in the patient’s 
local/home area, areas of travel, or the office/treatment center.  The patient can request 
unblinding after discussion with the treating physician.  The treating physician must then 
request unblinding and notify the study PI. The patient should be encouraged to continue 
pembrolizumab maintenance if so assigned; patients may also elect to withdraw consent for 
treatment, but in that case, they are strongly encouraged to remain on study follow up.  The 
patient’s request is to be respected whether or not the treating physician or study PI agree.   
 
Patients who are unblinded and are determined to have received placebo will enter follow up, 
but will continue scheduled study visits for exams, radiographic tumor measurements  and 
patient reported outcomes as planned per Tables 4.2 and 4.3. (21-MAY-2021)   
 

 
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Unblinding Procedures: 
The NRG Oncology SDMC maintains an unblinding service that is in operation 24 hours a 
day, seven days a week.  When unblinding is required, the institution representative (PI or 
CRA) must telephone the NRG Oncology SDMC office at 412-624-2666 and the institution 
representative will be referred to the Unblinding Administrator. In order to unblind the study 
drug assignment, the Unblinding Administrator will ask the institution representative to 
identify the protocol number, the patient ID number, the patient initials (LFM), and the 
reason for the unblinding request. In addition, to facilitate the process an email should be sent 
to Mary Jo Antonelli antonellim@nrgoncology.org stating that they wish to unblind a 
patient’s study drug assignment. The treating physician is to be copied on the email, which is 
to include the protocol number, patient ID, most recent treatment cycle completed, date of 
most recent treatment cycle, date of most recent scans and results of those scans (for 
example, disease progression, stable disease, etc.) and the reason for the request to unblind.  
After this information has been obtained and the indication for unblinding is confirmed, the 
site representative will be notified immediately of the patient’s treatment assignment and a 
computer record will be created identifying the patient as having been unblinded.  
 
The institution is still responsible for providing continued follow-up for patients whose 
treatment assignment has been unblinded on the same schedule as indicated in the 
study protocol. 
5.3 
Radiation Therapy 
 
Not Applicable. 
 
5.4 
Surgery  
Not Applicable. 
 
5.5 
Device  
Not Applicable. 
 
5.6 
Imaging  
Diagnostic image collection will be utilized for this study.  Images from radiographic studies 
should be uploaded for blinded independent central review (BICR) of progression free 
survival via TRIAD Digital Image Submission as detailed in Appendix VII.  BICR is a 
means of independently verifying endpoints.  
 
5.7 
Integral Biomarker Assay (09-MAR-2022) 
Slides for Centralized mismatch repair protein immunohistochemistry (IHC) and PD-L1 IHC 
must be submitted prior to Step 2 registration/randomization. (See Section 10.2 for details.) 
Sites in Japan, see Appendix XIV. 
 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
For all cycles where paclitaxel is to be administered, it is recommended that a preparative 
regimen be employed, to reduce the risk associated with hypersensitivity reactions.  This 
regimen should include a standard dose of dexamethasone (either IV or PO), an anti-
histamine H1 (diphenhydramine 25-50 mg IV or orally, or an alternate H1blocker), and a 

 
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standard dose of antihistamine H2 IV (such as ranitidine or famotidine).  Paclitaxel 
preparative regimen can be altered at the discretion of the treating investigator. 
 
It is anticipated that nausea and vomiting may be a significant side effect of this regimen (due 
to carboplatin administration).  An antiemetic regimen is suggested (per institutional, NCCN 
and/or ASCO guidelines).  Antiemetic regimen can be altered at the discretion of the treating 
investigator. Use of oral steroids as an antiemetic regimen is permitted during the 
combination phase of the trial, although consideration should be given to minimize steroid 
use as much as possible and to employ non-steroid containing regimens wherever possible. 
(14-OCT-2020) 
 
5.8.1 Concomitant Medication 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician; however, the decision to continue the 
patient on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, and the patient. 
 
5.8.1.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for serious adverse events (SAEs). 
 
5.8.1.2 Prohibited Concomitant Medications/Therapy (07/03/2019) (09-MAR-2022) 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
− 
Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol 
− 
Immunotherapy not specified in this protocol 
− 
Chemotherapy not specified in this protocol 
− 
Investigational agents other than pembrolizumab (MK-3475) 
− 
Radiation therapy  
− 
Interval or cytoreductive surgery, after start of treatment on this trial, and prior to 
documentation of disease progression, is NOT permitted. 
− 
Live vaccines within 30 days prior to the first dose of trial treatment and while 

 
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participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
− 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology or for chemotherapy premedication as part 
of treatment on trial (see Section 5.8).  The use of physiologic doses of corticosteroids 
may be approved after consultation with the study chair.  
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Patients may receive other medications that the investigator deems to be medically necessary. 
 
The list above describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.9 
Duration of Therapy (14-OCT-2020) (08-DEC-2020) (09-MAR-2022) 
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 
• Unblinding at time of maintenance in patients receiving placebo 
• Unblinding for subsequent treatment planning upon progression of disease 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s), as described in Section 6 
• Any dosing interruption lasting > 9 weeks with the following exceptions: 
o Dosing interruptions > 9 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Study Chair.  Prior to re-initiating treatment in a patient 
with a dosing interruption lasting > 9 weeks, the Study Chair must be consulted. 
*Tumor assessments should continue as per protocol even if dosing is interrupted. 
*PRO assessments should continue on schedule even if dosing is interrupted—See 
Section 11.1. 
• Patient requires systemic steroid or other immunosuppressive treatment (aside from those 
required to manage treatment-related side effects, those required for safe administration 
of paclitaxel per institutional standard, and/or those requiring steroid premedication for 
IV CT contrast).  
• 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. 
 
 

 
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6. 
TREATMENT MODIFICATIONS/MANAGEMENT (14-OCT-2020) (21-MAY-2021) 
 
Agent 
Starting Dose 
Dose -1 
Dose -2 
paclitaxel 
175mg/m2 
135mg/m2 
110mg/m2 
carboplatin 
AUC 5 
AUC 4 
N/A 
pembrolizumab (MK-3475)/placebo 
200 mg* 
N/A 
N/A 
* Pembrolizumab (MK-3475)/placebo will be given at 200 mg IV every 3 weeks during 
the combination phase, when given with chemotherapy.  During the maintenance phase, 
pembrolizumab (MK-3475)/placebo will be given at 400 mg IV every 6 weeks. 
 
 
In the event that pembrolizumab is held for immune-related adverse events during the 
combination phase of the study, paclitaxel and carboplatin should be continued per 
protocol timelines (if clinically appropriate).  After resolution of pembrolizumab-
associated AE, as detailed in section 6.2, pembrolizumab can be resumed at the next 
planned treatment cycle. 
 
6.1 
Paclitaxel and Carboplatin Dose Modification and Supportive Care Guidelines for 
Drug-Related Adverse Events (07-FEB-2020) (21-MAY-2021) 
Subsequent courses of treatment which contain cytotoxic chemotherapy (paclitaxel and/or 
carboplatin) will not begin (day 1 of each cycle) until the ANC is ≥ 1,000 and the platelet 
count is ≥ 100,000. 
 
 
Paclitaxel and carboplatin dose modification and supportive care guidelines can be modified 
per treating investigator’s discretion and/or institutional, NCCN and/or ASCO guidelines. 
 
Filgrastim, pegfilgrastim or biosimilars can be used per treating investigators discretion 
and/or institutional, NCCN and/or ASCO guidelines. 
 
Dose limiting hematologic toxicities are defined as: 
• Febrile neutropenia 
• Prolonged grade 4 neutropenia persisting for greater than 7 days 
• Grade 4 thrombocytopenia (platelet count <25,000) 
• Bleeding associated with grade 3 thrombocytopenia (25,000 to <50,000) 
 
Dose modification for dose limiting hematologic toxicity or cycle delay > 7 days due to 
hematologic toxicity: 
ANC 
PLT 
First Occurrence 
Second Occurrence 
Third Occurrence 
Yes 
No 
Add filgrastim, 
pegfilgrastim or 
biosimilar 
Reduce carboplatin 
one AUC unit (AUC 
4) 
Reduce paclitaxel one 
dose level 
Yes 
Yes 
Add filgrastim,  
pegfilgrastim or 
biosimilar AND 
reduce carboplatin one 
AUC unit (AUC 4) 
Reduce paclitaxel one 
dose level 
Reduce paclitaxel one 
dose level 
No 
Yes 
Reduce carboplatin 
Reduce paclitaxel one 
Reduce paclitaxel one 

 
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one AUC unit (AUC 
4) 
dose level 
dose level 
Note:  For patients meeting criteria for dose modification after third recurrence, notify study 
chair 
 
Peripheral neuropathy:  for grade 2 (or greater) peripheral neuropathy: 
Hold paclitaxel until recovered to grade 1, then paclitaxel should be reduced one dose level. 
Chemotherapy can be delayed for a maximum of 3 weeks.  If neuropathy does not recover to 
grade 1, paclitaxel should be omitted from subsequent cycles. 
 
Renal toxicity:  Renal toxicity is not expected from paclitaxel and/or carboplatin as a direct 
complication of chemotherapy in this patient population given the required treatment free 
interval in the pre-treated population.  As such, there are no specific dose modifications for 
renal toxicity.  However, see Appendix IV for carboplatin dose calculation instructions for 
criteria for recalculation of dose. 
 
Hypersensitivity reaction:  In general, the occurrence of a hypersensitivity reaction to 
paclitaxel and/or carboplatin can be managed with administration of medication to prevent 
hypersensitivity reactions and/or adjustments in infusion rates, per institutional standards. 
 
If a patient experiences a hypersensitivity reaction to carboplatin, platinum graded challenge 
or desensitization may be allowed after discussion with the study chair.  However, if despite 
these safety measures repeat attempt at infusion of the inciting drug results in a recurrent 
hypersensitivity reaction, the patient will discontinue this agent. 
 
Severe hypersensitivity reactions to paclitaxel do not have to proceed with a re challenge. It 
is acceptable to substitute docetaxel or paclitaxel protein-bound particles for injectable 
suspension in patients who had a reaction to paclitaxel with a failed re-challenge (or not 
amendable to re-challenge). Institutional guidelines can be used for infusion duration.  For 
Japanese sites, the starting dose and modified doses of docetaxel should be 60-70 mg/m2. 
 
Agent 
Starting Dose 
Dose -1 
Dose -2 
Docetaxel (Taxotere) 
75mg/m2 
65mg/m2 
55mg/m2 
Paclitaxel protein-bound particles 
for injectable suspension (Abraxane) 
175mg/m2 
135mg/m2 
110mg/m2 
 
*If substitution of paclitaxel for Docetaxel or paclitaxel protein-bound particles for injectable 
suspension (Abraxane) is required for reasons other than hypersensitivity reaction (e.g., drug 
shortage), contact the study team for review and approval prior to making the substitution. 
(09-MAR-2022) 
 
 

 
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6.2 
Pembrolizumab (MK-3475)/Placebo Dose Modification and Supportive Care 
Guidelines for Drug-Related Adverse Events (24-FEB-2023) 
 
6.2.1 Dose Modifications 
 
Adverse events (both non-serious and serious) associated with pembrolizumab (MK-
3475)/placebo exposure may represent an immunologic etiology.  These AEs may occur 
shortly after the first dose or several months after the last dose of treatment.  Pembrolizumab 
(MK-3475)/placebo must be withheld for drug-related toxicities and severe or life-
threatening AEs as per the table in Section 6.2.3. 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption.  The reason for interruption should be documented in the patient's 
study record. 
 
Modification and toxicity management of infusion reaction related to Pembrolizumab (MK-
3475) can be found in Section 6.2.4. 
 
6.2.2 Supportive Care Guidelines 
 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are also outlined in the table in Section 6.2.3.  Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab (MK-3475)/placebo. 
  
Note:  If after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event. 
 
6.2.3 Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab (MK-3475) (24-FEB-2023) 
 
AEs associated with pembrolizumab (MK-3475) exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab (MK-3475) treatment and may affect more than 

 
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one body system simultaneously. Therefore, early recognition and initiation of treatment is 
critical to reduce complications. Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab (MK-3475), 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab (MK-3475) and administer corticosteroids. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab (MK-3475) are provided 
in the table below. 
 
Note that non-irAEs will be managed as appropriate, following clinical practice 
recommendations. 

 
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Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab (MK-3475) 
(09/24/2019) 
 
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should consider the use of IV corticosteroids 
followed by oral steroids.  Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids.  Some non-endocrine irAEs do not require steroids.  For example, celiac disease induced by pembrolizumab 
can be controlled by diet alone. 
2. For non-endocrine-related toxicities, pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. Generally, when corticosteroids are used, investigators should begin a taper when the irAE is ≤Grade 1 and continue at least 
4 weeks. 
4. If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab may generally resume after the irAE has 
decreased to ≤Grade 1 after a corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab  
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Add prophylactic antibiotics 
for opportunistic 
infections 
 
Monitor participants for signs 
and symptoms of 
pneumonitis 
Evaluate participants with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment 
 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor participants for signs 
and symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal pain, 
blood or mucus in stool 

 
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Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
Patients who do not respond 
to corticosteroids should 
be seen by a 
gastroenterologist for 
confirmation of the 
diagnosis and 
consideration of 
secondary immune 
suppression 
 
 
with or without fever) and 
of bowel perforation (i.e. 
peritoneal signs and ileus) 
Specifically assess for celiac 
disease serologically, and 
exclude Clostridium 
difficile infection 
Participants with ≥Grade 2 
diarrhea suspecting 
enterocolitis should 
consider GI consultation 
and performing 
endoscopy to rule out 
enterocolitis and assess 
mucosal severity 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. 
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion 
AST or ALT 
elevation or Increased 
Bilirubin 
Grade 2 a 
Withhold 
Administer corticosteroids 
(initial dose of 0.5 to 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable) 

 
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Grade 3 b or 4 c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
 
Investigate for diabetes.  In 
the absence of 
corticosteroids or diabetes 
medication non-
adherence, any grade 
hyperglycemia may be an 
indication of beta-cell 
destruction and 
pembrolizumab-induced 
diabetes akin to type 1 
diabetes.  This should be 
treated as a Grade 3 
event.  Given this risk, 
exercise caution in 
utilizing non-insulin 
hypoglycemic agents in 
this setting.  After a 
thorough investigation of 
other potential causes, 
which may involve a 
referral to an 
endocrinologist, follow 
institutional guidelines.   
Monitor glucose control. 

 
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New onset T1DM 
(evidence of -cell 
failure) or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and glucose 
levels are stable 
Initiate treatment with 
insulin 
If patient is found to have 
diabetic ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with 
appropriate management 
and laboratory values 
(e.g. anion gap, ketones, 
blood pH, etc.) reported 
 
Monitor for glucose control 
Strongly consider referral to 
endocrinologist 
Obtain C-peptide level paired 
with glucose, 
autoantibody levels (e.g. 
GAD65, islet cell 
autoantibodies), and 
hemoglobin A1C level 
 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids 
and initiate hormonal 
replacements as 
clinically indicated 
Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Provide adrenal insufficiency 
precautions including 
indications for stress dose 
steroids and medical alert 
jewelry 
Strongly consider referral to 
endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms 
are controlled, and 
thyroid function is 
improving 
Treat with nonselective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
Initiate treatment with anti-
thyroid drug such as 
Monitor for signs and 
symptoms of thyroid 
disorders 
Strongly consider referral to 
endocrinologist 
 

 
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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
methimazole or 
carbimazole as needed 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according to 
increased creatinine 
or acute kidney injury 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed 
by taper 
Monitor changes of renal 
function 
Strongly consider referral to 
nephrologist 
Grade 3 or 4 
Permanently 
discontinue 
Cardiac Events 
(including 
myocarditis, 
pericarditis, 
arrhythmias, impaired 
ventricular function, 
vasculitis) 
Asymptomatic 
cardiac enzyme 
elevation with clinical 
suspicion of 
myocarditis 
(previously CTCAE 
v4.0 Grade 1), or 
Grade 1 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 
or better, taper 
corticosteroids over ≥1 
month 

 
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Grade 2, 3 or 4 
Permanently 
discontinue 
Initiate treatment with 
corticosteroids 
equivalent to 1-2 
mg/kg/day IV 
methylprednisolone and 
convert to 1-2 
mg/kg/day oral 
prednisone or equivalent 
upon improvement 
If event does not improve 
within 48 hours after 
initiating corticosteroids, 
consider adding an 
immunosuppressive 
agent 
Initiate treatment per 
institutional guidelines 
and consider 
antiarrhythmic drugs, 
temporary pacemaker, 
extracorporeal 
membrane oxygenation 
(ECMO), ventricular 
assist device (VAD), or 
pericardiocentesis as 
appropriate 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 
or better, taper 
corticosteroids over ≥1 
month 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN, 
or DRESS 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or 
exclude other causes 
Strongly consider referral to 
dermatologist 
Consider skin biopsy for 
evaluation of etiology 
Confirmed SJS, TEN, 
or DRESS 
Permanently 
discontinue 

 
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All Other irAEs 
Persistent Grade 2 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or 
exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
 
 
6.2.4 
Infusion-Related Reactions (24-FEB-2023) 
 
Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at 
subsequent dosing 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
  
Grade 1 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for ≤24 hrs. 
Grade 2 
• Stop Infusion. 
• Additional appropriate medical therapy 
may include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
Participant 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg PO 
(or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic). 

 
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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at 
subsequent dosing 
(e.g. from 100 mL/hr. to 50 mL/hr.). 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 

 
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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at 
subsequent dosing 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary infiltrates) 
 
 
 
Grade 3 
• Stop Infusion. 
• Additional appropriate medical therapy 
may include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids (e.g. methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 
6 hours) 
• Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
 
No subsequent dosing. 
 

 
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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at 
subsequent dosing 
Life-threatening; 
pressor or ventilator 
support indicated 
 
Grade 4 
Admit participant to intensive care unit (ICU) and 
initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. 
Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
Follow Grade 3 recommendations as applicable. 
No subsequent dosing. 
 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; ECMO=extracorporeal membrane oxygenation; GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; 
ir=immune related; IV=intravenous; MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic 
Epidermal Necrolysis; ULN=upper limit of normal; VAD=ventricular assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if 
baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
If control achieved or ≤Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (e.g. vasculitis 
and sclerosing cholangitis). 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov. 

 
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6.2.5 
Neurological Toxicities (24-FEB-2023) 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue pembrolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 
2 
• Withhold pembrolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
pembrolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding pembrolizumab, permanently discontinue 
pembrolizumab. c 
• For facial paresis: 
o If event resolves fully, resume pembrolizumab. b 
o If event does not resolve fully while withholding 
pembrolizumab, permanently discontinue pembrolizumab. 
c 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 
3 or 4 
• Permanently discontinue pembrolizumab. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any grade) 
• Permanently discontinue pembrolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an assessment 
of benefit−risk by the investigator and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
pembrolizumab should be based on investigator's assessment of benefit−risk and documented by 
the investigator (or an appropriate delegate). 
 
 
 

 
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Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue pembrolizumab unless symptoms worsen or do 
not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue pembrolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
• Permanently discontinue pembrolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
pembrolizumab should be based on investigator's assessment of benefit−risk and documented by 
the investigator (or an appropriate delegate). 
 
6.2.6 Criteria to Resume Treatment with Pembrolizumab (MK-3475)/Placebo (07/03/2019) (14-
OCT-2020) 
 
For non-autoimmune or inflammatory events, patients may resume treatment with 
pembrolizumab (MK-3475)/placebo when the drug-related AE(s) resolve to ≤ Grade 1 or 
baseline value, with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue.  
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin. 
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed. 
• Patients with drug-related endocrinopathies (not including drug-related adrenal 
insufficiency or hypophysitis) adequately controlled with only physiologic hormone 
replacement may resume treatment after replacement correction and clinically stable 

 
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regimen. 
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than 
the next scheduled time point per protocol.  However, if the treatment is delayed past the next 
scheduled time point per protocol, the treatment should resume at the earliest convenient 
point that is within the 9-week period.  
 
 
If treatment is delayed >3 weeks (9 week maximum between doses), the patient must be 
permanently discontinued from study therapy, except as specified in Section 5.9 (Duration of 
Therapy). 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Protocol Agents 
 
 
Investigational Agents 
The investigational agent administered in NRG-GY018 is pembrolizumab (MK-3475), which 
is being made available under an IND sponsored by DCTD, NCI.  Determination of whether 
an adverse event meets expedited reporting criteria, see the reporting table in section 7.5.1.1 
of the protocol. 
 
Commercial Agents 
The commercial agents in NRG-GY018 are carboplatin and paclitaxel. In this study, the commercial 
agents are used in combination with investigational agent; therefore, the expedited adverse event 
reporting criteria for an investigational agent apply. See the reporting table in section 7.5.1.1 
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 (CAEPR) for MK-
3475 (pembrolizumab, NSC 776864) (27-FEB-2020) (06-OCT-2021) (24-
FEB-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 3793 patients. Below is the CAEPR 
for Pembrolizumab (MK-3475). 
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 2.7, December 13, 20221 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
 
 
 
Lymph node pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
 
Endocrine disorders - Other 
(hypoparathyroidism) 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  

 
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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
 
 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - 
Other (acute graft-versus-host-
disease)2,3 
  
 
 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased2 
 
  
 
Blood bilirubin increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Arthritis2 
 
  
 
Back pain 
 
  
 
Joint range of motion decreased 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)2 
  
 
 
Nervous system disorders - 
Other (neuromyopathy)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious myelitis) 
  
 
 
Nervous system disorders - 
Other (optic neuritis) 
  
 
 
Nervous system disorders - 
Other (polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 

 
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 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. 
 
2Immune-mediated adverse reactions have been reported in patients receiving Pembrolizumab (MK-3475).  
Adverse events potentially related to Pembrolizumab (MK-3475) may be manifestations of immune-mediated 
adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and managed with 
interruptions of Pembrolizumab (MK-3475), administration of corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with Pembrolizumab (MK-3475) who 
received hematopoeitic stem cell transplants. 
 
Adverse events reported on Pembrolizumab (MK-3475) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Pembrolizumab (MK-3475) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal hemorrhage; 
Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other 
(intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal hemorrhage; 
Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; Facial 
pain; Gait disturbance; General disorders and administration site conditions - Other (general physical health 
deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - CPK increased; Cholesterol high; Creatinine increased; Fibrinogen decreased; 
Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Joint effusion2; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - 
Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pleuritic pain2; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: Pembrolizumab (MK-3475) 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. 

 
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7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information. 
 
7.5 
Expedited Reporting of Adverse Events (09-MAR-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 the CTEP web site, 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. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made 
to CTEP for this study by telephone at 301-897-7497 and to the NRG Regulatory Affairs by 
phone at 215-854-0770.  An electronic report must be submitted immediately upon re-
establishment of the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
• Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-AERS 
24-hour notification must be submitted within 24 hours of learning of the adverse event.  
Each CTEP-AERS 24-hour notification must be followed by a complete report within 5 
days. (07/03/2019) 
• 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 
301-879-7404 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.  
 
 

 
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7.5.1.1 Expedited Reporting Requirements for Adverse Events  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.5.2 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. 

 
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7.5.3 Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be completed 
and submitted to CTEP.  Any pregnancy occurring in a patient from the time of consent to 90 
days after the last dose of study drug must be reported and then followed for outcome.  
Newborn infants should be followed until 30 days old.  Please see the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for 
more details on how to report pregnancy and its outcome to CTEP.  
 
7.5.4 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. 
 
7.6 
Routine Reporting Requirements for Adverse Events (14-OCT-2020) 
All Adverse Events must be reported in routine study data submission.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions. 
See the Rave-CTEP-AERS integration section and Section 13.3. 
 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (07/03/2019) (14-OCT-2020) 
 
8.1 
Investigator and Research Associate Registration with CTEP (24-FEB-2023) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to 
NCI-sponsored trials to register with their qualifications and credentials and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  Investigators and clinical site staff who are significant 

 
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contributors to research must register in the Registration and Credential Repository (RCR).  
The RCR is a self-service online person registration application with electronic signature and 
document submission capability. 
RCR utilizes five person registration types. 
• Investigator (IVR) – MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) – advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
• Associate Plus (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 a 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An active CTEP-IAM user account with a linked ID.me account (the latter required 
immediately for new CTEP-IAM accounts, and by July 1, 2023 for all users is required to 
participate in NCI clinical trials supported by the Cancer Trials Support Unit (CTSU) and to 
access all CTEP and CTSU websites and applications.  In addition, IVRs and NPIVRs must 
list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
 
 
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) 
 
CV (optional) 
 
 
 

 
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• Addition to a site roster; 
• Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN; 
• Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
• Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL). 
 
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 
Cancer Trials Support Unit Registration Procedures (09-MAR-2022) (24-FEB-2023) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(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. 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 
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 

 
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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: 
• Have an active CTEP status; 
• Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating organization’s roster; 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Have 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 applicable protocol-specific requirements (PSRs). 
 
Requirements for NRG-GY018 Clinical Investigators: 
 
• Each Clinical Investigator must ensure all site personnel complete a protocol-specific 
training course. Training slides are available on the CTSU web site.  The CI must 
submit a signed Certificate of Review. The Certificate of Review lists all applicable 
staff and attests their completion of the training.  The signed Certificate of Review is 
then submitted to the Regulatory Submission Portal on the www.ctsu.org members’ 
area website.  Once the study is activated, the site CI must attest that new study 
personnel completed the protocol-specific training course by submitting a revised 
Certificate of Review. 
 
No site will be able to enroll until this requirement is met. 
 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and their associated investigators and staff on a 
participating roster. To view/download site registration forms: 
▪ Log in to the CTSU members’ website  (https://www.ctsu.org) using your CTEP-IAM 

 
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username and password or linked ID.me account (ID.me accounts are required for all 
newly created CTEP-IAM accounts and by July 1, 2023 for all users; 
▪ Click on Protocols in the upper left of the screen 
o Enter the protocol number [NRG-GY018] 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 number [NRG-GY018]. 
▪ 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.) 
 
Protocol Specific Requirements for NRG-GY018 Site Registration (21-MAY-2021) 
 
• 
IRB/REB approved consent (International and Canadian sites only: English and native 
language versions*) English version must be submitted to NRG Oncology (NRG-GY-
Regulatory@nrgoncology.org) for review prior to IRB/REB submission. International and 
Canadian Institutions must provide certification/verification of IRB/REB consent translation 
to NRG Oncology as described below. 
 
*Translation of documents is critical. The institution is responsible for all translation costs. 
All regulatory documents, including the IRB/REB approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to the 
prohibitive costs involved NRG will accept, at a minimum, a verified translation. A verified 
translation consists of the actual REB approved consent document in English and in the 
native language, along with a cover letter on organizational/letterhead stationery that includes 
the professional title, credentials, and signature of the translator as well as signed 
documentation of the review and verification of the translation by a neutral third party. The 
professional title and credentials of the neutral third party translator must be specified as 
well. 
 
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: at 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 

 
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Checking Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
 
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• 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. 
 
Delegation of Tasks Log (DTL) (09-MAR-2022) (24-FEB-2023) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section of the CTSU members’ website. The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site 
receiving an approved site registration status and enrolling patients to the study. To maintain 
an approved site registration status the CI must re-sign the DTL at least annually and when a 
new version of the DTL is released; and to activate new task assignments requiring CI sign-
off. Any individual at the enrolling site on a participating roster may initiate the site DTL. 
Once the DTL is submitted for CI approval, only the designated DTL Administrators or the 
CI may update the DTL. Instructions on completing the DTL are available in the Help Topics 
button in the DTL application and describe DTL task assignments, CI signature, and CTEP 
registration requirements, as well as include a Master Task List. 
Effective February 6, 2023, all patients were unblinded. Submission and maintenance of a 
Pharmacy Agreement for unblinded site personnel is no longer required. A new DTL 
(without the Unblinded Study Personnel task) is available on the CTSU website and must be 
completed and signed by the site CI.   
 
Canadian sites participating under the Canadian Cancer Trials Group (CCTG), should 
complete the DTL in CCTG’s Roster Interface Program & Participants List Environment 
(RIPPLE) application when CCTG holds the Clinical Trials Agreement with Health Canada.  
RIPPLE is integrated with the CTSU DTL application for this trial. 
8.3 
Patient Enrollment (24-FEB-2023) 
8.3.1 Patient enrollment for this 2-step (registration and randomization) trial will be facilitated 
using the Oncology Patient Enrollment Network (OPEN).  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. 
 
 

 
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Requirements for OPEN access:   
• A valid CTEP-IAM account and linked ID.me account (ID.me accounts are required for 
all newly created CTEP-(AM accounts and by July 1, 2023 for all users); 
• 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; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold the 
OPEN Registrar task on the DTL for the site; and 
• 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 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes; and 
• All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
 
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. 
 
NOTE: Step 2 registration requires a second web registration for all patients.  
 
8.3.2 KIT ORDERING for Centralized MMR IHC Testing and PD-L1 IHC Testing 
(09/24/2019) (09-MAR-2022) (19-MAY-2022) 
 
Initial orders of PPD Laboratories’ supplies can be requested by the site user via the web 
application, PPD Lab Supply Registration, available at 
https://apps.nrgoncology.org/LabKitRegistrationApp/PPDLabKitStartPage.aspx. Your 
CTEP-IAM credentials are required to access the PPD supplies ordering software. Once 
logged in you will be able to order supplies for any site you are affiliated with on the NRG 
Oncology roster. 
 
To order your supplies, your site must first be approved to request PPD supplies through this 
application. Approvals are processed by NRG Oncology Regulatory staff and access to the 
PPD supply ordering software will be granted 24-48 hours after your site has satisfied the 

 
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following requirements: 
- 
IRB approval 
- 
DTL approval 
- 
NRG-GY018 Certificate of Review for protocol training for all staff listed on DTL 
- 
Signed Pharmacy AgreementWhen ordering your initial supply via this application, site 
address and contact details are requested. Please use this application to keep your site and 
contact details up to date to ensure proper and timely delivery. Additional supply orders 
should be made through the PPD Laboratories Preclarus portal. Individual e-mail links will 
be sent from PPD Laboratories to each site after the initial kit order. 
 
There is a 14 business day turnaround time (from the day your supply is requested from PPD 
Laboratories) to receive the MMR and PD-L1 IHC testing supplies. There is no expedited 
shipping. 
 
PPD will provide the following in your initial shipment: 
 
 
 
For any related questions or concerns please contact NRG-GY-
Regulatory@nrgoncology.org.  
 
8.3.3 Summary of Registration Procedures (21-MAY-2021) (09-MAR-2022) 
 
This is a 2-step registration study. 
• All eligibility criteria, as determined by pre-screening and patient’s medical 
history/pathology report, must be met prior to Step 1 registration. (No assessments per 
Sec 4.1 need to be completed prior to Step 1.) 
• All patients will be registered to Step 1. 
o Slide submission is required for the central MMR IHC and PD-L1 IHC after Step 1 
registration has been completed and a case number has been assigned. (Refer to 
Section 10.2 and Appendix VIII for details on tissue submission.) 
• After slides are sent to Neogenomics for centralized testing, patients can be registered to 
Step 2. Sites do not have to wait for central testing results to return. (Sites in Japan, see 
Appendix XIV.) 
 

 
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8.4 
Data Submission / Data Reporting (09/24/2019) (09-MAR-2022) (24-FEB-2023) 
 
Medidata Rave is the 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 linked ID.me account (ID.me accounts are required 
for all newly created CTEP-IAM accounts and by July 1, 2023 for all users); 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; 
• 
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. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata. To accept the invitation, site staff must either 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. (07-
FEB-2020) 
 
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in the Regulatory application 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 

 
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Management > Rave section or by contacting the CTSU Help Desk at 1-888-823-5923 or by 
email at ctsucontact@westat.com.   
Central Monitoring (CM) (24-FEB-2023) 
Central Monitoring (CM) Review is required for this protocol. CM allows Lead 
Protocol Organizations (LPOs) to remotely compare data entered in Rave to source 
documentation to ensure that sites are adhering to the protocol and central monitoring 
plan as well as accurately transcribing data from patients’ charts (i.e., source data 
verification).  
Sites can upload source documents required for CM Review as documented in the 
central monitoring plan using the Source Document Portal (SDP) application. This 
application is also available on the CTSU members’ website under Auditing & 
Monitoring and may also be accessed using a direct link within Rave on the CM Alert 
form. Site staff with any of the Rave roles on a relevant site roster can view and 
upload source documents. Prior to saving source documents on the SDP, each site is 
responsible for removing or redacting any Personally Identifiable Information (PII) 
(note that functionality to do this redaction exists within the SDP itself). Designated 
LPO staff will review each document after it has been loaded on the SDP to ensure 
the appropriate documents have been uploaded and to ensure PII is redacted. 
Additional information on the SDP is available on the CTSU SDP application under 
Browsering > Document Repository in the Help Topics button or by contacting the CTSU 
Help Desk (1-888-823-5923 or ctsucontact@westat.com).  
Please see Section 13.3. 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting, and facilitates entry in 
CTEP-AERS for those AEs requiring expedited reporting. Sites must initiate all AEs 
for this study in Medidata Rave.   
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period, and is used to collect AEs that start during the 
period or persist from the previous reporting period. AEs that occur 30 days after the 
last administration of the investigational study agent/intervention are collected using 
the Late Adverse Event Form.  
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct; and 
• AEs are recorded and complete (no missing fields) and the form is query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the 
CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 

 
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evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the 
box Send All AEs for Evaluation and save the form). Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave for AEs that 
meet reporting requirements. The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
Contact the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com if you have any issues submitting an expedited report in 
CTEP-AERS. 
In the rare occurrence, that internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and 
• Additional resources: Resources > CTSU Operations Information> User 
Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
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. Site staff should review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website. Staff who have Rave study access can access the Rave study data via 
direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each 
Rave study that a site is participating in. Additional site staff can subscribe and 

 
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unsubscribe to these notifications using the CTSU Report and Information 
Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button displayed 
on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and 
DQP Reports modules. 
8.5 
Agent Ordering and Agent Accountability (09-MAR-2022) (24-FEB-2023) 
8.5.1 NCI-supplied agents may be requested by authorized designees on behalf of eligible 
participating Investigators (or their authorized designee) at each participating institution.  The 
CTEP-assigned protocol number and subject ID 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).   
 
No starter supplies will be available for this study. The initial patient specific clinical 
supplies will be sent to the pharmacy shipping address of the registering investigator at the 
time of randomization and should arrive within approximately 5 to 7 days. (Section 9.4.5) 
 
 
Patients Randomized to Pembrolizumab (MK-3475) 
The initial request will be submitted automatically following the completion of patient 
registration and randomization. Subsequent patient-specific agent supply requests may only 
be submitted through the PMB AURORA application. Access to AURORA 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.   
Patients Randomized to Placebo 
 
The initial request will be submitted automatically following the completion of patient 
registration and randomization.  The initial shipment will contain an empty patient-specific 
carton containing a memo identifying the subject ID as being randomized to placebo and 
detailing how placebo infusions are to be compounded. No saline vials will be included. 
 
As of amendment 9 (version date 09-MAR-2022), all patients randomized to placebo will 
have their placebo infusions prepared using stock supplies from the site.  Pembrolizumab 
placebo (saline) vials will no longer be available to order through the OAOP application.  
 
8.5.2 Investigator Brochure Availability  
The current version of the pembrolizumab (MK-3475) IB will be accessible to site 
investigators and research staff through the PMB AURORA application. Access to 
AURORA requires the establishment of a CTEP IAM account and the maintenance of an 
“active” account status and a “Current” password. Questions about IB access may be directed 
to the PMB IB Coordinator via email. 
 
8.5.3 Agent Accountability (24-FEB-2023) 

 
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The investigator, or a responsible party designated by the investigator must maintain a 
careful record of the agent receipt, dispensing and final disposition of all agents received 
from the PMB using the NCI Investigational Agent (Drug) Accountability Record (DARF) 
available on the CTEP forms page. 
 
Maintain separate NCI Investigational Agent Accountability Records for each study 
participant and ordering investigator on this protocol. Once the final blinded pembrolizumab 
vials are removed from inventory, the DARF should be closed by marking an ‘X’ through the 
remaining lines on the page.  A new patient-specific DARF should be started to record 
unblinded pembrolizumab vials.  The manufacturer, lot number and expiration date from the 
vial labels are to be recorded on the unblinded DARF.  
 
As of February 6, 2023, all patients have been unblinded. Once blinded supplies have 
been exhausted, blinded DARFs should be closed out and new patient-specific DARFs 
should be started for any patient continuing on open label treatment. Blinded DARFs 
should be retained for future auditing purposes.  
8.5.4 PMB Useful Links and Contacts (07/03/2019) (24-FEB-2023) 
• 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 AURORA application: https://ctepcore.nci.nih.gov/aurora  
• 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  
• 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) 
 
8.6 
ePRO Registration Process (07/03/2019) 
8.6.1  Medidata Patient Cloud ePRO (21-MAY-2021) 
This study includes the use of Medidata Patient Cloud ePRO, (electronic patient-reported 
outcomes). After the patient is registered to the trial via OPEN, and if the patient can read or 
understand English, French, or Spanish, the site staff will complete a registration for the 
patient to the Patient Cloud ePRO through iMedidata. Note: Site staff must have already 
completed eLearning for the Patient Cloud ePRO application to register a patient. 
Information about the training is in Appendix XII. The registration to the Patient Cloud 
ePRO will create a unique patient registration code that the site staff will provide to the 
patient. The patient (with assistance from the site staff) should be instructed to download the 

 
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Patient Cloud ePRO app onto his/her own device (IOS, Android, phone, or tablet) and use the 
unique patient registration code to create an account. Once the patient's account is set up, the 
patient will be able to complete the submission of patient-reported outcomes electronically 
for the trial.  
For sites providing a shared institutional device for use by multiple patients on site: The site 
staff should assist the patient with access and registration to the Patient Cloud ePRO app, and 
the patient can then complete the electronic data submission independently. Site staff may 
need to assist patients with logging on to the device at each visit.  
If a patient prefers paper-based survey or using phone/tablet is not possible at the scheduled 
time, a paper questionnaire should be provided for the patient to complete manually. The 
questionnaires can be found on the CTSU website. 
 
Sites in Japan and Korea will use paper-based PRO surveys. 
8.6.2  CRA Patient Registration Instructions for ePRO  
Please visit the Medidata Learning Tool for reference information on Patient Cloud ePRO for 
CRAs.  
i. The subject registration process starts in iMedidata. Begin by selecting the Patient 
Cloud ePRO Registration link for your study.  
ii. The patient management app will display, select your STUDY and SITE from the drop 
downs and click Launch.  
iii. Now you can register your first patient. Create a subject ID and select a Country / 
Language from the drop down (these are the only required data fields). The subject 
initials are optional, but are helpful in identifying which subject ID maps with which 
activation code. When finished, click Add.  
iv. The subject is added and will include the date the patient was added, the subject ID, 
subject initials (if included), and a unique auto-generated activation code. The 
activation code is unique for each patient and linked to the subject ID, it is not 
interchangeable. In addition, there is a status section, which indicates if the patient has 
registered. When the patient has registered, the status will change from "invited" to 
"registered".  
Reminder – site staff must have already completed the Medidata Patient Cloud training in 
order to register study participants. Please visit the Medidata Learning Tool for reference 
information on Patient Cloud ePRO for CRAs.  
 
 

 
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9. 
DRUG INFORMATION  
9.1 
Investigational Study Agent: pembrolizumab (MK-3475) (NSC# 776864) /CTEP-
supplied placebo (14-OCT-2020) (09-MAR-2022) 
 
9.1.1 Other Names: Pembrolizumab, SCH 900475, KEYTRUDA® 
 
Classification: Anti-PD-1 MAb  
 
Molecular Weight: 148.9-149.5 KDa  
 
CAS Number: 1374853-91-4 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor 
expressed by T cells. When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 
negatively regulates T-cell activation and effector function. The pathway may be engaged 
by tumor cells to suppress immune control. MK-3475 blocks the negative immune 
regulatory signaling by binding to the PD-1 receptor, inhibiting the interaction between PD-
1 and its ligands. 
9.1.2 Description: Pembrolizumab (MK-3475) is a humanized MAb of the IgG4/kappa isotype. 
9.1.3 
How Supplied: Pembrolizumab (MK-3475) for subjects enrolled to the Active treatment arm is 
supplied by Merck & Co., Inc. and distributed by the Pharmaceutical Management Branch, 
CTEP/DCTD/NCI under a Collaborative Agreement between the Pharmaceutical Collaborator 
and the DCTD, NCI (see Appendix V).  
 
Active Agent 
Pembrolizumab (MK-3475) injection is a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution for intravenous use.  Each single dose vial 
contains 100 mg of pembrolizumab (MK-3475) in 4 mL of solution.  Each 1 mL of solution 
contains 25 mg of pembrolizumab (MK-3475) and is formulated in: L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.  (14-OCT-2020) 
 
Placebo 
Site-supplied 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP in an 
infusion bag will be used as Placebo.  
9.1.4 
Preparation: Pembrolizumab solution for infusion must be diluted prior to administration. 
Allow vials to equilibrate to room temperature. Do not shake the vials. Do not use if opaque 
or extraneous particulate matter other than translucent to white proteinaceous particles are 
observed. Do not use if discolored. To prepare the infusion solution add 8 mL (200 mg) or 16 
mL (400 mg) of pembrolizumab to an infusion bag containing 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP.  Gently invert the bag 10-15 times to mix the 
solution. The final volume must be between 20 mL to 200 mL (1 mg/mL to 10 mg/mL).  
 
 
Pembrolizumab placebo infusions will be prepared using supplies provided by the site.  The 
pembrolizumab placebo infusion can be prepared using 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP in an infusion bag.   The final volume must be between 
20 mL to 200 mL.  To maintain the blind, manage infusion bag injection port(s) as for a 

 
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pembrolizumab infusion. 
 
 (14-OCT-2020) 
 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, or 
PE lined polyolefin. 
(24-FEB-2023) 
9.1.5 Storage: Store provided vials as stated in the protocol and PMB applied box label.   
 
Store intact vials of pembrolizumab between 2°C - 8°C (36°F - 46°F). Do not freeze. Protect 
from light. Do Not remove vials from the original carton. 
 
If a storage temperature excursion is identified, promptly return pembrolizumab to between 2-
8°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. (24-FEB-2023) 
9.1.6 Stability:  Stability testing of investigationally labeled pembrolizumab vials is on-going.  
Commercially labeled pembrolizumab will contain a manufacturer’s expiration date on the 
label. Do not administer past this date.  The manufacturers’ expiration date from the vial 
label must be recoded on the UNBLINDED, patient-specific DARF. 
 
Administer prepared solutions of pembrolizumab immediately after preparation. If not 
administered immediately, prepared solutions may be stored refrigerated for up to 24 hours. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 6 
hours. This includes room temperature storage of liquid drug product solution in vials, room 
temperature storage of infusion solution in the IV bag, and the duration of infusion. (14-OCT-
2020) (24-FEB-2023) 
 
9.1.7 
Route of Administration: IV infusion only. Do not administer as an IV push or bolus 
injection. 
 
Method of Administration: Infuse over approximately 30 minutes (range: 25 - 40 minutes) 
using an infusion set containing a low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone or polysulfone. Infusion rate should not exceed 6.7 mL/min. A central line 
is not required; however if a subject has a central venous catheter in place, it is recommended 
that it be used for the infusion. Do not co-administer other drugs through the same infusion 
line.  Following the infusion, flush the IV line with normal saline. 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri- (2-
ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
Patient Care Implications: Refer to Section 6 for information on evaluation and 
management of potential immune-related adverse events. 
9.1.8 Adverse Events: Please see Section 7.3 for the MK-3475 CAEPR. 
9.2 
Provision of  Pembrolizumab (MK-3475) and Placebo (09-MAR-2022) 
 
9.2.1 Pembrolizumab (MK-3475) will be provided free of charge by Merck & Co., Inc. and 
distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation 

 
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Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer 
Institute (NCI).  Clinical supplies inside the PMB-supplied box are not provided in a blinded 
fashion.  Thus, Unblinded Study Personnel are required to employ efforts throughout the 
course of the trial to maintain the study blind for enrolled study subjects and other site 
personnel.  
 
A nationwide shortage of normal saline (placebo) vials has affected Merck’s ability to 
provide the NCI an adequate supply of normal saline vials used as pembrolizumab placebo 
for this trial.  To continue the conduct of this trial, pembrolizumab placebo infusions will be 
prepared using stock supplies from the site without the addition of saline from PMB .  See 
Section 9.1.4 for preparation instructions and Section 9.2.4 for documentation instructions. 
 
9.2.2 Effective February 6, 2023, the Unblinded Study Personnel (USP) task is no longer 
required for the NRG-GY018 DTL. A new version of the DTL has been released 
without the USP task and will need to be completed and signed by the site CI. 
 
For subjects randomized to the Active treatment arm, study agent will be provided in cartons 
containing eight vials of pembrolizumab.  The carton will be tamper-evident-sealed. The 
vials of pembrolizumab inside the carton will not be blinded. Each vial within the carton will 
contain an auxiliary label with the patient’s study ID number. (09/24/2019) (24-FEB-2023) 
 
9.2.3 Each patient-specific carton will be labeled with …  
 
• the protocol number (i.e., “NRG-GY018”)  
• the total number of vials per box (i.e., “8 vials”)—Pembrolizumab shipments only (21-
MAY-2021) 
• the patient ID number (e.g.,"AAXXX-GY018-XXXXX", which represents the unique 
patient identifier assigned at registration)  
• the patient initials (i.e., Last initial, First initial, Middle initial [e.g., "L, FM"])  
• the agent identification (i.e., “Pembrolizumab 100 mg”  
• a blank line for the pharmacist to enter the patient’s name  
• administration instructions (i.e., “Dilute in NS or D5W to a final volume between 20-200 
mL.”)  
• storage instructions (i.e., “Store between 2°C - 8°C in the original box. Do not freeze.”) 
•  
• a Julian date  
 
The Julian date indicates the day the vials were labeled and shipped and is composed of the 
last two digits of the calendar year (e.g., 2019 = 19, 2020 = 20) and a day count (e.g., January 
1 = 001, December 31 = 365). For example, a bottle labeled and shipped on January 1, 2019 
would have a Julian date of ‘19001’ and a bottle labeled and shipped on December 31, 2019 
would have a Julian date of ‘19365’. The Julian date will be used by PMB for recalls. When 
a lot expires, PMB will determine the last date the expired lot was shipped and will recall all 
vials (i.e., both Pembrolizumab (MK-3475) and 0.9% sodium chloride) shipped on or before 
that date.  
 

 
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Once the final blinded pembrolizumab vials are removed from inventory, the DARF should 
be closed by marking an ‘X’ through the remaining lines on the page.  A new, patient-
specific DARF should be started to record unblinded pembrolizumab vials.  The 
manufacturer, lot number and expiration date are to be recorded on the unblinded DARF. 
(24-FEB-2023) 
 
9.2.4 No starter supplies will be available for this study. Patient specific clinical supplies will be 
sent to the registering investigator at the time of randomization and should arrive within 
approximately 5 to 7 days. This randomization will be performed by the NRG Oncology 
SDMC. The assigned NRG patient ID number must be recorded by the registering institution. 
Once a patient has been randomized, the NRG Oncology SDMC will electronically transmit 
a clinical drug request for that patient to the PMB. This request will be entered and 
transmitted by the NRG Oncology SDMC the day the patient is randomized, provided it is 
before 3PM ET.  If the patient is randomized after 3PM ET, the order will be transmitted the 
next business day.  Orders will be processed by the PMB the next business day after 
transmission and shipped the following business day. Orders are not shipped the day 
before a Federal Holiday.  Shipments within the United States will be sent by FedEx Next 
Day. Shipments to United States sites can be expedited to early morning delivery by the 
provision of an express courier account name and number to the PMB at the time the patient 
is randomized. Please note that additional processing time is required for QA/QC checks on 
patient-specific/blinded orders and next day delivery is not available.  
 
 
Orders to Canadian sites are shipped Monday through Wednesday only. 
 
Orders to Japan and South Korea are shipped on Fridays only. 
 
 
Please see the chart below for order timelines for shipments to the US: 
 
Drug Order Submitted to PMB* 
Drug Order Shipped to Site 
from PMB 
Drug Received at Site 
Monday 
Tuesday 
Wednesday 
Tuesday 
Wednesday 
Thursday 
Wednesday 
Thursday 
Friday 
Thursday 
Friday 
Monday 
Friday 
Monday 
Tuesday 
*if received by 2pm ET.  (21-MAY-2021) (24-FEB-2023) 
 
Patients Randomized to Pembrolizumab (MK-3475) 
The initial request will be submitted automatically following the completion of patient 
registration and randomization.  The request will contain 8 vials [a 4 cycle (12 week) supply] 
of Pembrolizumab (MK-3475) 100 mg vials.  At the time the cycle 4 dose is prepared, sites 
may order an additional 8 vials [a 4 cycle (12 week)] supply using AURORA, the PMB’s 
web-based inventory management system. Note: Sites must monitor their supply as the 
pembrolizumab dose increases to 400 mg (4 vials) at maintenance. The assigned patient 
ID number (e.g., "AAXXX-GY018-XXXXX") and the patient initials (e.g., "L, FM") should 
be entered in the "Patient or Special Code" field. A separate order is required for each patient 
ID number (e.g., "AAXXX-GY018-XXXXX") being requested. All drug orders will be 

 
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shipped directly to the address of the shipping physician as designated upon patient 
registration. (14-OCT-2020) (21-MAY-2021) (24-FEB-2023) 
 
Patients Randomized to Placebo 
 
The initial request will be submitted automatically following the completion of patient 
registration and randomization.  The initial shipment will contain an empty patient-specific 
carton and a memo identifying the subject ID as being randomized to placebo and detailing 
how placebo infusions are to be compounded. No saline vials will be included. 
 
 
As of amendment 9 (version date 09-MAR-2022), all patients randomized to placebo will 
have their placebo infusions prepared using stock supplies from the site.  Pembrolizumab 
placebo (saline) vials will no longer be available to order through the OAOP application.  
 
Documenting the dispensing of each placebo infusion bag on a patient specific DARF is not 
required.  However, if a patient specific DARF is maintained, it is to be completed per 
institutional procedures.  
 
All transfers (e.g., from one patient to another patient or from one protocol to another 
protocol., the principal investigator at a given clinical site changes) must be approved in 
advance by the PMB. To obtain an approval for transfer, investigators (or their designee) 
should complete and submit via email to the PMB a Transfer Investigational Agent Form 
available on the PMB home page (https://ctep.cancer.gov/branches/pmb/default.htm) or by 
calling the PMB. The patient ID number (e.g. "AAXXX-GY018-XXXXX"') and the patient 
initials (e.g. "L, FM") should be entered in the "Received on NCI Protocol No." and the 
"Transferred to NCI Protocol No." fields in addition to the protocol number (i.e. "NRG-
GY018").  In the event of a patient institution transfer, the site to which the patient 
transferred cannot order study drug until the patient is officially transferred through the 
CTSU. (24-FEB-2023) 
 
Drug Returns 
When it is necessary to return undispensed study drug (e.g. sealed vials remaining when a 
patient permanently discontinues protocol treatment, expired vials recalled by the PMB), US 
sites must return the study drug to the PMB using the NCI Return Drug List available on the 
PMB home page or by calling the PMB. The patient ID number (e.g. "AAXXX-GY018-
XXXXX") and the patient initials (e.g. "L, FM") should be entered in the "Lot Number" 
field. When returning unblinded vials, complete the NCI Return Drug List per the instruction 
of the form. (21-MAY-2021) (24-FEB-2023) 
 
Non-US sites will utilize the PMB Local Destruction process.  Sites must contact PMB for 
a copy of the Request for Authorization for Local Destruction form prior to destroying 
patient-specific supplies.  Approval for local destruction must be received prior to vial 
destruction and should be maintained in the study file for documentation of final agent 
disposition. (21-MAY-2021) 
 
Reporting Errors 
If a medication error involves patient-specific supplies (e.g. blinded studies), report the 

 
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incident immediately to PMB by calling 240-276-6575 and asking for the pharmacist 
responsible for the blinded agent supply. 
 
9.3 
Commercial Agent: Carboplatin 
Please refer to the current FDA- approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage.  
9.3.1 Product Description 
Carboplatin is commercially available.  Carboplatin aqueous solution injection is a premixed 
aqueous solution of 10 mg/mL carboplatin.  Dosage forms include 50mg/5mL, 150 
mg/15mL, 450 mg/45mL and 600 mg/60 mL aqueous solution in multidose vials. 
9.3.2 Solution Preparation 
See the carboplatin package insert for preparation instructions. 
9.3.3 Route of Administration (07/03/2019) 
Carboplatin AUC 5 IV over approximately 30-60 minutes. See Section 5.1. (07-FEB-2020) 
9.3.4 Agent Ordering 
Carboplatin is commercially available. 
9.3.5 Adverse Events 
 
Hair loss, Vomiting/Nausea, Infection, Anemia, Bruising/Bleeding, Belly pain, 
Diarrhea/Constipation, Peripheral Neuropathy, Allergic Reaction. 
Please see the Carboplatin package insert for the most current and complete information. 
9.4 
Commercial Agent: Paclitaxel 
Please refer to the current FDA- approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage.  
9.4.1 Product Description (21-MAY-2021) 
 
Paclitaxel is a clear, colorless to slightly yellow viscous solution.  It is supplied as a 
nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous 
infusion Paclitaxel is available in 30 mg (5mL), 100 mg (16.7 mL), and 300 mg (50 mL) 
multidose vials.  Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg 
of purified Cremophor ® EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated 
alcohol, USP. 
 
9.4.2 Solution Preparation 
 
See the paclitaxel package insert for preparation instructions. 
 
9.4.3 Route of Administration (07/03/2019) 
 
Paclitaxel 175 mg/m2 IV over approximately 3 hours.  See Section 5.1. 
 
9.4.4 Agent Ordering 
 
Paclitaxel is commercially available. 

 
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9.4.5 Adverse Event List 
 
Neutropenia, Alopecia, Anemia, Arthralgia/myalgia, Diarrhea, Leukopenia, 
Nausea/Vomiting, Opportunistic infections, Peripheral neuropathy, Thrombocytopenia, 
Mucositis, Hypersensitivity, Renal impairment, Hypotension. 
 
 
Please see the paclitaxel package insert for the most current and complete information.  
 
10. 
PATHOLOGY/BIOSPECIMEN   
 
10.1 
Central Pathology Review Guidelines   
Not Applicable 
 
10.2 
Biospecimen Selection for Integral Biomarker Testing (09/24/2019) (21-MAY-2021) (19-
MAY-2022) 
Formalin-fixed, paraffin-embedded unstained sections for centralized mismatch repair 
(MMR) immunohistochemistry (IHC). Sections must be prepared using the Superfrost slides 
provided by PPD. 
 
PPD Laboratories will provide the supplies required to collect, prepare, and ship MMR and 
PD-L1 IHC samples for this study. 
 
***Note: There is an approximate 14 day turnaround time between placing a kit request 
and receiving a kit. Please plan accordingly.*** 
 
10.2.1 Integral Biomarker Testing Requirements and Reporting (09-MAR-2022) 
 
Testing Requirements 
• All sites must have submitted patient slides for centralized MMR IHC testing prior to 
Step 2 registration/stratification/randomization. (Sites in Japan, see Appendix XIV.) 
 
Reporting 
• MMR IHC results will be reported to the NRG SDMC (07-FEB-2020) 
• Reporting will consist of proficient (pMMR), deficient (dMMR), or inconclusive. If the 
result is inconclusive, additional slides may be requested and used until a result is 
obtained. 
• Sites in Japan—see Appendix XIV. 
 
10.2.2 Method of Integral Biomarker Testing 
Immunohistochemistry 
• MMR IHC Class 2 commercial kit (LDT) 
• All specimens will be stained using the VENTANA MMR IHC Panel (Ventana 
Medical Systems, Inc., Tucson, AZ). Specific components of the VENTANA MMR 
IHC Panel are listed below. Briefly, 4μm sections on Superfrost plus glass slides will 
be stained using the OptiView DAB IHC Detection and, for VENTANA anti-PMS2 

 
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(A16-4) antibody, OptiView Amplification Kit on the BenchMark ULTRA 
instrument. 
o The VENTANA MMR IHC Panel includes: VENTANA anti-MLH1 (M1) Mouse 
Monoclonal Primary Antibody, VENTANA anti-PMS2 (A16-4) Mouse  
Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219-1129) Mouse 
Monoclonal Primary Antibody, VENTANA anti-MSH6 (SP93) Rabbit Monoclonal 
Primary Antibody, and VENTANA BRAF V600E (VE1) Mouse Monoclonal Primary 
Antibody. 
• Only a certified pathologist should score samples. Samples should only be scored on 
glass slides, not from digital scanned images. 
 
10.2.3 Location of Integral Biomarker Testing (09/24/2019) 
NeoGenomics Laboratories, Inc., Aliso Viejo, CA 
 
10.2.4 Biospecimen Submission for Integral Biomarker Testing (07/03/2019) (09/24/2019) (07-
FEB-2020) (21-MAY-2021) (09-MAR-2022) (19-MAY-2022) 
 
Refer to Appendix VIII for details. Note: Instructions for PD-L1 IHC samples are listed in 
Biospecimen Submission for Exploratory Biomarker Testing (section 10.5.4). 
• Shipping supplies and instructions will be provided by PPD. See Section 8.3.2 for 
details.  
o Note: There is an approximate 14 business day turnaround time between placing 
a supply request and receiving a kit. Please plan accordingly. 
• Nine (4µm, charged) unstained sections of FFPE primary or metastatic tumor tissue 
must be submitted for MMR IHC. Sections must be prepared using the Superfrost slides 
provided by PPD. 
o The tumor lesion submitted must not have been previously irradiated. 
• Sections should be fresh cut within 48 hours of shipping from a block that is less than 
five years old. 
o A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, 
bone, bone marrow, cytologic specimen, decalcified, or formalin fixed sample that 
was frozen at any point will not be acceptable for analysis. 
o A minimum of 100 viable tumor cells is required for MMR IHC; otherwise, the 
sample will be reported as “not evaluable.” If possible, samples with greater than 
50% tumor cellular content is preferred if available. 
• Each slide must be labeled with two identifiers. Label each slide with the NRG Patient 
ID and Block ID (i.e., Surgical Pathology number and block number). Serially number 
slides in the order they were sectioned with indelible ink. The same two identifiers must 
also be included on the Tissue Sample Transmittal Form. 
o Failure to include both identifiers on each slide and the Tissue Sample 
Transmittal Form will result in testing delays. 
• Unstained sections should be shipped directly to NeoGenomics Laboratories, Inc. 
(address below) Monday through Thursday only. 
o Sectioned slides should be shipped refrigerated year round. Refer to the instructions 
provided by PPD for additional details. 
o A completed copy of the Tissue Sample Transmittal Form (a paper version of this 

 
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form will be provided by PPD but should only be used when the Rave GY018 EDC 
System is not available to the site) and corresponding pathology report must be 
included. 
• Incomplete transmittal forms will cause processing delays. 
• Sites should retain a copy of the completed form for their records. 
• Site in Japan—see Appendix XIV. 
 
NeoGenomics Laboratories, Inc. 
Attn: Pharma Services Dept. 
31 Columbia 
Aliso Viejo, CA 92656 
Email: pharma_project_support_team@neogenomics.com 
Phone: 949-445-7300, x7103 
 
• If the central lab is unable to obtain a result due to technical error and not due to the 
sample submitted, additional slides may be requested and used until a result is obtained. 
• See Appendix VIII for additional details. 
 
10.3 
Biospecimen Selection for Integrated Biomarker Testing 
Not Applicable. 
 
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 (07-FEB-2020) (21-MAY-2021) (09-MAR-2022) 
  
Not applicable 
 
10.4.2  Optional Biospecimen Submissions (09-MAR-2022) 
If the patient gives permission to participate in this optional study component, then 
participating sites are required to submit the patient’s biospecimens as outlined below. 
 
Required Biospecimen (Biospecimen Code) 
Collection Time Point 
Sites Ship 
Biospecimens To 
FFPE TUMOR TISSUE (Submit one of the following – Listed in order of preference) 
FFPE Persistent Primary Tumor (FPP01) or 
Metastatic Tumor (FPM01)1 
1st choice: block 
2nd choice: 10 unstained slides (charged, 5µm) 
Prior to study treatment; lesion 
must not have been previously 
irradiated 
NRG Oncology BB-
Columbus within 8 
weeks of registration2 
 
Sites in Korea: KGOG 
central lab within 8 
weeks of registration3 
 
Sites in Japan: Central 
lab within 8 weeks of 
registration4 
FFPE Recurrent Primary Tumor (FRP01) or 
Metastatic Tumor (FRM01)1 
1st choice: block 
2nd choice: 10 unstained slides (charged, 5µm) 
Prior to study treatment; lesion 
must not have been previously 
irradiated 
FFPE Primary Tumor (FP01) or Metastatic Tumor 
(FM01)1 
1st choice: block 
2nd choice: 10 unstained slides (charged, 5µm) 
Prior to all treatment; lesion 
must not have been previously 
irradiated 

 
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FFPE Primary Neoadjuvant Tumor (FPT01) or 
Metastatic Neoadjuvant Tumor (FMT01)1 
1st choice: block 
2nd choice: 10 unstained slides (charged, 5µm) 
Prior to study treatment; lesion 
must not have been previously 
irradiated. Only submit if tumor 
collected prior to any treatment 
is not available. 
BLOOD BIOSPECIMENS 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) tube(s) 
and frozen4 
Prior to study treatment 
NRG Oncology BB -
Columbus within 1 
week of registration2 
 
Sites in Korea: KGOG 
central lab within 5 
weeks of registration3 
 
Sites in Japan: Central 
lab within 5 weeks of 
registration4 
1 A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the NRG BB-
Columbus. Sites in Korea and Japan must provide an English translated copy of the corresponding pathology report. 
Note: The entire report must be translated, typed, and include diagnosis, clinical history, gross description or block 
number, and microscopic findings. 
2 NRG Oncology BB-Columbus / Protocol NRG-GY018, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org 
3 Sites in Korea should ship to the KGOG central lab. The KGOG central lab will batch ship all biospecimens to the 
US. 
4 Sites in Japan should ship to the central lab.  The central lab will batch ship all biospecimens to the US. 
5 Do not use glass blood collection tubes. 
 
10.5 
Biospecimen Selection for Exploratory Biomarker Testing (09/24/2019) (21-MAY-2021) 
(09-MAR-2022) (19-MAY-2022) 
Formalin-fixed, paraffin-embedded unstained sections for PD-L1 immunohistochemistry 
(IHC). Sections must be prepared using the Superfrost slides provided by PPD. 
 
PPD Laboratories will provide the one kit required to collect, prepare, and ship MMR and 
PD-L1 IHC samples for this study. 
 
***Note: There is an approximate 14 business day turnaround time between placing a 
kit request and receiving a kit. Please plan accordingly.*** 
 
10.5.1 Exploratory Biomarker Testing Requirements and Reporting (09-MAR-2022) 
 
Testing Requirements 
• All sites must submit patient tumor tissue for PD-L1 IHC.  The slides for this testing 
should be submitted with the slides for MMR IHC testing (12 slides total). 
 
Reporting 
• PD-L1 IHC results will be reported back to the NRG SDMC. 
 

 
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10.5.2 Method of Exploratory Biomarker Testing 
Immunohistochemistry 
PD-L1 22C3 PharmDx IHC assay will be used for assessment of PD-L1 expression. 
Investigational Use Only (IUO) kits to be provided by Agilent to Neogenomics for 
assessment of PD-L1 expression. (07-FEB-2020) 
 
Assay Performance 
Monoclonal mouse anti-PD-L1, clone 22C3, immunoreactivity was tested on a panel of 
neoplastic tissues including uterine adenocarcinoma (clear cell and endometrium) and 
squamous cell carcinoma. Plasma membrane staining was observed on immune cells and 
cells of epithelial origin. Cytoplasmic staining was noted in some cell types but was not 
recorded as positive staining. There were no unexpected results observed in the tumor 
biospecimens tested; observed staining was consistent with the reported literature for PD-L1 
IHC expression in neoplastic tissues. Clone 22C3 showed no immunoreactivity (plasma 
membrane staining, cytoplasmic staining, or non-specific staining) in normal uterus tissues. 
 
Scoring 
As per manufacturer’s instructions, PD-L1 expression using clone 22C3 is determined by 
Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, 
lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 
100. Theoretically, this score can be greater than 100, although the maximum value is capped 
at 100. All viable tumor cells on the entire tissue section must be evaluated and included in 
PD-L1 expression assessment; however, a minimum of 100 viable tumor cells must be 
present in the PD-L1 stained slide for the biospecimen to be considered adequate for 
evaluation. 
 
From previously published reports describing the clinical utility of CPS for PD-L1 
expression in biospecimens from patients with gastric and gastroesophageal junction 
adenocarcinoma (Kulangara, et al), external reproducibility assessments demonstrate 
interpathologist overall agreement of 96.6% (95% CI 94-98.7%) and intrapathologist overall 
agreement of 97.2% (95% CI 95.3-98.9%). Thus, CPS is a robust, reproducible PD-L1 
scoring method, which has been previously evaluated in a pan-tumor manner (e.g., using 
biospecimens from KEYNOTE-012, -028, and -059). Importantly, the clinical utility of CPS 
is underscored by the September 2017 FDA approval of pembrolizumab (MK-3475) for 
treatment of patients with PD-L1 expressing gastric or gastroesophageal junction 
adenocarcinomas. 
 
10.5.3 Location of Exploratory Biomarker Testing 
NeoGenomics Laboratories, Inc., Aliso Viejo, CA 
 
10.5.4 Biospecimen Submission for Exploratory Biomarker Testing (09/24/2019) (07-FEB-
2020) (21-MAY-2021) (09-MAR-2022) (19-MAY-2022) 
Refer to Appendix VIII for details. Note: Instructions for MMR IHC samples are listed in 
Biospecimen Submission for Integral Biomarker Testing (section 10.2.4). 
• Shipping supplies and instructions will be provided by PPD. 
• Three (4µm, charged) unstained sections of FFPE primary or metastatic tumor tissue 

 
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must be submitted for PD-L1 IHC. Sections must be prepared using the Superfrost slides 
provided by PPD.  
o The tumor lesion submitted must not have been previously irradiated. 
• Sections should be fresh cut within 48 hours of shipping from a block that is less than 
five years old. 
o A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, 
bone, bone marrow, cytologic specimen, decalcified, or formalin fixed sample that 
was frozen at any point will not be acceptable for analysis. 
o A minimum of 100 viable tumor cells is required for PD-L1 IHC; otherwise, the 
sample will be reported as “not evaluable.” If possible, samples with greater than 
50% tumor cellular content is preferred if available. 
• Each slide must be labeled with two identifiers. Label each slide with the NRG Patient 
ID and Block ID (i.e., Surgical Pathology number and block number). Serially number 
slides in the order they were sectioned with indelible ink. The same two identifiers must 
also be included on the Tissue Sample Transmittal Form. 
o Failure to include both identifiers on each slide and the Tissue Sample 
Transmittal Form will result in testing delays. 
• Unstained sections should be shipped directly to NeoGenomics Laboratories, Inc. 
(address below) Monday through Thursday only. 
o Sectioned slides should be shipped refrigerated year round. Refer to instructions 
provided by PPD for additional details. 
o A completed copy of the Tissue Sample Transmittal Form (a paper version of this 
form will be provided by PPD but should only be used when the Rave GY018 EDC 
System is not available to the site) and corresponding pathology report must be 
included. 
• Incomplete transmittal forms will cause processing delays. 
• Sites should retain a copy of the completed form for their records. 
 
• If the sponsor-designated laboratory is unable to obtain a result due to technical error and 
not due to the sample submitted, additional slides may be requested and used until a 
result is obtained. 
• See Appendix VIII for additional details. 
 
10.6 
Banking Biospecimens for Future Research 
 
Note: Additional integrated or exploratory biomarker testing of banked biospecimens will not 
occur until an amendment (integrated) to this treatment protocol or separate correlative 
science protocol (exploratory) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
Details regarding the banking and use of biospecimens for future research can be found in 
Appendix VI. 
 
 

 
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11. 
SPECIAL STUDIES (Non-Tissue) 
11.1 
Patient Reported Outcomes (PROs) in the pMMR population  
1. Quality of Life, as measured by the Functional Assessment of Cancer Therapy – 
Endometrial Trial Outcome Index (FACT-En-TOI). 
2. Fatigue, as measured by the 7-item Patient Reported Outcomes Measurement Information 
System (PROMIS) fatigue short form. 
3. Neurotoxicity, as measured by the FACT/GOG-Neurotoxicity (Ntx) 4-item subscale. 
4. Bother from side effects, as measured by a single-item GP5 “I am bothered by side 
effects of treatment,” rated on a 5-point Likert scale, is part of the FACT-G. 
5. Physical function as measured with the PROMIS-physical function scale short form (8c 
7-Day). 
 
Justification for PROs in NRG GY018 
 
NRG-GY018 is being proposed as a randomized phase III study examining paclitaxel and 
carboplatin combination chemotherapy with the checkpoint inhibitor, pembrolizumab (MK-
3475) or placebo, in patients with advanced stage or recurrent endometrial cancer. This 
proposal builds upon GOG-0209, which was a phase III clinical trial comparing the 
combination regimen of paclitaxel and carboplatin (TC) to TAP.  In this trial, investigators 
demonstrated less toxicity and small HRQoL differences favoring TC, and a non-inferior 
PFS and OS with the doublet regimen (Miller, 2012). Consequently, with demonstrated non-
inferiority to TAP, TC has emerged as the global first-line standard for advanced endometrial 
cancer. 
 
Moreover, immunotherapy has emerged as a therapeutic strategy in patients with advanced 
stage or recurrent EC (Vanderstraeten, 2014, Coosemans, 2014), and presents the opportunity 
to improve response rates and quality of life.  However, as noted by Langer (2016), 
pembrolizumab (MK-3475) with chemotherapy was recently tested on a small cohort of 
female patients, and in this trial, the most common treatment related adverse event of any 
grade was fatigue (64% pembrolizumab (MK-3475) + chemotherapy vs 40% chemotherapy 
alone).  While preclinical and clinical observations support the safety and efficacy of 
checkpoint inhibitors in combination with a cytotoxic chemotherapy backbone (paclitaxel 
and carboplatin) in patients with advanced stage or recurrent endometrial cancer, it is 
important to examine the potential HRQoL benefits and risks associated with this new 
therapeutic strategy within a Phase III trial for advanced or recurrent endometrial cancer 
patients.  
 
Patient-reported Outcomes Objectives & Hypotheses 
 
Building upon the results from GOG-0209, we will measure PROs in order to determine 
whether the addition of pembrolizumab (MK-3475)/placebo to standard combination 
chemotherapy is associated with improved physical function and quality of life due to 
decreasing disease burden and whether fatigue is significantly worse in the treatment arm 
containing pembrolizumab (MK-3475).  In addition, we will explore whether pembrolizumab 
(MK-3475) is associated with neurotoxicity since little is known about the effect of 
pembrolizumab (MK-3475) on peripheral neuropathy when combined with paclitaxel. We 

 
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will also explore whether there are overall between-arm differences on patients global self-
reported bother from side effects. 
 
We hypothesize that the addition of pembrolizumab (MK-3475) will improve the efficacy of 
paclitaxel and carboplatin in advanced stage and recurrent endometrial cancer patients with 
acceptable toxicity and an associated improvement in physical function and quality of life.  
Therefore the primary QOL question examines whether chemotherapy + pembrolizumab 
(MK-3475) is associated with improved physical function and quality of life due to its 
presumably enhanced anti-tumor effect, compared to chemotherapy + placebo.  An 
alternative and additional question is whether the possible increased toxicity of 
chemotherapy + pembrolizumab (MK-3475) will offset any advantages it may have over the 
chemotherapy backbone alone in clinical outcome (response rate, time to progression or 
survival). Further, it is reasonable to explore the extent to which any additional side effects 
might affect QOL (i.e., if fatigue for example is significantly worse for patients included in 
the pembrolizumab (MK-3475) arm, how does this affect their overall quality of life?).   
 
Patient Reported Outcomes and Assessment Intervals 
 
The PROs described below represent state-of-the-science HRQoL measurement for 
endometrial cancer trials, most recently demonstrated through GOG-0249 (M Randall et al, 
ASTRO 2017 Plenary; V von Gruenigen et al, ASCO 2018). Measures include the FACT-–
Endometrial Trial Outcome Index (FACT-En-TOI), the FACT/GOG-Neurotoxicity (Ntx) 4-
item Subscale, and a 7-item Patient Reported Outcomes Measurement Information System 
(PROMIS) fatigue short form. 
 
Quality of Life will be measured by the Functional Assessment of Cancer Therapy – 
Endometrial Trial Outcome Index (FACT-En-TOI).  The FACT Measurement system 
produces three subscales that are clinically relevant to the physical and functional issues of 
cancer patients, two of which are general, cutting across all cancers, one that is targeted to 
endometrial cancer.  The FACT-En TOI, comprised of a 7-item Physical Well-being (PWB) 
scale, a 7-item Functional Well-being (FWB) scale, and a 16-item Endometrial Cancer 
Subscale (ECS) will be analyzed as the primary comparison between treatment arms.  Bother 
from side effects, as measured by a single-item GP5 “I am bothered by side effects of 
treatment”, rated on a 5-point Likert scale, is part of the PWB, and will serve as an 
exploratory endpoint to further understand potential between-arm differences. Physical 
function will be measured with the 8-item PROMIS-physical function short form (8c 7-Day). 
 
Neurotoxicity will be measured by the FACT/GOG-Neurotoxicity (Ntx) 4-item scale.  This is 
a brief, reliable and valid assessment of pain, numbness and tingling in the extremities, and 
functional limitations caused by peripheral neuropathy from chemotherapy, and has been 
shown to be sensitive to treatment arm differences across numerous gynecologic oncology 
trials (Huang et al, 2007)). 
 
Fatigue will be measured by the 7-item PROMIS-Fatigue Short Form. A recent psychometric 
validation study conducted in cancer patients indicated that the PROMIS Cancer Fatigue 
Short Form items loaded on a single factor (CFI = 0.948), and the scale demonstrated good 

 
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internal consistency reliability in two cancer patient samples (Cronbach's alphas = 0.86). 
Correlations with psychosocial measures were significant (p values < .0001) and in the 
expected direction, offering evidence for convergent and concurrent validity. PROMIS 
Fatigue scores were significantly higher in patients who met case definition criteria for 
cancer-related fatigue (p < .0001), demonstrating criterion validity. This provides evidence 
that the PROMIS Cancer Fatigue Short Form is a reliable and valid measure of fatigue in 
cancer patients (Cessna et al, 2016). Validation analyses of this measure in the endometrial 
cancer patient population of GOG-0249 is currently underway, pending publication of the 
GOG-0249 clinical manuscript.  
 
Assessment Intervals (14-OCT-2020) 
All pMMR patients will be asked to complete a survey at five time points:  
1. Week 0. Baseline/prior to cycle 1. The baseline time point permits a pre-treatment status 
assessment. 
2. Week 6. Cycles 3 and 6 examine active treatment differences, in which disease may be 
responding and side effects may or may not differ between treatment arms. 
3. Week 18. Start of maintenance  
4. Week 30. Cycle 9 may indicate the chemotherapy recovery phase since patients are 15 
weeks from the last cytotoxic therapy.    
5. Week 54. Cycle 13 may represent the median PFS.      
 
Note that even if treatment stops early, assessments are to be completed at the same 
time the patient would have been scheduled to receive treatment (i.e., baseline, 6 weeks, 
etc).   
 
If treatment is delayed, conduct the assessment at the time the treatment is scheduled 
(not the time the treatment is actually given) so that the effect of the treatment on QOL 
or toxicities is measured.  IT IS ACCEPTABLE TO CONDUCT THESE 
ASSESSMENTS BY TELEPHONE.   
 
PRO Assessments will be completed through Medidata Patient Cloud 
ePRO (see Section 8.6) at the scheduled times, even for patients who are 
removed from study treatment. (07/03/2019) 
 
A Coversheet is always required even if assessment cannot be completed, in order to 
document reasons that the data were not captured. (08-DEC-2020) 
12. 
ASSESSMENT OF EFFECT  
12.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1). [Eur J Ca 45:228-247, 2009] Changes in the largest diameter (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.  
  
12.1.1 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately measured 

 
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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 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. 
 
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.  
 

 
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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. 
  
12.1.2  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. 
  
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 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 

 
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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. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when measurable disease has met criteria for response 
or stable disease. This confirmation is necessary to differentiate response or stable disease 
versus progressive disease, as an effusion may be a side effect of the treatment. 
 
12.2 
Response Criteria (07/03/2019) 
Determination of response should take into consideration all target (See 12.2.1) and non-
target lesions (See 12.2.2). 
 
12.2.1 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.  
 
12.2.2  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) Progressive Disease (PD): 

 
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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. 
  
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular time 
point. 
  
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). 
 
12.2.3 Evaluation of Best Overall 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 baseline). The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria in some circumstances. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., 
Target Disease) 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
 
Target 
Lesions 
Non-Target 
Lesions 
 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
 
No 
CR 
CR 
Non-CR/Non-PD 
 
No 
PR 
CR 
NE 
 
No 
PR 
PR 
Non-PD or NE 
 
No 
PR 
SD 
Non-PD or NE 
 
No 
SD 
NE 
Non-PD 
 
No 
NE 
PD 
Any 
 
Yes or No 
PD 
Any 
PD** 
 
Yes or No 
PD 
Any 
Any 
 
Yes 
PD 

 
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Time Point Response for Patients with only Non-Measurable Disease at baseline 
(i.e., Non-Target Disease) 
 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion 
 
** ‘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 
 
12.2.4 Best Overall Confirmed Response  
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error.  This will 
also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. 
 
However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies 
where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of results.  Therefore, for GY018, 
confirmation of response is not required. 
 
Time Point 
Response 
First time point 
Time Point Response
Subsequent time 
point 
BEST overall 
confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
Non-Target Lesions 
 
New Lesions* 
Time Point 
Response 
CR 
 
No 
CR 
CR 
 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
 
No 
Non-CR/non-PD* 
NE 
 
No 
NE 
Unequivocal PD 
 
Yes or No 
PD 
Any 
 
Yes 
PD 

 
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CR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
PR 
CR 
  PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD 
duration met, 
otherwise, NE 
NE 
NE 
NE 
 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR).  However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR 
or SD, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR or SD and the best response is PR or SD. 
 
In non-randomized trials where response is part of the primary endpoint, confirmation of 
CR or PR is needed to deem either one the “best overall response.”   Responses (CR and 
PR) require confirmation at greater than or equal to 4 weeks from initial 
documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment or 
die without objective evidence of disease progression at that time should be reported to be off 
study treatment due to “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
12.3 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 

 
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Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since date of study entry, including the baseline measurements. 
 
12.4 
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, or date of last contact if neither progression 
nor death has occurred. 
 
12.5 
Survival 
Survival is defined as the duration of time from study entry to time of death or the date of last 
contact. 
 
13. 
DATA AND RECORDS (24-FEB-2023) 
 
13.1 
NRG Data Management Forms 
Refer to the CTSU member website for the table of Required Forms and Materials. 
 
13.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of patients enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times during the trial using Medidata Rave®. Additionally, certain adverse 
events must be reported in an expedited manner for more timely monitoring of patient safety 
and care. See Sections 7.5.1, 7.5.1.1 and 7.6 for information about expedited and routine 
reporting.   
 
13.3 
Enhanced Centralized Monitoring 
 
13.3.1  Eligibility 
The source records which document the eligibility for the first patient enrolled from each site 
(as identified by a unique NCI identifier) will be reviewed for completeness and consistency 
with the eligibility criteria, the data reported during the enrollment process and the data 
reported on the case report forms (CRFs). Sites enrolling rapidly to the trial may undergo 
monitoring for up to three patients. 
For eligibility review, documents are to be submitted within two weeks of patient enrollment 
by uploading into the Auditing and Monitoring portal on the CTSU website.   
The pre-enrollment documents to be reviewed include: 
• Signed and dated consent forms will be submitted to review for signatures, date of 
consent, and patient consent to optional studies. 
• Baseline imaging reports to confirm RECIST measurable disease. 
• Medical history and physical examinations records and laboratory results, including all 
blood tests and pregnancy test when appropriate. 

 
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• Pathology report, including MMR IHC results, documenting histology of original 
primary tumor. (Note: institutional (local) MMR IHC results are not required for sites in 
Japan.) (08-DEC-2020) 
13.3.2 Drug Accountability, Drug-Dose Compliance, and Adverse Events (19-MAY-2022) 
The source records and adverse events (AEs) after the first 6 cycles of treatment (all 
treatment prior to maintenance phase) for the first patient enrolled at each site will be 
reviewed for compliance with the protocol, completeness and consistency with the data 
reported on the case report forms, and drug accountability records.   The documents listed 
below are to be uploaded to the Auditing and Monitoring portal on the CTSU website 
approximately 5 months after study enrollment. 
The documents to be reviewed include: 
• Study drug orders, treatment dose calculations and administration records. 
• Reports from protocol-directed laboratory studies. 
• Reports from any additional tests performed to document an adverse event. 
• All progress notes relating to pre-therapy history and physical and AE assessments 
• Summaries of hospital admissions and discharge for hospitalizations.  
• Summaries of surgical procedures performed. 
 
The review of pharmacy drug accountability records will be coordinated by the NRG 
Oncology monitor. Unblinded pharmacy records MUST NOT be uploaded to the CTSU 
website. Pharmacy records MUST only be shared by the designated unblinded personnel.  
 
13.4 
Enhanced Auditing (21-MAY-2021) 
• Additional Cases Audits 
During the audit visits that occur under the CTEP audit procedures, additional cases will 
be reviewed to ensure that all sites that enrolled patients to the Study will be selected for 
review. 
• Off Cycle Audits for High Accruing Sites 
Any individual site enrolling 5 or more patients will undergo an off-cycle site visit audit, 
in addition to their regularly scheduled audit, if that site is not due for a regular audit 
within 1 year of enrolling 5 or more patients. 
13.5 
Global Reporting/Monitoring (09/24/2019) 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  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 website  

 
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(http://ctep.cancer.gov/reporting/cdus.html). 
 
CDUS-Abbreviated reporting has been assigned to this study; no adverse event reporting 
(routine or expedited) is required to be reported via CDUS, but expedited adverse events are 
still required to be submitted via Rave-CTEP-AERS integration. 
 
14. 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design (07/03/2019) (09/24/2019) (19-MAY-2022) (30-SEP-2022) 
 
This is a study of two populations, making it essentially two clinical trials. One population 
under study has proficient mismatch repair (pMMR) as determined by a central laboratory. 
The other population has deficient mismatch repair (dMMR) as determined by a central 
laboratory. The primary alternative hypothesis for each population is that the addition of 
pembrolizumab (MK-3475) to the standard of care will prolong the time of progression-free 
survival (PFS). Patients will be randomized in a 1:1 fashion to treatment arms 1 and 2 after 
prospectively stratifying them by mismatch repair deficiency (yes versus no), performance 
status (0 or 1 versus 2), and prior chemotherapy (yes versus no). Block randomization will be 
used. Accrual will continue with MMR proficient (pMMR) patients until 590 are enrolled or 
medical judgement intervenes. The dMMR patients will continue to enroll until 220 of this 
population are accrued. When a population meets its accrual goals, further accrual to that 
population is to be avoided. Patients can enter according to their local MMR status, but the 
statistical analyses will be based the central laboratory determined MMR status. Patients who 
do not have a central MMR status will be excluded. 
 
An interim efficacy analysis will occur after the population (both pMMR and dMMR) 
completes accrual even if a sufficient number of PFS events are observed beforehand. An 
O’Brien-Fleming (OBF) type of stopping boundary will be used with a Lan-Demets alpha 
spending function. The spending function is provided below: 
 
𝛼(𝑡) = 2 ∗[1 −Φ(𝑧𝛼/2/√𝑡)] 
 
The total alpha for each population will start at 0.0125 one-sided. It is anticipated that 
approximately 70% or more of the information will be available at the time of the interim 
analysis for both populations. The accrual should complete in 29.5 months and 44 months for 
the pMMR and dMMR patients, respectively. If the interim analysis is conducted with 70% 
of the information, then the study should have 58% and 50% power to detect the alternative 
hypotheses for the respective populations (Ha: HR=0.70 for pMMR and Ha: HR=0.60 for 
dMMR). 
 
If accrual to both populations completes before 50% of the information time (IT) is acquired 
in either population, then the study will wait until at least 50% IT is obtained in that 
population before the efficacy interim analysis is conducted. Each population (the dMMR 
and the pMMR groups) will be evaluated separately and independently. If a population is at 
least 50% IT when the study closes to both populations, then the efficacy interim analysis for 
that population will be conducted at that time. In mathematical terms, the approximate timing 
of the efficacy interim analysis for population k is the maximum of the time when the study 

 
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closes to both populations and the time when population k has at least 50% of the planned 
information for the final analysis. 
 
If the null hypothesis for one group (e.g. dMMR) is rejected before the other group is tested, 
then all of the alpha (a total of 0.0125) will be forwarded to the other group (e.g. pMMR). 
The alpha spent on the other group using the OBF function will be adjusted according to the 
rules outlined by Maurer and Bretz (e.g. see their example on pages 317-8). In the case(s) 
where both null hypotheses are being tested at the same time (e.g. if both groups had more 
than 50% at the time of study closure to accrual), the null hypothesis associated with the 
dMMR population will be tested first, then followed by the pMMR population. If the null 
hypothesis can be rejected for the dMMR population, then its alpha will be forwarded. 
Otherwise, the order of testing will be dictated by the timing of data maturation and the alpha 
forwarded as appropriate. 
 
Patients within the pMMR group will be monitored until 394 have disease progression or die 
(PFS endpoint) for a final efficacy analysis. The null hypothesis of equal hazard rates (i.e. 
Ho: HR = 1.0) will be tested with a one-sided log-rank test. If the true hazard ratio is 0.70 
(i.e. Ha: HR = 0.70), then the study has at least 90% power of detecting this effect. The data 
in this group are expected to mature for a final analysis somewhere between 36 months and 
41 months after study activation assuming a conservative accrual rate of 20 patients per 
month. 
 
Patients within the dMMR group will be monitored until 168 PFS events occur. The null 
hypothesis of equal hazard rates (i.e. Ho: HR = 1.0) will be tested. If the true hazard ratio is 
0.60 (i.e. Ha: HR = 0.60), then the study has at least 85% power of detecting this effect. The 
data in this group are expected to mature somewhere between 55 months and 68 months after 
study activation assuming a conservative accrual rate of 5 patients per month. 
 
14.2 
Study Endpoints 
 
Primary 
 
1.  Progression-free survival (PFS) 
 
Secondary 
 
1. Adverse events as assessed by CTCAE. 
2. Objective tumor response as assessed by RECIST 1.1. 
3. Duration of objective response (the time difference between the dates of first response 
and first progression; patients who do not progress are considered censored). 
4. Overall Survival (OS). 
5. Quality of life (QOL) and patient-reported outcomes (PROs), measured by the FACT-En-
TOI, the FACT/GOG-Ntx subscale (short), PROMIS-Fatigue (short form), the PROMIS-
physical function (short form) and a single-item measuring bother from side effects of 
cancer therapy. 
6. Pembrolizumab (MK-3475) treatment and self-reported neurotoxicity with FACT/GOG-

 
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Ntx. 
7. Concordance between institutional MMR IHC testing and centralized MMR IHC. 
8. The effect of pembrolizumab (MK-3475) on PFS and OS by PD-L1 IHC (combined 
positive score (CPS)) within pMMR and dMMR populations. 
9. Measures of association between PD-L1 IHC (CPS) and MMR status. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints 
1.  The null hypotheses are that the hazard ratios of experimental to control regimens are 
equal to 1 versus the alternative hypotheses that the hazard ratios are less than 1 (i.e. 
𝐻0: 𝐻𝑅 ≥1 versus 𝐻1: 𝐻𝑅< 1). The endpoint for these hypotheses is PFS. 
14.3.2 How Primary Endpoints Will Be Analyzed 
1. The primary hypotheses will be tested with a stratified log-rank statistic. The distribution 
of these statistics will be approximately normally distributed, and this assumption will be 
used to draw inferences about regimen activity. 
14.3.3 Sample Size and Power Calculations: (19-MAY-2022) 
 
A first approximation to the number of events required in order to have a study with 
probability of type I error (𝛼) and power (1 −𝛽) is given by Schoenfeld’s equation: 
 
 
 
 
 
 
𝐷= 4(𝑍𝛼+ 𝑍1−𝛽)
2
(𝑙𝑛{𝐻𝑅})2
 
 
 
The values of alpha are 0.0125 for each population. If one analysis rejects the null 
hypothesis, alpha will be forwarded to the other population so that it can be tested at a higher 
level of significance. The value of beta is 10% (power = 1 – 0.10 = 0.90 or 90%) for the 
pMMR population when testing at the 0.0125 level. For the dMMR population, beta is 15% 
when testing at the 0.0125 level.   
 
Based on historical data within NRG Oncology (studies not published), we have the 
following models for PFS and OS: 
 
 
𝑆𝑝(𝑡) = 0.90𝑒𝑥𝑝(−0.07 𝑡) + 0.10 
 
𝑆𝑠(𝑡) = 0.90𝑒𝑥𝑝(−0.03244 𝑡) + 0.10 
 
The data indicate that the population under consideration has about 10% who do not progress 
or die for a long time. Using these models, the expected median PFS time is about 11.6 
months whereas the median OS is about 25 months in the reference arm. If the investigative 
regimen reduces the hazard of PFS by 0.70 relative to the reference regimen (proportional 
hazards), then the median PFS is delayed to 17 months (a 5.4 month delay). Likewise, if the 
investigative regimen reduces the hazard of death by 0.7 (proportional hazards), then the 
median OS is delayed to 36.9 months (11.9 months or almost a full year). This effect would 

 
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be considered by many investigators to be a substantial impact on OS. However, a 30% 
reduction in the hazard rate is somewhat small so fairly large samples are necessary to detect 
it. 
 
Using Schoenfeld’s equation with the PFS parameters, we obtain 𝑍𝛼= 2.241, 𝑍1−𝛽=
1.282, and 𝐷= 392 at a HR=0.70. To assure that the observation of 392 PFS events occurs 
in a reasonable timeframe, we plan on accruing 590 patients. Likewise for the dMMR 
patients, 𝑍𝛼= 2.241, 𝑍1−𝛽= 1.036, and 𝐷= 168  at a HR=0.60. To assure that the 
observation of 168 PFS events occurs in a reasonable timeframe, we plan on accruing 220 
patients. 
 
A plot of the reference regimen’s anticipated survival functions are provided below: 
 
 
 
Figure:  Progression-free survival (PFS) and overall survival (OS) functions against 
months of study entry. 
 
As indicated by the graph, almost 20% of the patients survive beyond 6 years. The proportion 
of long term progression-free survival patients is 10% in the reference regimen. If a 
proportional hazards assumption is assumed, then we expect 0.100.70 = 0.20 or 20% to 
survive progression-free for a long time when the HR is 0.70. Additionally, if the HR = 0.60, 
then we expect 25% of the patients to survive progression-free long term. If the experimental 
regimen does not produce this effect, the proportional hazards assumption will be violated. If 
the survival function for the experimental arm approaches the survival function for the 
reference regimen in the long term, the estimated hazard ratio is a function of follow-up time. 
Often the test becomes less significant the longer the investigators wait to conduct an 
analysis. 
 
An O’Brien-Fleming type of stopping boundary will be used with a Lan-Demets alpha 
spending function for a single efficacy interim analysis in each population (both pMMR and 
0
10
20
30
40
50
60
70
0.2
0.4
0.6
0.8
1.0
O S
P F S

 
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dMMR). The interim analysis necessitates a slight boost to the total number of events for the 
pMMR group, which is 394. The dMMR group requires roughly the same number of PFS 
events relative to the Schoenfeld estimate (i.e. 168 PFS events). (07/03/2019) (09/24/2019) 
 
14.4 
Study Monitoring of Primary Objectives (09/24/2019) (19-MAY-2022) (30-SEP-2022) 
(Interim Analysis) 
 
 
An interim futility analysis is planned for the pMMR group. At 50% information time (i.e. at 
approximately 196 PFS events), a Wieand type futility rule will be applied. That is, if the 
log-rank test statistic (experimental to reference) before squaring is greater than zero 
indicating a higher risk of eventing on the experimental arm, then the study will consider 
early termination for this population. If the null hypothesis is true, then the study has a 50% 
probability of early termination. The chance of this event is rare under the alternative 
hypothesis (e.g. 1 −Φ(−√𝐷∙𝑙𝑛{𝐻𝑅}/2) ) which is 0.0063 when the HR = 0.70. See 
Wieand et al. for further discussion. The timing of the interim futility analysis is expected to 
occur sometime between 22 and 24 months after activation. 
 
An interim futility analysis is also planned for the dMMR group. At 50% information time 
which is after 84 PFS events, a separate Wieand type futility rule will be applied. As before, 
if the log-rank test statistic (experimental to reference) before squaring is greater than zero 
indicating a higher risk of eventing on the experimental arm, then the study will consider 
early termination for this population. If the null hypothesis is true, then the study has a 50% 
probability of early termination. The chances of early termination are small when the HR = 
0.60 (about 0.01). The impact of the interim analysis on final power is minimal even when 
the HR=0.70. The timing of the interim analysis is expected to occur sometime between 32 
and 35 months after activation. 
 
An interim efficacy analysis will occur after the population (both pMMR and dMMR) 
completes accrual even if a sufficient number of PFS events are observed beforehand.  A 
“sufficient number” is defined as 50% information time. An O’Brien-Fleming type of 
stopping boundary will be used with a Lan-Demets alpha spending function. The spending 
function is provided below: 
 
𝛼(𝑡) = 2 ∗[1 −Φ(𝑧𝛼/2/√𝑡)] 
 
The total alpha for each population will start at 0.0125. It is anticipated that approximately 
70% or more of the information will be available at the time of the interim analysis for both 
populations. The accrual should complete in 29.5 months and 44 months for the pMMR and 
dMMR patients, respectively. If the interim analysis is conducted with 70% of the 
information, then the study will spend about 0.003 alpha (Z=2.765) and should have 58% and 
50% power to detect the alternative hypotheses for the respective populations (Ha: HR=0.70 
for pMMR and Ha: HR=0.60 for dMMR). 
 
If accrual to both populations completes before 50% of the information time (IT) is acquired 
in either population, then the study will wait until at least 50% IT is obtained in that 
population before the efficacy interim analysis is conducted. Each population (the dMMR 

 
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and the pMMR groups) will be evaluated separately and independently. If a population is at 
least 50% IT when the study closes to both populations, then the efficacy interim analysis for 
that population will be conducted at that time. In mathematical terms, the approximate timing 
of the efficacy interim analysis for population k is the maximum of the time when the study 
closes to both populations and the time when population k has at least 50% of the planned 
information for the final analysis. 
 
If the null hypothesis for one group is rejected before the other group is tested, then all of the 
alpha (a total of 0.0125) will be forwarded to the other group. The alpha spent on the other 
group using the OBF function will be adjusted according to the rules outlined by Maurer and 
Bretz (e.g. see their example on pages 317-8). In the case(s) where both null hypotheses are 
being tested at the same time (e.g. if both groups had more than 50% at the time of study 
closure to accrual), the null hypothesis associated with the dMMR population will be tested 
first, then followed by the pMMR population. If the null hypothesis can be rejected for the 
dMMR population, then its alpha will be forwarded. Otherwise, the order of testing will be 
dictated by the timing of data maturation and the alpha forwarded as appropriate. 
 
In each group, at the time of the final PFS analysis (significant interim or final analysis), an 
interim OS futility analysis will be performed and the (OS interim analysis) results released 
along with the PFS results, at that time. The null hypothesis of Ho: HR = 1.0 will be tested 
against the one-sided alternative Ha: HR > 1.0 at the 10% level of significance. Rejection of 
Ho would be indicative of a concern for worse OS in the experimental arm. We anticipate 
about 250 deaths in the pMMR group and 115 deaths in the dMMR group at their respective 
final PFS analysis. The final OS analysis will be performed when about 364 (150) OS events 
are observed in pMMR (dMMR) group, respectively. This corresponds to about 60 and 86 
months after trial activation in the pMMR and dMMR groups respectively. 
 
Interim Monitoring by the DMC  
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.  
 
Compliance with follow-up and patients lost to follow-up during the maintenance phase after 
unblinding will be carefully monitored by the NRG Oncology Data Monitoring Committee. 
(14-OCT-2020) (21-MAY-2021) 
 
14.5 
Accrual/Study Duration Considerations 
 
  
The maximal accrual rate for GOG 286B was about 25 patients per month. We believe this 
accrual can be attained on this study and may accrue at a higher rate due to expanded 
eligibility and increased participation in other countries. The accrual goal is 590 patients with 
proficient MMR tumors and 220 patients with deficient MMR tumors. The period of active 
accrual to the pMMR group is expected to be 29.5 months. The period of active accrual to 
the dMMR is expected to be about 44 months.  
 

 
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14.6 
Secondary or Exploratory Endpoints (including correlative science aims) (07/03/2019) 
(09-MAR-2022) 
 
These tests will be 1-sided.  The power of a test of the null hypothesis of equal hazards 
across both treatments can be approximated with: 
 
𝑃𝑜𝑤𝑒𝑟= Φ [−𝜃√𝐷
2
−1.645] 
 
 
where D is the number of events/deaths and 𝜃= 𝑙𝑛(𝐻𝑅).  
 
Toxicities will be screened for differences between treatments by using an exact method or a 
Chi-Sq test. For a given adverse event, each patient will be graded according to the worse 
grade experienced while on therapy (and within 30 days of treatment). These toxicities will 
then be divided into two or three categories such as mild, moderate, and severe or mild to 
moderate versus severe. The rates of severe toxicities may be characterized by risk ratios or 
odds ratios with confidence intervals (unadjusted for multiplicity). The number of toxicities 
examined is usually fairly large, so these analyses will be considered exploratory and may be 
inspected in light of other studies. 
 
Historical data on GOG 286B indicate that between 50 and 70% of patients were evaluable 
for response. That translates to about 300 to 400 pMMR patients with measurable disease on 
this study. The probability of response on the reference regimen should be about 20%. The 
power of the study to detect an increase in the probability of response by 15% should be at 
least 88% (e.g. Ho: p1 = p2 = 0.20 versus Ha: p1 + 0.15 <= p2; n1 = n2 = 150). This test can 
be carried out with a Fisher’s Exact Test. The duration of response will be characterized and 
compared by treatment with KM curves. No formal testing will be done. 
 
The patient’s MMR IHC status will be assessed for prognostic value by conducting stratified 
log-rank tests or Cox Proportional Hazards (PH) modeling when assessing the impact on PFS 
or OS. When assessing the impact on the probability of response, a logistic regression model 
will be considered and include other pertinent variables that may influence response.  
 
Assessing the predictive value of MMR IHC status for regimen efficacy is generally 
considered more challenging due to low statistical power even in large sample sizes such as 
the one given by this study. The lack of balance between MMR proficient and dMMR makes 
the success of this study less likely (if there is one actually present). A Cox PH model will be 
used to assess this effect through an interaction term. A similar type of analysis may be 
attempted with response using logistic regression. 
 
The concordance of institutional MMR IHC testing and centralized MMR IHC will be 
characterized by agreement statistics such as kappa statistics (e.g. Cohen’s kappa 
coefficient). 
 
The effectiveness of pembrolizumab (MK-3475) will be compared by PD-L1 status (CPS). A 

 
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formal test will be conducted by examining the interaction term between pembrolizumab 
(MK-3475) treatment (yes or no) with PD-L1 status. Since these tests often have poor power, 
descriptive examinations of the HR for pembrolizumab (MK-3475) treatment can be 
provided in subset analyses by PD-L1 CPS assessment. If the association between PD-L1 
status is highly associated with MMR IHC status, it may not be possible to do separate 
analyses within the MMR IHC groups. In this case, the analyses will be conducted by 
pooling the MMR IHC groups together. 
 
The association between PD-L1 CPS status and MMR IHC status will be assessed with odds 
ratios. A test may be conducted with a Fisher’s Exact Test, and confidence intervals will be 
provided. 
 
14.6.1 Secondary Hypotheses and Endpoints: The expected level of detail for secondary hypotheses 
will be less than for the primary hypothesis and endpoint. 
 
The secondary endpoints are listed in section 14.2. The null hypothesis for secondary 
objective 1 is that the probability of having a severe toxicity in the treatment regimen is the 
same as in the reference regimen. The null hypothesis for secondary objective 2 is that the 
probability of response in the treatment regimen is the same as in the reference regimen. The 
null hypothesis for secondary objective 4 is that OS is the same by MMR IHC status. 
Another null hypothesis for this objective is that MMR IHC status does not interact with 
treatment to produce a differential impact on OS. In this case, MMR IHC status may be 
prognostic but still not predictive. The null hypothesis for objective 8 is that the hazard ratio 
for pembrolizumab (MK-3475) treatment to placebo treatment is the same irrespective of 
PD-L1 CPS (<1 and  1). This hypothesis may be evaluated separately within the pMMR and 
dMMR groups if there is a sufficient number of PD-L1 groups in each subset. If the 
association between PD-L1 and MMR IHC status is very high, then MMR IHC status may be 
ignored. The null hypothesis for objective 9 is that the odds ratio of PD-L1 and MMR IHC 
status is 1.0. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
See sections 14.2 and 14.6. 
 
14.6.3 Interim Analysis for All Other Endpoints  
 
 
See section 14.4. 
 
14.6.4 Power Calculations: power can be provided as applicable for selected secondary endpoints, if 
any. The power is based on the sample size for the primary endpoints. 
 
See section 14.6. 
 
14.6.5 Expected Sample Size or Patient Cohorts:  
 
See sections 14.3.3 and 14.5. 

 
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14.6.6 Patient reported outcome (PROs) (08-DEC-2020) 
The QOL/PRO hypotheses are to assess whether the patient-reported quality of life (QoL), 
physical function, and fatigue are different when adding pembrolizumab (MK-3475) to 
chemotherapy (carboplatin + paclitaxel) during treatment and maintenance period. Due to the 
lack of sufficient statistical power in the dMMR group, the analysis for QOL/PRO will be 
conducted only in the pMMR patient population. 
 
The QOL/PRO endpoints are the patient-reported QoL as measured with the FACT-En TOI, 
physical function as measured with the PROMIS-physical function short form, fatigue as 
measured with the PROMIS-Fatigue (short form), and neurotoxicity symptoms as measured 
with the FACT/GOG-Ntx subscale (short). Items in the FACT-En TOI and the FACT/GOG-
Ntx subscale (short) are scored using a 5-point scale (0 = not at all; 1=a little bit; 2 = 
somewhat; 3 = quite a bit; 4 = very much).  According to the FACIT measurement system, a 
subscale score was the summation of the individual item scores if more than 50% of subscale 
items were answered.  Negative statements (or questions) were reversed prior to score 
calculation. When unanswered items existed, a subscale score was prorated by multiplying 
the mean of the answered item scores by the number of items in the subscale.  A total FACT-
En TOI score is the sum of the subscale scores if more than 80% of the FACT-En TOI items 
provide valid answers. The items in the PROMIS-Fatigue short form are rated on a five-point 
scale (1=never; 2=rarely; 3=sometimes; 4=often; 5=always).  A PROMIS Fatigue score and a 
PROMIS physical function score are calculated by summating the item scores. In case some 
items are not answered or the answers are invalid, a PROMIS-Fatigue score will be imputed 
using the same method described in FACIT measurement system. A PROMIS-Fatigue score 
and a PROMIS physical function score ranges from 7 to 35 and from 8-40 respectively, 
which both can be converted to the PROMIS Scale scores. 
 
The QOL/PRO endpoints will be compared at 6 weeks  (pre-cycle 3), 18 weeks (pre-cycle 6), 
30 weeks (pre-cycle 9), and 54 weeks (pre-cycle 13) post the starting of protocol 
chemotherapy. However, death, illness, noncompliance, and missed appointment can cause 
missing information that increases over time. A patient is considered evaluable for 
QOL/PRO analysis if she provides valid baseline and at least one follow-up QOL/PRO 
assessments. At least 80% evaluable patients are expected for the QOL/PRO analysis.  
 
A linear mixed model for repeated measures will be used to estimate and compare the mean 
differences between the treatment groups.  Model covariates will include the patients’ 
randomly assigned study treatment, age at enrollment onto the study, pre-treatment 
QOL/PRO score, assessment time and treatment-by-time interaction. The stratification 
factors will be the same factors included in the clinical primary analysis.  Hochberg’s step-up 
multiple testing procedure (Hochberg, 1988) will be used to adjust p-values for each 
assessment time points estimated from the fitted model.  
 
QOL/PRO will not be used for labeling purposes. They will be considered as supplemental 
information. Therefore the QOL/PRO will be tested at a significant level of 5% (two-sided). 
To control the overall type I error for the multiple QOL/PRO endpoints (the FACT-En TOI, 
PROMIS-Physical function, and the PROMIS-Fatigue short form), each of the QOL/PRO 
endpoints will be tested at a significant level of 1.67% (two-sided).  

 
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Exploratory analyses will be conducted to explore whether pembrolizumab (MK-3475) is 
associated with patient-reported neurotoxicity symptoms and whether patients are bothered 
more from side effects when adding pembrolizumab (MK-3475) to chemotherapy and will be 
examined at significant level of 5% respectively. 
Missing PRO information 
Patient death, noncompliance, missed clinic appointments, and patient illiteracy can cause 
observations to be missed.  One or more of the PRO assessments may be missing for an 
individual on any occasion.  Missing information is troublesome particularly in studies 
involving repeated patient assessments.  The frequency that assessments are missed will be 
monitored every 6 months throughout the study.  Study Coordinators will be working with 
the Study Team and the NRG’s Patient Centered Outcomes Research Committee to identify 
reasons that data are missing and recommending remedial actions when possible. 
  
The PRO instruments used in this study have been translated to different languages (Spanish, 
French).  Women who are unable to read or have difficulty reading, will not be required to 
participate in the PRO component of this study, however, a woman may elect to have the 
items read to her and be assisted in completing the instruments. 
 
14.7 
Exploratory Hypothesis and Endpoints (07/03/2019) 
 
 
Exploratory Hypotheses and endpoints are discussed in sections 14.2 and 14.6.1. 
 
14.8 
Gender/Ethnicity/Race Distribution (21-MAY-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 
6 
 
0 
 
6 
Asian 
17 
 
0 
 
17 
Native Hawaiian or Other 
Pacific Islander 
1 
 
0 
 
1 
Black or African American 
78 
 
0 
 
78 
White  
452 
 
23 
 
475 
More Than One Race 
12 
 
4 
 
16 
Total 
566 
0 
27 
0 
593 
 
 
 

 
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Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
5 
 
0 
 
5 
Asian 
145 
 
0 
 
145 
Native Hawaiian or Other 
Pacific Islander 
0 
 
0 
 
0 
Black or African American 
0 
 
0 
 
0 
White  
67 
 
0 
 
67 
More Than One Race 
0 
 
0 
 
0 
Total 
217 
 
0 
 
217 
 
 
15. 
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APPENDIX I - CARCINOMA OF THE ENDOMETRIUM FIGO CLASSIFICATION 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 II – 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 III- CARBOPLATIN DOSE CALCULATION INSTRUCTIONS (09/24/2019) 
(07-FEB-2020) (21-MAY-2021) 
 
1) The Cockcroft-Gault formula will be used in NRG Oncology trials. 
 
Dosing of Carboplatin: 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) according to the 
Calvert formula using creatinine clearance (mL/min) from the Cockcroft-Gault formula. 
 
2) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine clearance should 
be estimated using a minimum value of 0.7 mg/dL.   
 
3) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity greater than 
or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring dose modification, the 
dose of carboplatin will not need to be recalculated for subsequent cycles, but will be subject to dose 
modification for toxicity as noted in the protocol. 
 
4) Carboplatin doses are recommended to be recalculated if the patient has a weight change of greater than 
or equal to 10%. Patients are permitted to have chemotherapy doses recalculated for < 10% weight 
changes. 
 
5) At the time of dose modification, if the patient’s age had changed (the patient has had a birthday), the site 
can use the current age. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR [or estimated CrCl] + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated creatinine 
clearance. The estimated creatinine clearance (mL/min) is calculated by the method of Cockcroft-
Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x actual body Weight* (kg)   {x 0.85 if female}  
                                                                
72 x serum creatinine (mg/dl)  
 
Notes: 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient. 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater than 
or equal to 25  

 
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d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) (+ 45.5 females) or (+ 50 for men)  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time of a 
dose modification is higher than the creatinine used to calculate the previous dose, use the current 
(higher) creatinine. This will ensure that the patient is actually receiving a dose 
reduction. 
 
 
 
 
 

 
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APPENDIX IV – GENERAL TREATMENT GUIDELINES (14-OCT-2020) (21-MAY-2021) 
 
 
• For cycle lengths greater than or equal to 21 days, a patient will be permitted to have 
a new cycle of chemotherapy delayed up to 7 days (without being considered a 
protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled).  Documentation to 
justify this decision should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window before and after the protocol-defined date” for “Day 1” treatment of 21-
day or greater cycles.  If the treatment due date is a Friday, and the patient cannot be 
treated on that Friday, then the window for treatment would include the Thursday (1 
day earlier than due) through the Monday (day 3 past due). 
• Chemotherapy doses can be “rounded” according to institutional standards without 
being considered a protocol violation (most institutions use a rule of approximately 
+/- 5% of the calculated dose). 
• Chemotherapy doses are recommended to be recalculated if the patient has a weight 
change of greater than or equal to 10%.  Patients are permitted to have chemotherapy 
doses recalculated for < 10% weight changes. 

 
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APPENDIX V - CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent supplied by CTEP, DCTD, NCI used in this protocol is 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 

 
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described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
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: 
 
E-mail: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 

 
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APPENDIX VI - TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES (21-MAY-
2021) (09-MAR-2022) 
 
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 if you need assistance (support@nrgoncology.org). 
 
II. Requesting Translational Science Biospecimen Kits 
One single chamber kit will be provided per patient for the collection and shipment of frozen whole 
blood; however, whole blood from more than one patient may be shipped together in one kit. 
 
Sites can order kits online via the Kit Management link (https://kits.bpc-apps.nchri.org/). Each site may 
order two kits per protocol per day (daily max = 6 kits).  
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should arrive 
within 3-5 business days. 
 
Note: Unused materials and kits should be returned to the NRG BB-Columbus. A pre-paid shipping 
label for the return of unused supplies and kits may be obtained via the Kit Management system. Select 
“Empty Kit” for package contents when returning unused kits. 
 
Sites in Korea and Japan: Translational science biospecimen kits are not provided by the NRG BB-
Columbus for sites in Korea and Japan. 
 
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). 
 
o Archival primary (FP01) and metastatic (FM01) tumor should be collected prior to the patient 
receiving any treatment. 
 
o 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. 
 
o Primary neoadjuvant (FPT01) and metastatic neoadjuvant (FMT01) tumor should be 

 
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collected after the patient receives neoadjuvant treatment. Neoadjuvant tumor should only be 
submitted if tumor collected prior to receiving any treatment (FP01 or FM01) is not available.  
 
• Only one block may be submitted per tissue type. 
 
• All FFPE tissue should be submitted with the corresponding pathology report, a completed copy 
of the FFPE Materials Verification Form (Appendix X), and an electronically-completed copy of 
Form TR. 
o Sites in Korea and Japan must provide an English translated copy of the corresponding 
pathology report. Note: The entire report must be translated, typed, and include diagnosis, 
clinical history, gross description or block number, and microscopic findings. 
 
FFPE Biospecimen Requirement 
Every attempt should be made to provide a block on a permanent basis; however, if a block cannot be 
provided on a permanent basis, then 10 unstained slides (charged, 5µm) should be submitted.  All tissue 
sections should be cut sequentially from the same block.  
 
Labeling FFPE Tissue 
A waterproof permanent marker or printed label should be used to label each translational science tissue 
biospecimen with: 
 
  
* Leading zeros may be omitted when labeling biospecimens with the Bank ID.  For example, 
N000000010 may be written as N10. 
 
Failure to label biospecimens with all data fields shown in the sample label above may result in 
delayed processing and/or inability to utilize biospecimens. 
 
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. Do not use glass blood collection tubes. 
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. Immediately freeze the whole blood in an upright position in a -70oC to -80oC freezer or by direct 
exposure with dry ice until ready to ship. If a -70oC to -80oC freezer is not available for storage, store 
and ship on dry ice within 24 hours of collection. Sites in Korea and Japan should ship to the 
respective central lab within 5 weeks of patient registration. 
 
Labeling Whole Blood 

 
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A waterproof permanent marker or printed label should be used to label each translational science whole 
blood biospecimen with: 
 
 
* Leading zeros may be omitted when labeling biospecimens with the Bank ID.  For example, 
N000000010 may be written as N10. 
 
Failure to label biospecimens with all data fields shown in the sample label above may result in 
delayed processing and/or inability to utilize biospecimens. 
 
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 Folder) has been 
completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each biospecimen shipped to 
the NRG BB-Columbus. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the NRG BB-Columbus if biospecimens are not collected. 
 
Form TR 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.  
  
Retain a printout of the completed form for your records. 
  
Please contact User Support if you need assistance (Email: support@nrgoncology.org). 
 
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-GY018 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 

 
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Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Sites in Korea and Japan should ship to the respective central lab. The central lab will batch ship all 
biospecimens to the US. 
 
A. FFPE Tissue Shipped to the NRG BB-Columbus 
FFPE tissue, a copy of the corresponding pathology report, and a completed copy of the FFPE Materials 
Verification Form (Appendix X) 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. 
 
B. Whole Blood Shipped to the NRG BB-Columbus 
Frozen whole blood should be shipped using the biospecimen kit provided to the NRG BB-Columbus 
(address above). 
 
Frozen biospecimens should be shipped Monday through Thursday for Tuesday through Friday 
delivery. Do not ship frozen biospecimens on Friday or the day before a holiday. Note: Saturday 
delivery is not available for frozen biospecimens.  
 
Frozen biospecimens should be stored in an ultra-cold freezing/storage space (i.e., ultra-cold ≤-70oC 
freezer, liquid nitrogen, or direct exposure with dry ice) until the biospecimens can be shipped. 
 
Shipping Frozen Translational Science Biospecimens in a Single Chamber Kit  
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen whole blood in a zip-lock bag. If whole blood from more than one patient is 
included in the same shipment, then place the whole blood from each patient in a separate zip-lock 
bag. 
3. Place the zip-lock bags in the biohazard envelope containing absorbent material. Put the secondary 
envelope into a Tyvek envelope. Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen biospecimens into the kit and fill the chamber to the 
top with dry ice. 
5. Insert a copy of Form TR for each biospecimen.  
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament or other durable 
sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management link ( (https:/kits.bpc-apps.nchri.org/ ). 
Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your site’s usual procedure or by calling 800-238-5355. 
 
VII. Banking Translational Science Biospecimens for Future Research (09-MAR-2022) 
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 their biospecimens for future health research. 
 

 
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Note: Biomarker testing of banked biospecimens will not occur until an amendment to this treatment 
protocol or separate correlative science protocol is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent document 
and electronically via the Specimen Consent form. At the time of biospecimen selection for project 
distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of their biospecimens at any time if 
the patient changes their mind. 
 
If the patient revokes permission to use their 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 their 
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:  DIAGNOSTIC IMAGE COLLECTION SUMMARY (07/03/2019) (14-OCT-
2020) (09-MAR-2022) (24-FEB-2023) 
 
Approximate scan collection per subject: 
a. ~5 scans per year up to 9 months or until progression 
b. After 9 months: ~4 scans per year until progression 
1. CT scan or MRI performed once every 9 weeks (+/- 7 days), and at any other time if clinically 
indicated based on symptoms or physical signs suggestive of progressive disease.  Imaging 
assessments can be discontinued if disease progression. 
2. If a patient discontinues study treatment for any reason other than progression, imaging studies 
should continue every 9 weeks (+/- 7 days) for the first 9 months, then every 12 weeks (+/- 14 
days) thereafter until progression. See Sections 4.2/4.3. 
 
TRIAD Digital Image Submission: 
Transfer of Images Data (TRIAD) is the American College of Radiology (ACR) image exchange 
application. TRIAD provides sites participating in clinical trials a secure method to transmit images.  
TRIAD anonymizes and validates images as they are transferred. 
 
TRIAD will be the sole means of image transfer to the IROC Philadelphia DI. TRIAD should be 
installed prior to study participant enrollment to ensure prompt secure, electronic submission of imaging. 
 
TRIAD Access Requirements: 
 
• A valid CTEP-IAM account and linked ID.me account (ID.me accounts are required for all 
newly created CTEP-IAM accounts and by July 1, 2023 for all users);  
• Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator (NPIVR), 
or Investigator (IVR). Refer to the CTEP Registration Procedures section (Section 8.1) for 
instructions on how to request a CTEP-IAM account and complete registration in RCR; and 
• TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
 
All individuals on the Imaging and Radiation Oncology Core provider roster have access to TRIAD, and 
may submit images for credentialing purposes, or for enrollments to which the provider is linked in 
OPEN. 
 
TRIAD Installation: 
 
To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD 
application on their workstation.  TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/  
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email: TRIAD-Support@acr.org or 1-703-
390-9858.  

 
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APPENDIX VIII –CENTRALIZED MMR IHC TESTING LABORATORY MANUAL (07-FEB-
2020) (21-MAY-2021) (09-MAR-2022) (19-MAY-2022) 
 
1. 
BIOSPECIMEN COLLECTION TABLE 
 
2. 
RATIONALE FOR COLLECTION 
The collection of archival tumor sectioned slides is for the purpose of MMR and PD-L1 IHC 
biomarker analysis. Submission of required slides for MMR and PD-L1 IHC simultaneously 
allows for more efficient utilization and processing of tissue samples on trial. 
 
3. 
GENERAL OVERVIEW AND RECOMMENDATIONS 
 
3.1 
SAMPLE REQUIREMENTS 
Sample 
Archival Formalin-Fixed, Paraffin-Embedded (FFPE) 
Tumor Tissue (slides) 
Time points 
Screening 
# samples per time point 
12 unstained slides (each 4 micron in thickness) from FFPE block 
Label 
Each slide must be labeled with two identifiers. Label each 
slide with the NRG Patient ID and Block ID (i.e., Surgical 
Pathology number and block number). Serially number slides in 
the order they were sectioned with indelible ink. The same two 
identifiers must also be included on the Tissue Sample 
Transmittal Form. 
Process 
Archival tissue samples should be submitted as freshly cut slides. 
Slides must be sent within 48 hours of sectioning to 
NeoGenomics Laboratories, Inc. 
 
Sections must be prepared using the Superfrost slides 
provided by PPD. 
   
Place slides in the plastic slide holder provided; put foam pad on 
top of slides. Tape shut and wrap plastic slide holder with bubble 
wrap. Place bubble wrapped slide holder in biohazard bag. 
 
Package slides with 2-3 cold packs and ship to NeoGenomics 
Laboratories, Inc., with Tissue Sample Transmittal Form for 
NRG-GY018/MK3475-868. 
Storage condition 
Refrigerated (2-8ºC), in dark 
Shipping Definitions 
The addition of cold/ice/gel packs or as otherwise instructed by 
PPD Laboratory Manual (Appendix XI), without requirements 
for temperature monitoring. 
Shipping condition 
Refrigerated, in dark 
Ship to 
NeoGenomics Laboratories, Inc. 
Courier 
Refer to PPD Laboratory Manual (Appendix XI) for details 

 
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• Tumor tissue for biomarker analysis from an archival tissue sample of a tumor lesion not 
previously irradiated must be provided in the form of 12 unstained slides freshly cut from an 
FFPE tissue block. Sections must be prepared using the Superfrost slides provided by PPD. 
• A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, bone, 
bone marrow, cytologic specimen, decalcified or formalin fixed sample that was frozen 
at any point will not be acceptable for analysis. PLEASE NOTE: Decalcification of the 
sample cannot occur during any part of the tissue processing/embedding/section cutting 
(surface decalcification) process. 
• Samples identified as “non-decalcified soft tissue from bone” will be accepted and processed 
IF the following criteria are met: 
o Confirmation by site, (via the Tissue Sample Transmittal Form), that decalcification was 
not performed on this sample.  
o Samples must be obtained using standard biopsy techniques normally employed for solid 
organs or soft tissues. Examples of such techniques include excisional or wedge biopsies 
obtained with a scalpel, core needle biopsies obtained with modest pressure in a single 
motion, or snare biopsies.  
o Conversely, an example of an unacceptable bone specimen is a needle biopsy that 
requires excessive pressure and/or a back-and-forth motion (i.e., bone marrow biopsy 
technique).  
• Any sample containing bone, irrespective of decalcification status, has a high possibility 
and risk to be not evaluable due to the following reasons: 
o Laboratory is unable to section the sample 
o Small bone particles destroy the tissue architecture upon sectioning 
o IHC assay potentially impacted due to bone in the sample 
• When completing the Tissue Sample Transmittal Form (for a soft-tissue from bone 
sample), please ensure the “Anatomic Location of Tumor Tissue Collection” section is 
completed as follows: “Other” box should be checked and a note entered that the sample is 
“non-decalcified soft tissue from bone.” 
o Please note, omission of these steps will trigger a query to your site to send a local 
pathology report, which will result in processing delay. If a pathology report is requested, 
any necessary translations required will result in further processing delays. 
• The provided sample should contain tumor specimen sufficient for pathology review and 
analysis of tumor sample: 
o A minimum of 100 viable tumor cells is required for PD-L1 and MMR 
immunohistochemical analysis or sample will be reported as not evaluable. If possible, 
greater than 50% tumor content is preferred if available. 
 
3.2 
SUBMISSION OF UNSTAINED SECTIONED SLIDES FROM FFPE BLOCKS  
 
3.2.1 Materials Required For Sample Collection and Shipment 
 
Provided by the Institution: 
• Formalin-Fixed, Paraffin-Embedded (FFPE) tissue block 
• Sectioning equipment 
 
Provided to the Institution: 
The following supplies and materials will be provided by PPD. Please see the PPD Manual 

 
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(Appendix XI) for details on ordering supplies and materials. 
 
• Slide holder (can accommodate up to 25 slides) 
• Positively charged Superfrost microscope slides 
o Please use only the positively charged Superfrost slides provided by PPD which are 
standard sized, positively charged microscope slides (75mm x 25mm x 1mm). Other sizes 
of slides cannot be accommodated. 
• Poly foam pouch 
• Tissue Sample Transmittal Form for NRG-GY018/MK3475-868 
• Biohazard bag 
• Shipping container 
 
3.2.2 Sample Preparation and Collection Procedures  
1. Sites must freshly cut sections and send out to NeoGenomics Laboratories, Inc., within 48 
hours from sectioning in order for samples to be received within 2 to 3 days (dependent 
upon length of shipping) of site slide cutting date. The date slides are cut by the site must be 
recorded on the tissue sample requisition form. 
2. Use the positively charged Superfrost slides provided by PPD when preparing the 
unstained slides. 
a. Standard sized positively charged slides are required for samples; slide measurements are 
75mm x 25mm x 1mm. 
b. Other sized slides cannot be accommodated for testing. 
c. Slides should be cut at 4um thickness (4um preferred, 4-5um acceptable) . 
3. Ensure the sample has the institutional block ID clearly marked on the outside of the tissue 
block for identification prior to sectioning. 
4. Obtain the 25 slide holder from the PPD bulk supply provided to your site. Each slide holder 
can hold a maximum of 25 slides. 
5. Twelve (12) unstained slides are required to be submitted. 
6. Each slide must be labeled with two identifiers. Label each slide with the NRG Patient ID 
and Block ID (i.e., Surgical Pathology number and block number). Serially number slides in 
the order they were sectioned with indelible ink.  
7. Label the 25-slide plastic slide holder.  
8. Prepare freshly cut serial sections at 4 micron thickness onto the positively charged 
microscope slides provide by PPD as close to the day of shipping as possible. Plan to ship cut 
slides right after sectioning (within 48 hours) to ensure cut slides are received within 2-5 
days, dependent upon shipping time, of cutting slides at NeoGenomics Laboratories, Inc.  
9. The date slides are cut by the site must be recorded on the Tissue Sample Transmittal Form 
along with other required information. 
10. Number the slides sequentially (serially). Only one section should be on a slide.  
11. Standard sized positively charged slides are required for samples; slide measurements are 
75mm x 25mm x 1mm. Please use the slides provided by PPD. Other sized slides cannot be 
accommodated. 
12. DO NOT BAKE SLIDES – Only air dry (12 – 24 hours) at room temperature prior to 
shipment. 
13. Place slides in slots of the plastic slide holder in order of sectioning, with a maximum of 25 
slides per plastic slide holder. Utilize multiple slide holders as needed. 

 
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14. Store in the dark at 2-8ºC until ready to ship.  
15. Place foam pad on top of slides, tape shut, and place in poly foam pouch and place in 
biohazard bag. 
16. Using the appropriate PPD-provided shipper, ship cold (2-8ºC) in the dark as specified by the 
PPD Laboratory Manual (Appendix XI). Sectioned slides should be shipped refrigerated year 
round. 
17. Place a copy of the local pathology report in the shipping container along with the specimen 
collection bag. Ensure all subject information has been appropriately redacted. 
18. Samples should be shipped to NeoGenomics Laboratories, Inc., on the days listed below to 
ensure arrival to the testing lab prior to the weekend: 
• Mondays through Thursdays 
19. Complete the Tissue Sample Transmittal Form for NRG-GY018/MK3475-868 in Rave and 
print to include with the specimen when packaging for shipment.  Make a copy to retain at 
the site for your records. 
• The same two identifiers included on each slide must also be included on the Tissue 
Sample Transmittal Form. 
• Failure to include both identifiers on each slide and the Tissue Sample Transmittal 
Form will result in testing delays.  
20. Using the appropriate PPD-provided shipper, ship cut slides overnight at 2-8C in the dark, 
along with a copy of the Tissue Sample Transmittal Form for NRG-GY018/MK3475-868, to 
NeoGenomics Laboratories, Inc., at the address below:  
 
NeoGenomics Laboratories, Inc. 
31 Columbia 
Aliso Viejo, CA 92656 
Email: pharma_project_support_team@neogenomics.com 
 
21. PPD will provide airway bills for shipping directly to NeoGenomics Laboratories, Inc. Refer 
to PPD Laboratory Manual (Appendix XI) and other PPD materials for additional shipping 
instructions and requisition forms. 
 
 

 
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APPENDIX IX - NRG-GY018 PHARMACY AGREEMENT (07/03/2019) (09/24/2019) (07-FEB-
2020) (09-MAR-2022) (24-FEB-2023) 
 
On February 6, 2023, all patient treatment assignments were unblinded. Submission and maintenance of 
a Pharmacy Agreement for unblinded site personnel is no longer required. A new DTL (without the 
Unblinded Study Personnel task) is available on the CTSU website and must be completed and signed by 
the site CI. 
 
The NCI Pharmaceutical Management Branch is usually responsible for blinding patient-specific study 
agent supplies prior to shipping to sites.  However, for NRG-GY018, a matching placebo for 
pembrolizumab (MK-3475) is not available from the manufacturer.  The blinding is integral to the 
conduct of the study and CTEP considers maintenance of the blind a significant contribution to the 
conduct of the study. Therefore, it is important to know who the responsible parties are for maintaining 
the blind and training appropriate staff at the site level.  These individuals should not have direct contact 
with study subjects. Documentation of these significant contributors is through registration in the NCI’s 
Registration and Credential Repository (RCR) and identification on the Delegation of tasks Log (DTL). 
NOTE: Registration in RCR may require the following documents, FDA 1572, NCI Biosketch, Financial 
Disclosure Form and documentation of Good Clinical Practice training. 
 
Every site participating on NRG-GY018 must have at least two unblinded individuals available to 
manage study agent supplies.  The unblinded personnel listed on the DTL must have an active CTEP-
IAM user account and appropriate RCR person registration at the Investigator (IVR), Non-Physician 
Investigator (NPIVR) or Associate Plus (AP) level, be rostered at the site and be assigned the Unblinded 
Study Personnel task on the site DTL.  At a minimum, this must include the site’s Shipping Designee 
and at least one other site staff identified as responsible for overseeing the site agent management 
processes of; receiving blinded study agent from the NCI; managing the patient-specific DARF; 
preparing infusion solutions; and returning blinded study agent to the NCI.  These individuals are 
responsible for training other Control and Satellite site dispensing area unblinded personnel if other staff 
involved in the process are not listed on the DTL.  Study personnel assigned the tasks of “Unblinded 
Study Personnel” and “Investigational Product Accountability” on the DTL cannot be responsible for 
direct patient care or evaluation during the study in order to reduce the risk of unblinding treatment.   
 
The external carton label of the pembrolizumab (MK-3475)/placebo package received from PMB is 
blinded, however, the internal contents of each carton are not blinded.  It is the responsibility of the 
site staff to ensure the integrity of the blind at the site level.  As a result, the number of staff members 
handling the study agent should be limited to the smallest number possible.  A minimum of two 
individuals from the site (one of whom is the Shipping Designee) must be assigned the Unblinded Study 
Personnel task on the site DTL and sign the Pharmacy Agreement after reviewing the NRG-GY018 
training materials.  By signing the agreement, the signee is confirming to take actions appropriate to 
prevent unblinding patient and study personnel to a patient’s treatment assignment.  If all site personnel 
responsible for handling the study agent and maintaining the blind are not assigned on the DTL, a site 
level SOP must be in place documenting the steps and training to ensure the integrity of the blind at the 
site level.  This documentation should include a list of trainees, dates of training and the signature of 
each trainee verifying training has been completed.  The list (sample table provided by the 
Pharmaceutical Management Branch) must be available for review during an audit. 
 
Each person to be designated on the DTL as Unblinded Study Personnel must read, understand and sign 
this Pharmacy Agreement.  No study agent supplies will be shipped until at least two study personnel 

 
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from the site have signed Pharmacy Agreements and been assigned the Unblinded Study Personnel task 
on the DTL. Individuals assigned as Unblinded Study Personnel cannot hold any other tasks on the DTL 
except for Agent Accountability. 
 

 
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NRG-GY018 PHARMACY AGREEMENT (21-MAY-2021) (09-MAR-2022) (30-SEP-2022) (24-
FEB-2023) 
As of the unblinding of all patients on February 6, 2023, this Pharmacy Agreement no longer applies. 
 
As a person holding the Unblinded Study Personnel task on the DTL, I agree to the following in the 
conduct of this clinical trial: 
1. 
Participating study subjects, medical staff, ancillary medical staff, and data managers will remain 
blinded as to the study subject assignment of pembrolizumab (MK-3475) or Placebo until notified 
by NRG that assignments may be released. 
2. 
Other site unblinded study personnel not identified on the DTL will be trained in the agent 
management processes for this study. As a DTL-designated Unblinded Study Personnel for my site 
I will oversee this training and document training of appropriate individuals (name and date of 
training) at the Control and any Satellite dispensing areas. 
3. 
Only persons holding the Unblinded Study Personnel task on the DTL or persons trained by me 
and listed on my site training log will manage study agent supply (i.e., order, receive shipments, 
prepare infusions, maintain accountability logs, return or destroy unused supplies as directed by 
PMB). 
4. 
Disposition of unused patient-specific Pembrolizumab (MK-3475) will be determined by the site’s 
location: 
 
a. US Sites will return unused Pembrolizumab (MK-3475) or Saline Placebo to the NCI by the 
Unblinded Study Personnel or persons trained by me and listed on my site training log after the 
subject’s protocol treatment is completed.  
 
b. Non-US (international) sites will request local destruction for any unused patient-specific 
Pembrolizumab (MK3475).  One of the Unblinded Study Personnel or persons trained by me 
and listed on my site training log will submit the NCI Return Investigational Agent Form 
(available at https://ctep.cancer.gov/forms/)  after the subject’s protocol treatment is completed. 
 
Name (print):   ________________________________________________________ 
 
CTEP Person ID:     _____________________________________________________ 
 
DTL Site Code (s):  _____________________________________________________ 
 
DTL Institution Name(s):_________________________________________________ 
 
 
Signature:        _______________________________________ Date:_____________ 
 
 

 
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Complete the Pharmacy Agreement form and attach it as training documentation for the Unblinded 
Study Personnel task on the site DTL through the CTSU DTL module. Keep a copy for your records. 
Newly designated Unblinded Study Personnel must either complete and sign the Pharmacy Agreement 
and be added to the Delegation of Task Log or be trained by a site DTL-designated Unblinded Study 
Personnel and listed on the site training log as having received appropriate training on agent 
management processes for the study prior to handling the blinded study agents. 
 
Sample Site Training Log 
 
Trained Staff 
Unblinded Study Personnel* 
Printed Name 
Signature 
Printed Name 
Signature 
Date of 
training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    * Must hold the Unblinded Study Personnel task designated on the site DTL 
 

 
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APPENDIX X - BIOSPECIMEN BANK-COLUMBUS FFPE MATERIALS VERIFICATION 
FORM 
 
This form should be completed by the person in the pathology department who provides the FFPE 
materials to the requestor. Please return this form, along with the FFPE materials, to the requestor. 
The requestor must include this completed form with the shipment of FFPE materials. 
 
REQUIRED FFPE MATERIALS 
• One of the following archival tumor types must be submitted (listed in order or preference): 
• persistent primary (FPP01) or persistent metastatic (FPM01) tumor – i.e., collected prior to 
study treatment; lesion must not have been previously irradiated; or 
• recurrent primary (FRP01) or recurrent metastatic (FRM01) tumor – i.e., collected prior to 
study treatment; lesion must not have been previously irradiated; or 
• primary (FP01) or metastatic (FM01) tumor – i.e., collected prior to any treatment; lesion must 
not have been previously irradiated; or 
• primary neoadjuvant (FPT01) or metastatic neoadjuvant (FMT01) tumor – i.e., collected 
prior to any treatment; lesion must not have been previously irradiated. Only submit if tumor 
collected prior to any treatment is not available. 
• Every attempt should be made to provide an FFPE block; however, if a block cannot be provided on 
a permanent basis, then 10 unstained slides (charged, 5µm) must be submitted. 
• All tissue sections must be cut sequentially from one block.  
 
PATIENT INFORMATION (to be completed by person requesting FFPE materials) 
Patient ID: ___________________________           Bank ID: ________________________________ 
 
FFPE MATERIALS (to be completed by person preparing FFPE materials) 
 
Surgical Pathology #: __________ Block #: __________ Date Collected: __ __ / __ __ / __ __ __ __ 
 
Tissue Type: □ Persistent Primary (FPP01)  
□ Persistent Metastatic (FPM01) 
□ Recurrent Primary (FRP01) 
□ Recurrent Metastatic (FRM01) 
□ Primary (FP01)  
 
□ Metastatic (FM01) 
□ Primary Neoadjuvant (FPT01) 
□ Metastatic Neoadjuvant (FMT01) 
 
Site: 
□ Corpus Uteri 
□ Other, specify __________________________________________ 
 
Materials Prepared  
Number Provided 
 
Thickness (μm) 
Block 
 
 
Not Applicable 
Charged slides 
 
 
 
 
_______________________________________________________________________ 
Name of person preparing materials 
 
 
Date

 
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APPENDIX XI – PPD LABORATORY MANUAL (07/03/2019) (09/24/2019) (09-MAR-2022) 
(19-MAY-2022) 
 
1. 
ORDERING PPD Supplies 
PPD supplies will be ordered electronically. See Section 8.3.2. Please allow at least 7-10 
business days for order requests to process. An additional 3-5 business days should be 
considered for delivery transit times. Thus, please order PPD supplies at least 14 
business days before they are needed. 
 
2. 
SUPPLIES PROVIDED 
PPD will provide supplies required to collect, prepare, and ship the FFPE tissue slides 
required for the integral (MMR IHC) and exploratory PD-L1 IHC biomarker testing. 
 
PPD Supplies contain: 
• 
Package of slides 
• 
Courier information and pre-printed airbills 
• 
Shipping boxes and materials/gel packs 
• 
The initial package is enough for 6 subjects 
 
3. 
SHIPPING SAMPLES TO NEOGENOMICS 
PPD supplies will include additional information regarding site shipment to NeoGenomics, 
Inc., including courier information and pre-printed airbills. 
 
 

 
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APPENDIX XII - MEDIDATA PATIENT CLOUD EPRO OPERATIONAL PROCEDURES 
(07/03/2019) (08-DEC-2020) 
 
In this document ePRO application refers to the application accessed by the site via iMedidata and 
Rave, and ePRO mobile app refers to the app accessed by the patient on a mobile device. 
 
1. Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata’s  ePRO application 
is preferred but not mandatory. Patients who will be submitting PRO data via the ePRO mobile app 
must be registered to the ePRO application by an authorized site staff  after the patient has been 
registered to the study. Patients may use their own mobile device or one provisioned by the site. 
Sites can use a site-specific tablet for multiple study participants. If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users. Multi-user mode lets multiple study participants 
log in to the ePRO mobile app with their passwords or their PIN codes on the same device. 
 
2. ePRO Mobile Application Download 
 
Note that there are multiple versions of the ePRO mobile app.  Patients should be instructed to 
download the version chosen by the study team for the protocol.  The patient will receive an error 
upon logging into the ePRO mobile app if the wrong version is downloaded. The version being 
used on this trial is: 
 
Patient Cloud 
 
 
 
 
 
 
3. CRA Site Users 
Site staff require access to the ePRO application. This access is granted through iMedidata, and is 
similar to the process of obtaining access to Rave studies. Site staff will receive an invitation to 
the ePRO application which they must accept in order to begin registering patients. Staff that 
have not previously activated their iMedidata/Rave account at the time of initial approval of site 
registration will also receive a separate invitation from iMedidata to activate their account. 
iMedidata Account Activation and Study Invitation Acceptance instructions are located on the 
CTSU website under Data Management > Rave Home>Learn More About Rave > Medidata 
Account Activation and Study Invitation Acceptance. Site staff will not be able to access the 
study in the ePRO application until all required Rave and study specific trainings (eLearnings 
assigned in iMedidata) are completed. 
 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Data Management tab and further under the Rave subtab or by contacting the CTSU Help Desk at 
1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 

 
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4. CRA Instructions for Setting the Patient Cloud Mobile App to Multi-User Mode 
Sites conducting studies entirely on-premises, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode. Multi-user mode lets multiple study participants log in 
to the ePRO mobile app with their passwords or their PIN codes on the same device. If patients 
will be using devices supplied by the institution, site staff will need to help the patient to access 
the device if the device is locked. 
 
The study provider will download the ePRO mobile app to the device and set the ePRO mobile app 
to multi-user mode if applicable. **Verify the correct ePRO mobile app (Patient Cloud OR Patient 
Cloud ePRO) is downloaded per the protocol requirements.  Note only 1 version of the app is 
active per protocol.  On this protocol the app is named Patient Cloud and its icon is:  
 
Patient Cloud 
 
 
To switch from personal mode (default setting) to multi-user mode: 
1. Tap About at the bottom of the log in screen. 
2. Scroll to the bottom and tap Advanced User. 
3. Tap Mode, then select Multi-User. 
4. Tap Yes to confirm. 
5. Tap the back arrows to return to the log in screen. 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. 
5. Patient Users 
To use the  ePRO mobile app, patients will need to use their own device (Apple iPhone or iPad, 
or Android phone or tablet). Short term data will only appear on the patient’s device until 
responses are completed and submitted. The patient data will import directly into the database 
once the patient selects the “Submit” button and will no longer be visible on the patient’s device. 
Sites can provide a site-specific tablet for multiple study participant use on site. If a site-specific 
tablet is used, study staff need to set up the tablet for multiple users. Multi-user mode lets 
multiple study participants log into the ePRO mobile app with their passwords or their PIN 
codes on the same device. Refer to Section 4 above on Setting the Patient Cloud App to 
Multi-User Mode. 
 
6. Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Downloading the Patient Cloud ePRO Mobile App 
If you are using your personal device, and you do not have the ePRO mobile app with the icon 
shown below, use the following instructions. When downloading the app, you must use the Apple 
ID or Google account associated with the device. If the ePRO mobile app is already on the 
device, or if you are using a provider's device, you can skip this section. There are multiple 
versions of the ePRO mobile app available.  Ensure that the correct version of the ePRO mobile 

 
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app is downloaded. For this study the app is named Patient Cloud and its icon looks like this: 
 
 
Patient Cloud 
 
You will need an email address that you agree to use for this purpose. The email address is 
needed to identify you on the ePRO Application, and to reset your password if needed. Your 
email address will only be used for this survey study, and will not be used for mail or marketing 
purposes. 
If you decide to use the electronic method to complete the questionnaires, and do 
not have an email address, you may sign up for one at no charge at many different 
websites. A few sites that are commonly used and will allow you to create an email 
address very easily are Yahoo, Gmail, and Outlook. 
For iOS (when using an Apple device): 
1. 
An Apple ID is required for downloading the ePROmobile app. 
2. 
Tap the App Store icon on your device. 
3. 
Search for the appropriate ePRO mobile app (“Patient Cloud,” see the icon above) and 
follow the installation instructions. 
 
For Android: 
1. 
A Google account is required for downloading the ePRO mobile app. 
2. 
Tap the Play Store icon. 
3. 
Search for the appropriate ePRO mobile app (“Patient Cloud,” see the icon above) and 
follow the installation instructions. 
 
Registering 
You must register in order to complete and submit your study forms. When you register, you will 
create a username, which is your email address, and a password that allows you to log in to the 
ePRO mobile app. 
Note: You must have an activation code to begin this process. If you do not have an activation 
code, please contact your provider. 
 
There are two possible ways to register. Your provider may have sent you a link to a web address 
where you may register from any web browser, including the one on your device. The other way 
to register is on the ePRO mobile app. 
1. If registering from the ePRO mobile app, open the Patient Cloud app, tap Register on the 
bottom of the log in page. If registering on the web, open the URL 
https://shield.imedidata.com/  on a web browser. 
2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 

 
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4. Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. Enter and confirm your email address. Tap Next. 
6. Enter and confirm your password. Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to display the 
question of your choice. 
8. Enter your response to the security question. 
9. Tap Create my account to complete your registration. 
If you registered on the ePRO mobile app, it automatically logs you out. If you registered on 
the web, you are presented with the option to download the ePRO mobile app (Patient Cloud). 
You can then proceed to log in with the credentials you created. 
 
Logging in to the ePRO mobile App 
1. Enter your Email and Password that you created during the registration process. (If you 
previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided. 
 
Setting a PIN Code 
The first time you log in to the ePRO mobile app, you are given the option to create a PIN code. 
A PIN code allows you to bypass the step of entering your email and password every time you 
need to log in to the ePRO mobile app (Patient Cloud). Instead, you can enter a four-digit PIN. 
1. If you wish to set a PIN code the first time you log in, tap Yes when prompted. 
2. Note: You can also set your PIN at a later time by tapping the options menu on the top 
right of most pages and selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
If you forget your PIN code, tap Forgot PIN and you can access the app using your email and 
password. You may reset your PIN by tapping the options menu (3 vertical dots) on the top right 
of most pages and selecting Set PIN. 
 
Resetting Your Password 
You can reset your password by using the options menu at the top right of most pages. 
1. Tap the options menu icon (3 vertical dots). 
2. Tap Reset Password. 
3. Follow the instructions to reset your password. 
 
Completing and Submitting Forms 
Once logged into the ePRO mobile app, forms related to your study are displayed on the Tasks 

 
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List page. Select a form, and complete and submit the form. New forms can appear on the Tasks 
page at any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• Scheduled Forms (with a 
 icon): These forms have a "Due Date" indicator in them so you 
are aware of the last day by which you will need to complete the form. If the form is due in less 
than one day, you will see the due time in hours. 
• Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator on them 
which tells the most recent date or time when you completed the form. If you start a form, but 
do not complete it, you will see an 'Incomplete" status beneath the form name, along with a 
half-moon icon.  
To complete and submit form(s): 
1. Select the appropriate form.  
2. Follow the on-screen instructions until you reach the end of the form where you may be 
given the opportunity to review and change your responses prior to submitting. 
3. If given the opportunity to review and update, review your responses by scrolling down 
the list; if you need to change an answer, tap the question to go back and change the 
answer. 
4. When you are ready to submit, tap Submit Your Data. 
Note: Once a form is submitted, you will be unable to edit any of your responses. In some cases, 
you may be asked to acknowledge your submission by entering your password. 
 
7. Patient Compliance 
The patient data imports directly from a device into the Rave database. There are no documents 
to audit. The patient-submitted electronic responses are the source documentation. 
8. Security 
All data is encrypted on the device (256 bit encryption and Hyper Text Transfer Protocol Secure 
[https]) and the app requires each user to have a unique username and password for access. If the 
user is idle for too long (5 minutes inactivity time), the app will time out, and the user will need to 
log in again. 
The data will only reside on the device for a short period of time.  Once the user clicks “Submit,” 
the data is securely transferred over HTTPS between the device and internal relay to the Rave 
database. Except for the patient's email address, no identifying information is stored in 
iMedidata. The patient's email links the device (used) and (ePRO) account to where the data is 
stored. The patient's email is not visible to anyone in the system. 
The Patient information (email/password) does not reside in Medidata Rave EDC, and the patient 
accounts are hidden in iMedidata from sites and LPOs. 
The ePRO application is 21 CFR Part 11 compliant and acts as a gateway between the device 
and Medidata Clinical Cloud (MCC). 

 
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Messages and information communicated to and from the Patient Cloud are encrypted and 
therefore this information cannot be read if intercepted while in transit. 
 
9. Site checklist for activities prior to consenting a patient 
 
Accept study invitation at iMedidata.com 
o Site staff must be rostered in RSS and have received an invitation to the ePRO 
application 
 Site staff must have already completed required eLearning assigned in iMedidata for 
the ePRO application before gaining access to the study in Rave.  Contact the LPO to 
request appropriate Rave access to register patients in the ePRO application. 
 Verify the IOS or Android operating system is using the most current version 
 Verify that the correct ePRO mobile app is being used. Note only 1 version of the 
ePRO mobile app is active per protocol. 
 If using institutional shared devices, for the first patient only: Verify the ePRO mobile 
app is in Multi-User mode  
 See the following webpage for more information about Patient Cloud iOS and Android 
ePRO apps.  The landing page contains general information as well as links to 
additional resources on the left side of the screen  https://learn.mdsol.com/patient-
cloud/ecoa/en/get-started-with-patient-cloud-ios-and-android-apps-125282823.html 
Note: Sites should consider copying this site checklist and placing it in the clinic or area where site 
is consenting patients to ePRO and also copy the correct image and name of the ePRO mobile app 
version with it to help remind staff and patients of the correct version being used in the protocol.  
The correct version for this protocol is named “Patient Cloud” and has an icon with a cloud and a 
sun. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX XIII – TREATMENT CONSIDERATIONS IN THE CONTEXT OF THE 
COVID-19 PANDEMIC AND PLACEBO DESIGN (14-OCT-2020) 
The novel coronavirus has persisted in the United States. The virus is named “SARS-CoV-2” and 
the disease it causes has been named COVID-19. This outbreak has impacted health care delivery, 
with specific considerations in patients receiving anti-cancer directed therapy. 
Given the potential impact of COVID-19 on the conduct of clinical trials, it has emerged as a 
priority to provide guidance to institutions in an effort to ensure patient safety, and appropriate 
clinical care. In 2020, the FDA issued a document on the conduct of clinical trials during the 
COVID-19 pandemic outlining important considerations. Importantly, the impact of COVID-19 on 
the conduct of clinical trials is anticipated to vary depending on several factors, including the 
nature of disease under study, the trial design, and in what region(s) the study is being conducted. 
Therefore, it is anticipated that institutions will develop different management strategies, based on 
clinical needs and available resources. Ultimately, the priority remains the safety of trial 
participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to 
trial integrity. 
NRG GY018 was designed as a placebo-controlled trial in order to preserve the integrity of the 
trial endpoint, while simultaneously examining a novel immunotherapy combination in patients 
with recurrent endometrial cancer and limited treatment options. The study team recognizes that 
the protection of a participant’s safety, welfare, and rights is best served by continuing a study 
participant in the trial as per the protocol. However, it is also clear that during some periods of 
time, in some geographic regions, administration of a placebo maintenance may not be feasible or 
deemed safe at an institution. Certainly, in regions where COVID-19 remains active, the 
risk/benefit balance may shift during the maintenance phase, supporting request for subject 
unblinding. Furthermore, institutional demands may necessitate temporary interruptions to subject 
accrual on trial, and it is anticipated that treatment sites will evaluate and mitigate on an individual 
level. 
As such, the study protocol was amended to clarify that unblinding can be requested by the patient 
and/or the patient’s treating physician because of safety concerns related to the COVID-19 
pandemic as detailed in protocol section 5.2. The patient or treating physician can determine that 
safety of the patient is potentially compromised by COVID-19 in the patient’s local/home area, 
areas of travel, or the office/treatment center.  The patient can request unblinding after discussion 
with the treating physician.  The treating physician must then request unblinding and notify the 
study PI. The patient should be encouraged to continue pembrolizumab maintenance if so 
assigned; patients may also elect to withdraw consent for treatment, but in that case, they are 
strongly encouraged to remain on study follow up (including maintenance of Radiologic Tumor 
Measurement schedule and Patient Reported Outcomes schedule per Tables 4.2 and 4.3). It is 
anticipated that all patients will continue in-person assessment and imaging reassessments on, or as 
close as possible to protocol directed intervals. The patient’s request is to be respected whether or 
not the treating physician or study PI agree. The priority will be to assure the safety of trial 
participants while minimizing risk to trial integrity.   

 
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The study protocol was also revised to allow for Q6 week administration of pembrolizumab (MK-
3475) or placebo in the maintenance phase. This was done with an intent to reduce the number of 
visits to the infusion center during the COVID-19 pandemic. We encourage investigators to make 
every effort to try and coordinate office, imaging and infusion visits as permitted based on the 
protocol specified timelines, in order to reduce the burden on participating patients, and possible 
COVID-19 exposures.  
 
 

 
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APPENDIX XIV: COUNTRY-SPECIFIC APPENDIX – JAPAN (09-MAR-2022) (19-MAY-
2022) (24-FEB-2023) 
 
Eligibility 
Section 3.2.1: If standard of practice in Japan is to not do local/institutional IHC testing for MMR, 
then centralized testing results will be used, and the pathology report does not have to include 
results of institutional MMR IHC testing. 
Assessments 
Section 4.1: institutional mismatch repair protein IHC results are not required for patients enrolled 
in Japan. 
Section 4.2: Chemistries: Bicarbonate is not required for patients enrolled in Japan 
Centralized MMR IHC Testing/Return of Results/Step 2 Randomization 
Sections 5.7, 8.3.3, 10.2.1, 10.2.4 
Sites in Japan with institutional MMR IHC results may use those results for Step 2 Randomization, 
after submission of additional slides to Neogenomics for centralized MMR IHC testing. 
Sites in Japan with MMR IHC results previously reported from Neogenomics can use those results 
to fulfill both local and centralized MMR IHC testing requirements for NRG-GY018. 
When NRG-GY018 centralized MMR IHC testing results through Neogenomics are the only 
MMR IHC results available, sites must wait until the patient’s centralized results are returned to 
proceed to Step 2 randomization. 
Please note: 
• Testing turnaround time is 7 business days from the day the sample is received by 
NeoGenomics. Please plan accordingly.   
• Do not contact Neogenomics for MMR IHC result status before 7 business days have 
elapsed since receipt of samples. 
 
NeoGenomics Laboratories, Inc. 
Attn: Pharma Services Dept. 
31 Columbia 
Aliso Viejo, CA 92656 
Email: pharma_project_support_team@neogenomics.com 
Phone: 949-445-7300, x7103 
 
• MMR IHC results will be reported to the NRG SDMC and can be found in the Pre-Entry 
folder in Rave. 
• Please see the “Confirmation to Proceed to Step 2” form in the Pre-Entry folder in Rave. 
This is the notification that you can proceed after the MMR IHC result is reported.  

 
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Investigational Drug Supply/Placebo 
 
• Pembrolizumab placebo infusions will be prepared without the addition of saline from vials 
provided by PMB. 
• A shipment containing an empty carton will be sent for initial orders.  A memo instructing 
sites how to prepare pembrolizumab placebo infusions will be placed in an empty carton.  
The carton will be sealed, and the two-part, patient-specific label attached to the outside.  
The small, patient ID label will be affixed to the memo, prior to its insertion into the empty 
carton. 
• PMB will continue to provide placebo shipments (preparation memo inside an empty 
carton) while patients randomized to the placebo arm are receiving treatment. 
• Unblinded study personnel at the site are responsible for submitting an order, timing its 
submission so the shipment is received not more than 4 weeks prior to next scheduled dose. 
 
Effective February 06, 2023, all patients were unblinded. Patients randomized to placebo (Arm 
1) will not receive additional placebo infusions. All other study related treatments and 
evaluations will proceed per protocol.