A Phase II Randomized Trial of Olaparib Versus Olaparib Plus Tremelimumab in Platinum-Sensitive Recurrent Ovarian Cancer
Phase: PHASE2
Conditions: Fallopian Tube Endometrioid Tumor, Fallopian Tube High Grade Serous Adenocarcinoma, Malignant Ovarian Endometrioid Tumor, Ovarian High Grade Serous Adenocarcinoma, Platinum-Sensitive Fallopian Tube Carcinoma, Platinum-Sensitive Ovarian Carcinoma, Platinum-Sensitive Primary Peritoneal Carcinoma, Primary Peritoneal High Grade Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Fallopian Tube Endometrioid Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Ovarian Serous Adenocarcinoma, Recurrent Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Endometrioid Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

 
NRG-GY021 
 
Version Date: August 27, 2021 
i
SUMMARY OF CHANGES 
 
For Protocol Amendment #2 to: NRG-GY021 
NCI Protocol #: NRG-GY021 
Local Protocol #: NRG-GY021 
NCI Version Date: 08/27/2021 
 
This amendment for NRG-GY021 is being submitted in response to an RRA from Dr. Percy Ivy 
(ivyp@ctep.nci.nih.gov).  
 
Section 
Comments 
Title Page(s)  
• NCI Version Date is now August 27, 2021. 
• Protocol Administrator changed to Kathryn Miller, contact info 
updated. 
1.3 
 
Note now reads: “The final biomarker assays and analyses at CIMAC-CIDC 
will be based on the “Proposal Intake Form for Investigators Using the 
CIMAC-CIDC Network” for this trial. The Intake Form will be reviewed and 
approved by NCI and the CIMAC-CIDC coordination center before testing of 
banked biospecimens.” 
2.6 
Note now reads: “The final biomarker assays and analyses at CIMAC-CIDC 
will be based on the “Proposal Intake Form for Investigators Using the 
CIMAC-CIDC Network” for this trial. The Intake Form will be reviewed and 
approved by NCI and the CIMAC-CIDC coordination center before testing of 
banked biospecimens.” 
7.3 
Revised Olaparib CAEPR (Version 2.5, July 1, 2021) inserted into protocol: 
•The SPEER grades have been updated. 
•Added New Risk:  
o Rare but Serious: Allergic reaction; Febrile neutropenia; Skin and 
subcutaneous tissue disorders - Other (angioedema); Skin and 
subcutaneous tissue disorders - Other (erythema nodosum) 
o Also Reported on Olaparib Trials But With Insufficient Evidence for 
Attribution: Arterial thromboembolism; Atrial fibrillation; Death NOS; 
Dermatitis radiation; Enterocolitis; Erythema multiforme; Esophageal 
stenosis; Hypoxia; Muscle weakness upper limb; Obstruction gastric; 
Peripheral ischemia; Reversible posterior leukoencephalopathy 

 
NRG-GY021 
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Section 
Comments 
syndrome; Sinus bradycardia; Soft tissue necrosis lower limb; 
Treatment related secondary malignancy 
• 
Increase in Risk Attribution:  
o Changed to Likely from Less Likely: Abdominal pain 
o Changed to Less Likely from Also Reported on Olaparib Trials But 
With Insufficient Evidence for Attribution: Mucositis oral; Muscle 
cramp; Myalgia; Pain in extremity; Rash maculo-papular 
•Decrease in Risk Attribution:  
o Changed to Rare but Serious from Less Likely: Platelet count 
decreased 
o Changed to Also Reported on Olaparib Trials But With Insufficient 
Evidence for Attribution from Less Likely: Fever; Lymphocyte count 
decreased 
•Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:  
o Added to SPEER: Back pain; Neutrophil count decreased 
•Provided Further Clarification: 
o Infection listed under Less Likely is now captured as “Upper 
respiratory infection” and “Urinary tract infection” under Less Likely. 
10.0 
Note now reads: “The final biomarker assays and analyses at CIMAC-CIDC 
will be based on the “Proposal Intake Form for Investigators Using the 
CIMAC-CIDC Network” for this trial. The Intake Form will be reviewed and 
approved by NCI and the CIMAC-CIDC coordination center before testing of 
banked biospecimens.” 
10.5  
Note now reads: “The final biomarker assays and analyses at CIMAC-CIDC 
will be based on the “Proposal Intake Form for Investigators Using the 
CIMAC-CIDC Network” for this trial. The Intake Form will be reviewed and 
approved by NCI and the CIMAC-CIDC coordination center before testing of 
banked biospecimens.” 
Appendix VI 
• Note now reads: “The final biomarker assays and analyses at CIMAC-
CIDC will be based on the “Proposal Intake Form for Investigators 
Using the CIMAC-CIDC Network” for this trial. The Intake Form will 
be reviewed and approved by NCI and the CIMAC-CIDC coordination 
center before testing of banked biospecimens.” 
• NRG Oncology Biospecimen Bank-Columbus Kit Management URL 
has been updated throughout Appendix VI to “https://kits.bpc-
apps.nchri.org/”.  
ICDs 
Please see the ICDs for additional changes made. 
 

 
NRG-GY021 
 
Version Date: August 27, 2021 
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NRG ONCOLOGY 
NRG-GY021 
(ClinicalTrials.gov NCT # 04034927) 
 
A PHASE II RANDOMIZED TRIAL OF OLAPARIB VERSUS OLAPARIB PLUS 
TREMELIMUMAB IN PLATINUM-SENSITIVE RECURRENT OVARIAN 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; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team 
Principal Investigator/Gyn Oncologist 
Gyn Oncology Co-Chair 
Sarah Adams, M.D. 
Paul DiSilvestro, M.D. 
1201 Camino de Salud 
Women and Infants Hospital 
1 University of New Mexico MSC07-4025 
101 Dudley Street 
Albuquerque, NM 87131 
Providence, RI 02905 
505-495-0461/FAX: 505-495-0454 
401-453-7520 
sadams@salud.unm.edu  
PDisilvestro@wihri.org  
 
 
Statistician 
Translational Scientist 
Mark Brady, Ph.D. 
Heather Lankes, Ph.D., M.P.H 
NRG Oncology Biostatistical Center-Buffalo 
NRG Oncology-Philadelphia East 
Elm and Carlton Streets 
Four Penn Center, 1600 JFK Blvd, Ste 1020 
Buffalo, NY 10065 
Philadelphia, PA 19103 
716-854-5702/FAX: 716-845-8393 
lankesh@nrgoncology.org  
brady@gogstats.org    
 
 
 
Research Nurse 
Data Manager 
Sheri Westgate, RN 
Lynne Anderson 
University of New Mexico Cancer Center 
NRG Oncology SDMC-Pittsburgh 
1201 Camino de Salud 
201 N. Craig St., Suite 500 
Albuquerque, NM 87131 
Pittsburgh, PA 15213 
505-925-0383/FAX: 505-272-7799 
412-383-1203 
swestgate@salud.unm.edu  
andersonl@nrgoncology.org  
 
 
Protocol Coordinator (27-AUG-2021) 
 
Kathryn Miller 
 
NRG Oncology-Philadelphia East 
 
Four Penn Ctr, 1600 JFK Blvd., Ste 1020 
 

 
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Philadelphia, PA 19103 
 
215-854-0770/FAX: 215-854-0716 
 
millerk@nrgoncology.org   
 
 
NRG Oncology Contact Information 
Data Management 
For questions concerning data 
submission 
Data Manager  
Lynne Anderson 
NRG Oncology Statistics and Data Management 
Center- Pittsburgh  
201 N. Craig St., Suite 500 
Pittsburgh, PA 15213 
412-383-1203/FAX 412-624-1082 
andersonl@nrgoncology.org  
Protocol Development 
For questions concerning protocol and 
informed consent versions & 
amendments 
Protocol Coordinator  
Kathryn Miller 
NRG Oncology-Philadelphia East 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Philadelphia, PA 19103 
215-854-0770millerk@nrgoncology.org   
Biospecimen Bank 
For questions concerning biospecimen 
collection 
NRG BB-Columbus 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340 
Columbus, OH 43205 
614-722-2865/FAX 614-722-2897 
BPCBank@nationwidechildrens.org 
Regulatory 
NRG-GY-Regulatory@nrgoncology.org  
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 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Olaparib 
CTEP 
747856 
 
DCTD, NCI 
Tremelimumab 
CTEP 
744483 
DCTD, NCI 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
Document History 
Amendment 2  
August 27, 2021 
Amendment 1 
April 24, 2020 

 
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Initial 
10/02/2019 
 
 
 
 
  
 
 
 
CONTACT INFORMATION (24-APR-2020) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
 
Regulatory Submission Portal (Sign 
in at 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 at 1-866-651-2878 to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN).  OPEN is accessed 
at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-related 
questions by phone or email: 
1-888-823-5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Refer to the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on  the CTSU members’ website  (https://www.ctsu.org).  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU 
Regulatory Support System (RSS).   
 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by NRG Oncology nor does NRG Oncology 
assume any responsibility for unauthorized use of this protocol. 

 
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NRG Oncology Participating Institutions for Safety Lead-ins 
AZ151 
Arizona Cancer Center 
CA088 
University of California Medical Center at Irvine-Orange Campus 
CO070 
University of Colorado Cancer Center 
CT009 
Hartford Hospital 
GA020 
Georgia Regents University 
IA018 
University of Iowa Hospitals and Clinics 
IL057 
University of Chicago 
MD017 
Johns Hopkins University/Sidney Kimmel Cancer Center 
MO011 
Washington University School of Medicine 
NM004 
University of New Mexico Cancer Center 
NY016 
Memorial Sloan Kettering Cancer Center 
NY158 
Roswell Park Cancer Institute 
OH007 
Ohio State University 
OH027 
Cleveland Clinic Foundation 
OH029 
Case Western Reserve University 
OH274 
UHHS – Chagrin Highlands Medical Center 
OK003 
Oklahoma University 
PA015 
University of Pittsburgh Cancer Center 
PA075 
Abramson Cancer Center at the University of Pennsylvania 
PA086 
Fox Chase Cancer Center 
PA121 
Thomas Jefferson University 
RI012 
Women’s and Infants Hospital 
TX035 
M.D. Anderson Cancer Center 
VA009 
University of Virginia Health Systems 
VA010 
Virginia Commonwealth University 
WI013 
Froedtert and the Medical College of Wisconsin 
 
 

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TABLE OF CONTENTS
SCHEMA....................................................................................................................................- 8 -
OBJECTIVES.................................................................................................................- 9 -
Primary Objective...............................................................................................- 9 -
Secondary Objectives..........................................................................................- 9 -
Exploratory Objectives (27-AUG-2021) ............................................................- 9 -
BACKGROUND ............................................................................................................- 9 -
Platinum-sensitive ovarian cancer ....................................................................- 10 -
PARP inhibitors in ovarian cancer....................................................................- 10 -
CTLA4 immune checkpoint inhibition and ovarian cancer..............................- 11 -
Rationale for combining olaparib with CTLA4 immune checkpoint 
inhibition...........................................................................................................- 13 -
2.5  
Rationale for the control arm............................................................................- 15 -
2.6
Rationale for Exploratory Biomarker Testing in Collaboration with 
CIMAC (27-AUG-2021) ..................................................................................- 15 -
ELIGIBILITY, AND INELIGIBILITY CRITERIA ....................................................- 17 -
3.1
Eligibility Criteria.............................................................................................- 17 -
3.2
Ineligibility Criteria ..........................................................................................- 20 -
4.
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP .....- 23 -
PRE-TREATMENT ASSESSMENTS.............................................................- 23 -
ASSESSMENTS DURING TREATMENT.....................................................- 24 -
ASSESSMENTS IN FOLLOW UP..................................................................- 25 -
TREATMENT PLAN/Regimen description.................................................................- 26 -
Treatment Plan..................................................................................................- 26 -
General Concomitant Medication and Supportive Care Guidelines.................- 28 -
Duration of Therapy..........................................................................................- 29 -
TREATMENT MODIFICATIONS/MANAGEMENT................................................- 30 -
Olaparib Dose Modifications............................................................................- 30 -
Tremelimumab Dose Modifications .................................................................- 34 -
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................- 56 -
Protocol Agents.................................................................................................- 56 -
Adverse Events and Serious Adverse Events ...................................................- 56 -
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Olaparib (AZD2281, NSC 747856) (27-AUG-2021).......................................- 57 -
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Tremelimumab (CP-675,206, NSC #744483) ..................................................- 60 -
Expedited Reporting of Adverse Events...........................................................- 63 -
Secondary Malignancies...................................................................................- 66 -
8.
REGISTRATION AND STUDY ENTRY PROCEDURES (24-APR-2020)..............- 66 -

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Cancer Trials Support Unit (CTSU) Registration Procedures..........................- 67 -
Patient Enrollment ............................................................................................- 69 -
Data Submission / Data Reporting....................................................................- 70 -
Agent Ordering and Agent Accountability.......................................................- 73 -
DRUG INFORMATION ..............................................................................................- 74 -
9.1
Investigational Study Agent: Olaparib (AZD2281) (NSC # 747856) (24-
APR-2020)........................................................................................................- 74 -
9.2
Investigational Study Agent: Tremelimumab (NSC # 744483) (24-APR-
2020) .................................................................................................................- 76 -
Pathology/BIOSPECIMEN (27-AUG-2021)................................................................- 77 -
Central Pathology Review Guidelines..............................................................- 78 -
Biospecimen Selection for Integral Biomarker Testing....................................- 78 -
Biospecimen Selection for Integrated Biomarker Testing................................- 78 -
10.4
Biospecimen Submission Tables ......................................................................- 78 -
10.5
Exploratory Biomarker Testing (27-AUG-2021) .............................................- 79 -
ASSESSMENT OF EFFECT .......................................................................................- 79 -
Antitumor Effect – Solid Tumors .....................................................................- 79 -
DATA AND RECORDS ..............................................................................................- 85 -
Data Management/Collection ...........................................................................- 85 -
NRG Data Management Forms ........................................................................- 86 -
Summary of Data Submission ..........................................................................- 86 -
Global Reporting/Monitoring (24-APR-2020) .................................................- 86 -
STATISTICAL CONSIDERATIONS..........................................................................- 86 -
Study Design.....................................................................................................- 86 -
Study Endpoints................................................................................................- 87 -
Primary Objectives Study Design.....................................................................- 87 -
Study Monitoring of Primary Objectives..........................................................- 89 -
Accrual/Study Duration Considerations ...........................................................- 89 -
Secondary or Exploratory Endpoints................................................................- 89 -
Gender/Ethnicity/Race Distribution..................................................................- 90 -
REFERENCES .............................................................................................................- 92 -
APPENDIX I – FIGO OVARIAN CANCER STAGING 2014...............................................- 95 -
APPENDIX II – PERFORMANCE STATUS CRITERIA......................................................- 97 -
APPENDIX III – GENERAL THERAPY GUIDELINES.......................................................- 98 -
APPENDIX IV: PATIENT DRUG INTERACTIONS HANDOUT AND PATIENT DRUG 
INTERACTIONS WALLET CARD - OLAPARIB.....................................................- 98 -
APPENDIX V: PATIENT DRUG DIARY: OLAPARIB......................................................- 101 -

 
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APPENDIX VI – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES .......... - 102 - 
APPENDIX VII - BIOSPECIMEN BANK-COLUMBUS PATHOLOGY MATERIALS 
VERIFICATION FORM (24-APR-2020) .................................................................. - 108 - 
APPENDIX VIII – COLLABORATIVE AGREEMENT ...................................................... - 109 - 
APPENDIX IX – LETTER TO PATHOLOGISTS................................................................ - 111 - 

 
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NRG-GY021 
SCHEMA 
This study consists of three components, which will be conducted in sequence: 
1. Initial safety lead-in (Open to NRG Oncology Safety Lead-in Sites ONLY—see list in 
title pages) 
2. Second safety lead-in (Open to all NRG sites)  
3. Primary Phase II study (Open to all NCTN participants) 
 
Initial safety lead-in 
During the initial safety lead-in, treatment assignment will be randomized. At least 6 and as 
many as 25 patients receiving olaparib and tremelimumab will be assessed for DLT through 
cycle 3.  If the olaparib and tremelimumab regimen is deemed sufficiently safe following this 
review, then the second stage of the safety lead-in will be initiated. 
 
Second safety lead-in 
Treatment assignment will be randomized.  20 patients receiving olaparib and tremelimumab 
will be assessed for DLT through cycle 3.  If the olaparib and tremelimumab regimen is deemed 
sufficiently safe following this review, then the primary Phase II component of this study will be 
initiated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Randomization is 1:1 
Women with recurrent platinum-sensitive ovarian, fallopian tube or 
primary peritoneal cancer with known BRCA mutation screening results 
Stratification 
• BRCAm vs BRCAwt or unknown 
• Prior PARP inhibitor exposure 
RANDOMIZATION* 
Arm 1 
Olaparib 300 mg PO twice daily 
until disease progression or 
adverse events prohibit further 
treatment 
Arm 2 
Olaparib 300 mg PO twice daily until disease progression or 
adverse events prohibit further treatment 
 
Tremelimumab 750 mg* IV over 60 minutes Day 1 every 4 weeks 
for four doses, then every 12 weeks for up to 2 years 
*See Section 5.1 for dosing for patients ≤ 30 kg 

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OBJECTIVES
Primary Objective
1.1.1
Safety Lead-in Trial Components:
To determine whether olaparib plus tremelimumab has adequate safety in the study 
population.
1.1.2
Phase II Trial Component:
To compare the progression-free survival (PFS) duration of olaparib monotherapy versus 
olaparib plus tremelimumab in women with recurrent, platinum sensitive ovarian, 
primary peritoneal, or fallopian tube cancer.
Secondary Objectives
1.2.1
To compare the overall response rate (ORR) by RECIST 1.1 in women with recurrent, 
platinum sensitive ovarian, primary peritoneal or fallopian tube cancer treated with either 
olaparib monotherapy or olaparib plus tremelimumab. 
1.2.2
To compare the overall survival (OS) of women with recurrent, platinum sensitive 
ovarian, primary peritoneal or fallopian tube cancer treated with either olaparib 
monotherapy or olaparib plus tremelimumab.
Exploratory Objectives (27-AUG-2021)
Note: The final biomarker assays and analyses at CIMAC-CIDC will be based on the 
“Proposal Intake Form for Investigators Using the CIMAC-CIDC Network” for this 
trial. The Intake Form will be reviewed and approved by NCI and the CIMAC-CIDC 
coordination center before testing of banked biospecimens.
1.3.1
To explore whether conditions in the tumor microenvironment (as measured by gene 
expression signature in archived tumor samples) identify patients that benefit from 
combined olaparib and tremelimumab immunotherapy.
1.3.2
To explore whether mutations in BRCA1/2 genes or other evidence of homologous repair 
deficiency (HRD+) is prognostic and/or predictive of response to combined olaparib and 
tremelimumab immunotherapy.
1.3.3
To explore associations between PD1 expression in the tumor microenvironment and (1) 
outcome and (2) changes in circulating leukocyte populations.
1.3.4
To explore the correlation between tumor mutational burden and response to olaparib and 
tremelimumab immunotherapy.
1.3.5
To explore the impact of olaparib and tremelimumab versus olaparib monotherapy on 
circulating leukocyte subsets via exploration of the immunomodulatory effects of PARP 
inhibition and the added impact of CTLA4 blockade in this patient population.
1.3.6
To explore cytokine/chemokine levels using a multiplex immunoassay (Olink) and 
correlate these levels with clinical endpoints.
1.3.7
To use cell-free DNA to assess BRCA mutation status as a mechanism of acquired 
resistance to prior PARP inhibition and to compare with treatment efficacy.
BACKGROUND

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Platinum-sensitive ovarian cancer
In the United States, ovarian cancer has the highest mortality rate of any gynecologic 
malignancy (Coleman, 2013).  Although platinum-based frontline chemotherapy is 
effective, a majority of patients experience disease recurrence.  Platinum-sensitive 
recurrence is defined as disease recurring at least 6 months after the last receipt of 
platinum-based chemotherapy.  For these patients, additional platinum-based therapy is 
recommended, however repeated courses of platinum-based regimens result in 
cumulative toxicity and increased risks of allergic reaction to platinum.  There is a need 
for alternatives to platinum-based chemotherapy for women with recurrent platinum-
sensitive ovarian cancer.
PARP inhibitors in ovarian cancer
PARP inhibitors are a class of drugs that have demonstrated significant activity in the 
treatment of recurrent ovarian cancer in recent clinical trials (Ledermann, 2012; Liu, 
2014; Swisher, 2017).  While initial studies focused on women with germline mutations 
in BRCA1 or BRCA2 genes, emerging evidence indicates that PARP inhibitors have 
therapeutic benefit beyond this cohort of patients with hereditary cancer syndromes
(Fong, 2010).  When olaparib was evaluated for the treatment of recurrent ovarian cancer 
in a phase II trial that was not limited to women with germline BRCA mutations, 
objective responses were seen in 41% with a germline BRCA mutation and 24% without 
an identified mutation (Gemon, 2011).  Recent studies of other PARP inhibitors have also 
demonstrated benefit in women without germline BRCA mutations.  In a phase II trial of 
rucaparib in women with relapsed, platinum-sensitive high grade ovarian cancer, median 
progression-free survival among patients with wild type BRCA was 5.7 months (Swisher, 
2017).  Similar survival rates were demonstrated in a phase II study of olaparib versus the 
combination of olaparib and cediranib in a BRCAwt subset of women (Liu, 2014).  
Notably, the benefit of combined olaparib and cediranib was most pronounced among 
women with BRCAwt tumors, indicating that combinatorial regimens may enhance the 
efficacy of PARP-inhibitors particularly among BRCAwt patients (Liu, 2014).  
Olaparib has also been evaluated as a maintenance regimen in women with platinum-
sensitive recurrent high grade serous ovarian cancer (Ledermann, 2012; Mirza, 2016; 
Lheureux, 2017).   Results were not stratified by BRCA status and demonstrated a longer 
disease-free interval in the treatment group (8.4 vs 4.8 months; HR = 0.35, P<0.001)
(Ledermann, 2012).  With a recent phase III trial demonstrating a marked increase in 
progression-free survival with the addition of olaparib maintenance to frontline platinum-
based chemotherapy among women with BRCA-deficient ovarian cancer, PARP 
inhibition has been incorporated into the standard of care for this patient cohort (Moore, 
2018).  Importantly, the use of olaparib does not appear to limit the efficacy of 
subsequent chemotherapeutic regimens (Ang, 2013).
Olaparib
Olaparib (AZD2281, KU-0059436) is a potent inhibitor of polyadenosine 
5’diphosphoribose polymerase (PARP) developed as a monotherapy as well as for 
combination with chemotherapy, ionizing radiation and other anti-cancer agents 
including novel agents and immunotherapy. The capsule formulation of olaparib was 
approved in December 2014 by the United States (US) Food and Drug Administration 

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(FDA) as monotherapy in patients with deleterious or suspected deleterious germline 
BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have 
been treated with three or more prior lines of chemotherapy.  Recently, this approval was 
extended to maintenance therapy following front-line chemotherapy based on the results 
of the SOLO-1 trial (Moore, 2018).
Clinical PK
The recommended tablet monotherapy dose is 300 mg twice daily (bd). Following a 
single 300 mg po tablet dose the mean apparent oral plasma clearance was approximately 
7.4 L/h (Sd 3.9 L/h). Olaparib exhibited a mean volume of distribution of 158 L (Sd 136 
L), indicating distribution into the tissues. The plasma protein binding in vitro was 
moderate and showed evidence of concentration dependence (% unbound was 81.9% at 
10 μg/ml).
Clinical Safety Summary
As of 15 December 2016, approximately 6558 patients are estimated to have received 
olaparib in the clinical program including AstraZeneca-sponsored studies (3923 patients), 
a Managed Access Program (MAP; 676 patients), investigator-sponsored studies and 
collaborative group studies (1959 patients). Toxicities considered to be associated with 
administration of olaparib include hematological effects (anemia, neutropenia, 
lymphopenia, leukopenia, thrombocytopenia, mean corpuscular volume [MCV] 
elevation), decreased appetite, nausea and vomiting, diarrhea, dyspepsia, stomatitis, 
upper abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood 
creatinine, headache, dizziness, hypersensitivity, rash and dermatitis. In a small number 
of patients, pneumonitis, myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia 
(AML) and new primary malignancies have been reported.
CTLA4 immune checkpoint inhibition and ovarian cancer
Immunotherapy has been identified as a breakthrough in cancer treatment, leading to new 
treatment paradigms in multiple tumor types (Pardoll, 2012; McNutt, 2013).  Despite 
evidence that ovarian cancer is a target for immunomodulatory regimens, there are 
currently no approved immune therapies for ovarian cancer (Zhang, 2003). Multiple 
studies have demonstrated that tumor-infiltrating T cells are associated with improved 
prognosis for women with ovarian cancer, however the functional capacity of tumor-
specific lymphocytes is restricted in the immunosuppressive ovarian tumor 
microenvironment (Hwang, 2009; Lavoue, 2013).  One mechanism for T cell inhibition 
in ovarian cancers results from signaling through co-inhibitory receptors, restricting 
lymphocyte activation and promoting functional exhaustion (Topalian, 2015; Flies, 
2016).  Antibody-mediated blockade of these signaling pathways has achieved durable 
treatment benefit in melanoma and other solid tumors (Ott, 2013). To date, however, 
ovarian tumors have been relatively resistant to immune checkpoint inhibition (Hodi, 
2003).
CTLA-4 blockade is thought to maintain T cell activation and promote the establishment 
of tumor-specific immune responses. CTLA-4 inhibition was the first immune checkpoint 
blockade strategy to be approved by the FDA in 2011 based on phase III trials in 
melanoma (Hodi, 2010).  The observed disease stabilization and durable remissions 

 
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among patients who respond to CTLA-4 antibody therapy has significantly improved 
outcomes for this disease and other solid tumors (Sangro, 2013; Camacho, 2009; Ralph, 
2010; Millward, 2013). Women with ovarian cancer enrolled in early clinical trials of 
CTLA-4 antibody therapy had evidence of tumor marker reduction, but did not 
demonstrate the clinical benefit observed in subjects with melanoma (Hodi, 2003).  Here 
we present a strategy to use PARP inhibitors to sensitize ovarian tumors to CTLA-4 
immune checkpoint inhibition.   
 
2.3.1 Tremelimumab 
 
2.3.1.1 Mechanism of Action 
Tremelimumab is a human IgG2 mAb that is directed against cytotoxic T lymphocyte-
associated molecule (CTLA)-4 (CD152), a cell surface receptor that is expressed 
primarily on activated T cells and acts to inhibit their activation.  Tremelimumab 
completely blocks the interaction of human CTLA-4 with CD80 and CD86, resulting in 
increased release of cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T 
cells, peripheral blood mononuclear cells and whole blood (Tarhini and Kirkwood, 2008).  
Tremelimumab is being developed by AstraZeneca for use in the treatment of cancer.  
Refer to the current tremelimumab Investigator’s Brochure for a complete summary of 
non-clinical and clinical information including safety, efficacy and pharmacokinetics. 
 
2.3.1.2 Clinical PK 
Clinically, tremelimumab exhibits linear (dose-proportional) PK following IV infusion.  
The estimate of CL, volume of distribution at steady state (Vss), and terminal-phase half-
life is 0.132 mL/h/kg, 81.2 mL/kg and 22.1 days, respectively.  These values are 
consistent with those of natural IgG2. 
 
2.3.1.3 Clinical safety summary 
As of July 12, 2017, approximately 1617 patients have been exposed to one or more 
doses of tremelimumab monotherapy across company-sponsored studies, legacy studies, 
and externally sponsored studies.  Identified risks of tremelimumab monotherapy 
based on the DETERMINE study include diarrhea (47.1%), colitis/enterocolitis 
(9.2%/0.5%), intestinal perforation (0.8%), hypophysitis (1.1%), hypothyroidism (3.4%), 
hyperthyroidism (1.1%), adrenal insufficiency (1.3%), rash (20.8%), and pruritus 
(27.1%); in addition, increased amylase (2.1%) and lipase (4.7%) are identified 
laboratory abnormalities 
 
2.3.1.4 AESIs and irAEs  
 
Adverse events of special interest (AESIs) and immune-related adverse events (irAEs) 
associated with tremelimumab include hepatitis, including autoimmune hepatitis, and 
increased serum ALT and AST; pancreatitis; respiratory tract events, including 
pneumonitis and interstitial lung disease; nervous system events, including encephalitis, 
peripheral motor and sensory neuropathies, proximal muscle weakness, and Guillian-
Barre; cytopenias including thrombocytopenia, anemia and neutropenia; renal failure, 
acute kidney injury, nephritis and nephrotic syndrome, including autoimmune nephritis, 

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electrolyte abnormalities; autoimmune diseases including autoimmune arthritis, Sjogren's 
syndrome, giant cell temporal arteritis and ulcerative colitis; and hyperglycemia, 
including diabetes mellitus.
The incidence and/or severity of many of the AEs observed following administration of 
tremelimumab can be reduced by following current guidelines for the management of 
immune-mediated toxicities.  A detailed summary of tremelimumab monotherapy AE 
data can be found in the current version of the Tremelimumab Investigator’s Brochure 
(2017).  
Rationale for combining olaparib with CTLA4 immune checkpoint inhibition
2.4.1
Preclinical studies:  Evidence that PARP inhibition synergizes therapeutically with
CTLA-4 blockade comes from preclinical work in our lab (Higuchi, 2015).  These studies 
used an immune competent BRCA1m murine ovarian cancer model, which demonstrated
selective sensitivity to PARP-inhibition in vitro and evidence of in vivo tumor 
cytotoxicity.  Despite confirmed activity in vivo, monotherapy with the PARP-inhibitor 
did not improve overall survival, even at doses of 40mg/kg which is four-fold higher than 
the recommended treatment doses for patients (veliparib, olaparib 400mg BID).  In 
contrast, when a PARP-inhibitor was administered together with a single dose of CTLA-
4 antibody, all mice survived longer than controls and 80% demonstrated durable tumor-
free survival (p<0.001 compared with either agent alone).  In these experiments, 
combined therapy with the PARP-inhibitor and the CTLA-4 antibody successfully 
induced protective immune memory. 
We attribute the observed synergy of PARP inhibition and CTLA-4 blockade in ovarian 
cancer to dynamic interactions with conditions in the ovarian tumor environment 
(Higuchi, 2015; Klemm, 2015; Swartz, 2012; Quail, 2013; Su, 2016). PARP inhibition 
together with CTLA-4 blockade induces a marked increase in interferon-gamma 
production by tumor-associated CD4 and CD8 T cells that is sustained long after 
completion of therapy (Higuchi, 2015).  Interferon-gamma enhances the cytotoxic effects 
of PARP-inhibition in vitro and is required for a survival benefit in vivo (Higuchi, 2015; 
Warrener, 2012). This is in keeping with evidence that interferon signaling directs both 
cell-intrinsic and cell-extrinsic determinants of response to cytotoxic agents (Minn, 2015, 
2016).  We interpret these data as evidence of a positive feedback loop in which PARP 
inhibitor-induced tumor cell death results in the recruitment of T cells to the tumor 
environment.  Released from CTLA4 inhibition, these T cells produce high levels of 
interferon-gamma, which engages additional cytotoxic effects to promote tumor 
clearance.  These results indicate that the CTLA4 immune checkpoint may be an 
important therapeutic target in the ovarian tumor microenvironment. 
2.4.2
Clinical studies:  Based on the selective therapeutic synergy of CTLA-4 blockade and 
PARP inhibition in our preclinical studies, we launched INST 1419:  A phase I/II study 
of the combination of olaparib and tremelimumab in BRCA1 and BRCA2 mutation 
carriers with recurrent ovarian cancer (NCT02571725, S. Adams, Principal Investigator).  
Women with a confirmed germline BRCA1 or BRCA2 mutation and recurrent ovarian, 
tubal or peritoneal cancer are eligible for this trial.  The study has no restrictions on the 

 
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number or type of prior treatment, including prior PARP inhibitor or immune therapy, 
and women with both platinum-sensitive and platinum-resistant disease are eligible. As a 
result, subjects enrolled to date comprise a heavily pre-treated cohort with an average of 
3.2 prior chemotherapy regimens (range 1-7). Olaparib is administered at 300mg by 
mouth twice daily, and tremelimumab is dosed at 10mg/kg every 4 weeks for 4 to 6 
cycles followed by maintenance dosing every 12 weeks.   
 
The phase I portion of this study revealed no evidence of new toxicity in subjects 
receiving the combination of olaparib and tremelimumab beyond what has been reported 
with monotherapy regimens. The most common grade 3 adverse event has been colitis or 
gastroenteritis (17% of patients treated to date). Notably, grade 3 colitis or gastritis was 
significantly associated with a history of prior gastrointestinal surgery (Harris, 2018).  
Additional grade 3 toxicity observed among 36 patients receiving at least one cycle of 
treatment includes anemia (17%), electrolyte abnormalities (14%), fatigue (14%), 
hypophysitis or adrenal insufficiency (10%), rash (8%), myalgias (8%), muscle weakness 
(8%), headache (8%), fever (8%), leukocytosis (8%), and thrombocytopenia (8%).   
 
The primary endpoint for the phase II portion of the trial is overall response rate based on 
modified world health organization immune related response criteria (mWHO irRC) 
(Wolchock, 2009).  Among the first 13 patients who completed three cycles of treatment, 
clinical responses were observed in 10 (4 complete responses, 6 partial responses, ORR 
77%).  This compares favorably with historic response rates of 31% to olaparib 
monotherapy (Matulonis, 2016).   
 
Evidence that the clinical response to olaparib and tremelimumab is not exclusively due 
to the sensitivity of BRCAm cancers to PARP inhibition is demonstrated by the 
significant reduction in tumor burden observed in a subject whose tumor was refractory 
to prior olaparib monotherapy.  This patient previously received single-agent olaparib, 
but stopped treatment after 4 cycles when a CT scan demonstrated tumor progression.  
Following initiation of treatment on NCT02571725 with olaparib and tremelimumab in 
March 2016, she had a partial response by cycle 3 (63% reduction in tumor burden by 
mWHO).  Due to immune-related toxicity, tremelimumab was discontinued after cycle 5, 
however she had an additional 50% reduction in tumor burden from cycle 6 to cycle 9 
while receiving ongoing olaparib monotherapy on study.  These results indicate that the 
addition of tremelimumab to olaparib had benefit beyond olaparib monotherapy in this 
patient. 
 
While our current phase II single-arm study of olaparib and tremelimumab is limited to 
women with germline BRCA1/2 mutations, evidence that PARP inhibitors are active in 
the treatment of BRCAwt tumors indicates that a majority of women with ovarian cancer 
could benefit from the combination of PARP inhibition and CTLA4 blockade. With 
evidence that this regimen has significant clinical activity in heavily pre-treated women 
with ovarian cancer, we propose to test whether combined olaparib and tremelimumab 
will improve progression free survival for women with recurrent disease compared with 
olaparib monotherapy. This presents an opportunity to adapt the recent paradigm shift in 
cancer treatment to achieve lasting benefit for women with ovarian cancer by combining 
immune therapy with targeted cytotoxic agents. 

 
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2.5   
Rationale for the control arm 
Recent trials of olaparib restricted to women with platinum-sensitive recurrent disease 
have reported response rates of 63% among gBRCAm patients and as high as 32% in 
BRCAwt patients (Liu, 2014).  In light of the significant activity of olaparib monotherapy 
and the fact that this regimen is well-tolerated, we have chosen to use olaparib as the 
control regimen to determine whether the addition of tremelimumab can significantly 
improve patient outcomes beyond what has been achieved with olaparib monotherapy. 
 
2.6 
Rationale for Exploratory Biomarker Testing in Collaboration with CIMAC (27-
AUG-2021) 
Note: The final biomarker assays and analyses at CIMAC-CIDC will be based on the 
“Proposal Intake Form for Investigators Using the CIMAC-CIDC Network” for this 
trial. The Intake Form will be reviewed and approved by NCI and the CIMAC-CIDC 
coordination center before testing of banked biospecimens. 
 
2.6.1 Gene Expression Signatures 
We hypothesize that conditions in the tumor environment measured by gene expression 
signatures in archived tumor samples will identify patients who will benefit from 
combined therapy with olaparib and tremelimumab. 
 
IFNgamma: With evidence that IFNgamma is required for the treatment response to 
PARP inhibition and CTLA4ab in ovarian cancer models, will predict that an interferon 
gene expression signature will be linked with response to olaparib + tremelimumab 
(Weichselbaum, 2008). This analysis will follow the guidelines outlined by Pepe, et. al. 
for a Phase I/II biomarker trial, with the objective of 1) identifying and prioritizing 
potential biomarkers that correlate with survival; and 2) estimating the true positive, and 
false positive rate of these biomarkers. We will compare the TSP classifier based on the 
IRDS gene expression score in archived tumor from these subjects to determine the 
sensitivity of this score in predicting treatment outcomes. We will estimate the sensitivity 
and specificity of the TSP classifier and the receiver operating curve for the IRDS score. 
 
Autophagy: An autophagy-linked gene signature has been predictive of response to 
CTLA4ab but not PD1ab in melanoma (Shulka, 2018). With pre-clinical data 
demonstrating selective synergy of PARPi and CTLA4 blockade (Higuchi, 2015), we 
hypothesize that this autophagy-linked signature will also predict response to olaparib + 
tremelimumab.  
 
VEGF: A VEGFs signature has been linked with BRCAm status and T cell recruitment 
to tumor sites (Yin, 2016). With evidence that BRCAm status modulates tumor 
angiogenesis, with downstream effects on T cell infiltration, we hypothesize that VEGFs 
expression will correlate with response to olaparib + tremelimumab. 
 
NFkB pathway activation: We and others have demonstrated that PARP inhibitors 
suppress NFkB activation. We hypothesize that this effect modulates IFNg signaling 
pathways to promote immunogenic cell death in tumors, contributing to the therapeutic 

 
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synergy of PARP inhibition and CTLA4 blockade. We hypothesize that an NFkB 
activation signature will be predictive of response to olaparib + tremelimumab. 
 
2.6.2 Homologous Repair Deficiency (HRD) Status 
Based on evidence that ovarian cancers associated with mutations in BRCA1/2 genes or 
other evidence of homologous repair deficiency (HRD+) have a high neoantigen load, 
and that HRD+ tumors are more responsive to PARP-inhibition, we hypothesize that 
HRD status is not only prognostic, but also predictive for combined olaparib and 
tremelimumab treatment. Whole exome sequencing (WES) will be used to confirm 
BRCAm status and to identify sBRCAm tumors. 
 
2.6.3 Tumor Infiltrating Leukocytes 
Tumor infiltrating lymphocytes have been associated with a marked survival advantage 
in ovarian cancer (Zhang 2003, Hwang 2009). Subsequent work in ovarian cancer and 
other tumor types have provided additional evidence that leukocyte populations in the 
tumor microenvironment can identify patients likely to benefit from immune therapy. We 
hypothesize that high numbers of intraepithelial CD8 T cells, and low numbers of 
FoxP3+CD4 T cells will be associated with better overall survival and with clinical 
response to olaparib + tremelimumab. Additional exploratory assays will compare tumor 
infiltration by additional leukocyte subsets including tumor associated macrophages and 
dendritic cells. PDL1 expression on tumor cells, but not on myeloid cells in the TME, has 
been associated with outcomes in ovarian tumor models. We plan to compare PDL1 
expression in the TME with treatment outcomes and changes in circulating leukocyte 
populations. 
 
2.6.4 Tumor Mutational Burden 
Tumor mutational burden has been associated with response to immune checkpoint 
inhibition and CTLA4 blockade in particular. BRCAm tumors and HRD ovarian cancers 
have been shown to have high TMB. We hypothesize that TMB will correlate with 
response to olaparib + tremelimumab. TMB in cell-free DNA will be used to assess for 
changes in response to treatment and an association with clinical outcome. Tumor 
infiltrating lymphocytes are expected to be more prevalent in tumors with high TMB 
scores.  
 
2.6.5 Circulating Leukocyte Subsets 
Response to immune checkpoint blockade has been linked with changes in circulating 
lymphocyte subsets. In particular, an increase in PD1+Ki67+ “reactivated” T cells is 
linked with response to immune therapy in patients with melanoma. In addition, multi-
parameter analyses of circulating leukocytes has demonstrated that both myeloid and 
lymphoid subset remodeling is associated with immunotherapeutic efficacy in preclinical 
models (Gubin, 2018). We hypothesize that dynamic changes in circulating leukocyte 
subsets will predict response to olaparib + tremelimumab. We will also compare the 
impact of olaparib + tremelimumab with olaparib monotherapy on circulating leukocyte 
subsets to identify immunomodulatory effects of PARP inhibition and the added impact 
of CTLA4 blockade in this patient population. Multiplex IHC will be used to provide 
information about lymphocytes in the TME prior to treatment for comparison with 

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circulating subsets at baseline.
2.6.6
Cell-Free DNA
Mechanisms of drug resistance: Reversion of BRCA mutations has been identified as a 
mechanism of acquired resistance to PARP inhibitors. This can be measured in cfDNA, 
and has been associated with response to treatment in ovarian cancer (Lin, 2019). In our 
single-arm trial of olaparib + tremelimumab, we have observed a significant difference in 
response based on prior PARP inhibitor use. Notably, a patient with primary resistance to 
olaparib did have a clinical response to olaparib + tremelimumab. In contrast, patients 
who developed resistance following long-term treatment with a PARP inhibitor have not 
responded to olaparib + tremelimumab. Based on these observations, we hypothesize that 
specific mechanisms of resistance to prior PARP inhibitor therapy can determine a 
patient’s response to the combination of olaparib + tremelimumab. We propose to use 
cfDNA to assess BRCAm status as a mechanism of acquired resistance to prior PARP 
inhibition, and to compare this with treatment efficacy.
Tumor mutational burden: TMB has been successfully assessed using cfDNA in other 
tumor types (Anagnostou, 2019). Changes in TMB are predictive of response to immune 
checkpoint blockade in patients with lung cancer. We propose to compare TMB during 
treatment as a biomarker of response. We will additionally compare baseline and on-
treatment TMB with an assessment of TMB in archived tumor tissue to compare the 
predictive utility of these assays.
ELIGIBILITY, AND INELIGIBILITY CRITERIA
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page).
3.1
Eligibility Criteria
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met.
Submission of tumor tissue is required for all patients. Investigators should check with 
their site’s pathology department regarding release of biospecimens before approaching 
patients about participation in the trial. (See Section 10 for details.)
3.1.1
Patients must have platinum-sensitive, recurrent high-grade serous or high-grade 
endometrioid (grade 3) ovarian, primary peritoneal, or fallopian tube cancer.
Patients with other histologies are also eligible, provided that the patient has a known 
deleterious germline or somatic BRCA1 or BRCA2 mutation identified through testing at 
a clinical laboratory.
Submission of pathology reports and BRCA testing reports (germline and/or somatic) is 
required for all patients.

 
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3.1.1.1 Platinum-sensitive disease defined as no clinical or radiographic evidence of disease 
recurrence for > 6 months (or 182 days) after last receipt of platinum-based therapy. The 
date should be calculated from the last administered dose of platinum therapy. 
 
3.1.1.2 Patients must have had response (complete or partial) to their prior line of platinum 
therapy and cannot have had progression through prior platinum-based therapy.   
 
3.1.2 Patients must have RECIST 1.1 measurable disease.  Patients with biochemical 
recurrence based on CA125 levels alone are not eligible. 
 
3.1.3 Prior therapy: 
• Prior chemotherapy must have included a first-line platinum-based regimen with 
or without consolidation chemotherapy. 
• Prior bevacizumab therapy as a component of frontline or recurrent treatment is 
permitted. 
• Patients may have received an unlimited number of platinum-based therapies in 
the recurrent setting. 
• Patients may have received up to one non-platinum-based line of therapy in the 
recurrent setting.  Prior hormonal therapy will not be counted as this non-
platinum-based line. 
• Prior treatment with a PARP inhibitor: 
▪ Patients may not have had a prior PARP inhibitor in the recurrent setting.   
▪ Prior use of a PARP inhibitor in the upfront maintenance setting is 
allowed for women with a confirmed BRCA1 or BRCA2 germline or 
somatic mutation. 
▪ Women who received a PARP inhibitor for maintenance therapy in the 
frontline setting must have received at least one other chemotherapy 
regimen for recurrence prior to enrolling on this trial.   
▪ Patients who demonstrated disease progression while on a PARP inhibitor 
are excluded. 
• Prior hormonal therapy for ovarian, primary peritoneal, or fallopian tube cancer 
is acceptable. 
 
3.1.4 Age ≥ 18. 
 
3.1.5 Body weight >30 kg. 
 
3.1.6 ECOG Performance Status of 0, 1 or 2 (see Appendix II). 
 
3.1.7 Adequate hematologic function within 14 days prior to enrollment defined as follows: 
• ANC ≥ 1,500/mcl 
• Platelets ≥ 100,000/mcl 
• Hemoglobin ≥ 10 g/dL 
▪ Note: blood transfusions are not permitted within 28 days prior to 
enrollment (see section 3.2.17). 

 
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3.1.8 Adequate renal function within 14 days prior to enrollment defined as follows: 
• Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN) 
3.1.9 Adequate hepatic function within 14 days prior to enrollment defined as follows: 
• Total bilirubin ≤ 1.5 x institutional ULN. 
• AST and ALT ≤ 3 times institutional ULN. 
 
3.1.10 Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and 
TSH within normal limits.  Thyroid replacement therapy is permitted to achieve a TSH 
within normal limits. 
 
3.1.11 Patients must be able to swallow and retain oral medications and not have gastrointestinal 
illnesses that would preclude absorption of olaparib as judged by the treating physician. 
 
3.1.12 Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-
menopausal patients.  Women will be considered post-menopausal if they have been 
amenorrheic for 12 months without an alternative medical cause.  The following age-
specific requirements apply: 
 
• Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution/laboratory or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
 
• Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
 
• Administration of study drugs (olaparib, tremelimumab) 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 two (2) highly 
effective forms of contraception from up to 14 days prior to enrollment (for oral 
contraceptives), during treatment, and for 6 months after the last dose of study 
medication. 
 
3.1.13 Life expectancy ≥12 weeks. 
 
3.1.14 Patients with brain metastases are eligible if follow-up brain imaging after CNS-directed 
therapy shows no evidence of progression. Imaging studies must have been completed no 
later than 14 days prior to enrollment.  In addition, patients must have been successfully 

 
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weaned off steroid support.  Patients should not have received steroids for the treatment 
of brain metastases within 14 days prior to enrollment. 
 
3.1.15 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. 
3.1.16 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. 
 
3.2 
Ineligibility Criteria 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.2.1 Active infection requiring antibiotic therapy (except for uncomplicated urinary tract 
infections), including tuberculosis.  
 
3.2.2 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. 
 
3.2.3   Hormonal therapy directed at treatment for the cancer must be discontinued at least 28 
days prior to enrollment. Hormone replacement therapy for symptom management is 
permitted.  
 
3.2.4  Any other therapy directed at treating the cancer including chemotherapy, 
biologic/targeted agents, and immunologic agents, unless discontinued at least 28 days 
prior to enrollment.  
 
3.2.5 Any radiation therapy unless discontinued at least 28 days prior to enrollment. 
 
3.2.6 Major surgical procedure within 28 days prior to enrollment.   
 
3.2.7 Current or prior use of immunosuppressive medication within 14 days before enrollment.  
The following are exceptions to this criterion: 
 
a.  Intranasal, inhaled, topical steroids, or local steroid injections (i.e. intra-articular 
injection) 
 
b.  Systemic corticosteroids at physiologic doses not to exceed 10mg/day of prednisone 
or its equivalent 
 
c.  Steroids as premedication for hypersensitivity reactions (i.e. CT scan contrast allergy 
premedication) 
 

 
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3.2.8  Patients with active autoimmune disease that has required systemic treatment in the past 
2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
• Patients with autoimmune disease (e.g., psoriasis, extensive atopic dermatitis, severe 
asthma, IBD, M.S., uveitis, vasculitis) requiring concurrent use of any systemic 
immunosuppressants or steroids are excluded from the study. Patients with vitiligo, 
mild, intermittent asthma requiring only occasional beta-agonist inhaler use, or mild 
localized eczema are eligible.  
• Any patient with an allo-transplant of any kind is excluded, including xenograft heart 
valve.  
• Chronic use of immune-suppressive drugs (i.e. systemic corticosteroids) for the 
management of cancer or non-cancer related illnesses (i.e. COPD).  
 
Note: ongoing steroid use for the management of brain metastases is not permitted per 
section 3.1.14. 
 
3.2.9 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib or tremelimumab.  
 
3.2.10  Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 
interstitial lung disease, serious chronic gastrointestinal conditions associated with 
diarrhea, or psychiatric illness/social situations that would limit compliance with study 
requirements, substantially increase risk of incurring AEs or compromise the ability of 
the patient to give written informed consent.  
 
3.2.11  Subjects must not have evidence of bowel obstruction on imaging or symptoms 
consistent with a bowel obstruction.  Additional workup to rule this out is not required. 
 
3.2.12 Known potent CYP3A4 inhibitors or inducers must be discontinued prior to starting 
treatment. (See Section 5.2.2.)  
 
3.2.13  Symptoms associated with toxicities (> Common Terminology Criteria for Adverse 
Event [CTCAE v 5.] grade 2) caused by prior cancer therapy, excluding alopecia, 
vitiligo, and the laboratory values defined in the inclusion criteria. 
 
 
 
Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Chair.  
 
3.2.14 Patients who are receiving any other investigational agent. 
 
3.2.15  Resting ECG with QTc>470msec on two or more time points within a 24-hour period, or 
a family history of long QT syndrome. If an initial ECG is within normal limits, a repeat 
ECG is not required. 

 
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3.2.16 Patients who have previously received anti-CTLA-4 antibody therapy. 
 
3.2.17 Blood transfusions are not permitted within 28 days prior to study enrollment. 
 
3.2.18 Patients must not have signs or symptoms suggestive of myelodysplastic syndrome or 
acute myeloid leukemia.  
 
3.2.19 Pregnant or lactating patients (see Section 3.1.12) for information of contraception and 
pregnancy). 
 
3.2.20 Receipt of live attenuated vaccines within 30 days of enrollment.  Note: patients, if 
enrolled, should not receive live vaccines while receiving study treatment and up to 30 
days after the last treatment dose. Inactivated vaccines are permitted. 
 
 

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4.
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP
PRE-TREATMENT ASSESSMENTS
Assessments
See Section 10.4.1 for Mandatory Biospecimen 
Submission Information.
Prior to 
Registration
(calendar days)
Prior to 
Treatment
(calendar days)
(Cycle 1, Day 1)
History and Physical
≤14 days
≤14 days
Concomitant Medications
≤14 days
≤14 days
Vital Signs (weight required)
≤14 days
≤14 days
Performance Status
≤14 days
≤14 days
Toxicity Assessment
≤14 days
≤14 days
CBC/Differential/Platelets
≤14 days
≤14 days
Chemistries (BUN, creatinine, sodium, potassium, 
chloride, CO2, calcium, glucose, total bilirubin, total 
protein, albumin, alkaline phosphatase, AST, ALT) 
≤14 days
≤14 days
Thyroid stimulating hormone [TSH], with reflex T4 
(T4 can be omitted if TSH normal)
≤ 28 days
CA-125
≤ 28 days
≤ 28 days
Electrocardiogram (ECG)
≤ 28 days
≤28 days
Pregnancy test (for women of childbearing 
potential) Urine or serum testing is permitted
≤ 14 days
< 72 hours
Germline and/or somatic BRCA mutation testing
X
Radiographic Tumor Measurement*
≤ 28 days
≤ 28 days
*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.

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ASSESSMENTS DURING TREATMENT
Assessments
Prior to Each 
Cycle, Day 1 (after 
Cycle 1, Day 1)
Timed 
(Treatment 
Cycle 
Independent)
History and Physical
≤ 3 days
Concomitant Medications
X
Vital Signs, weight required. (See Sec 5.1.2 for 
additional monitoring during tremelimumab infusions)
X
Performance Status
X
Toxicity Assessment
X
Pregnancy test (for women of childbearing potential) 
Urine or serum testing is permitted
≤ 7 days
As clinically 
indicated
CBC/Differential/Platelets
≤ 3 days
Chemistries (BUN, creatinine, sodium, potassium, 
chloride, CO2, calcium, glucose, total bilirubin, total 
protein, albumin, alkaline phosphatase, AST, ALT)
≤ 3 days
Thyroid stimulating hormone [TSH]), with reflex T4 (T4 
can be omitted if TSH normal) (24-APR-2020)
NOTE:  FOR PATIENTS ENROLLED IN ARM 2
≤ 3 days
CA125
≤ 3 days
Radiographic Tumor Measurement
X1
Review of pill diary to assess treatment compliance
X
1
First assessment scan at 12 weeks (+/- 7 days), followed by every 8 weeks (+/- 7 
days) for the first 12 months; then every 12 weeks (+/- 7 days) thereafter. All scan 
dates calculated from cycle 1, day 1 (regardless of delays and/or changes in treatment 
schedule).  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 or physical signs suggestive of new or 
progressive disease. A tool is provided to calculate dates of re-imaging. Utilize same
imaging modality of abdomen, pelvis and chest (see footnote under Pre-Treatment 
Assessments) as for pre-cycle 1 baseline assessment. PET CT should not be used.

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ASSESSMENTS IN FOLLOW UP
Assessments
Timed
Vital Status
1
Physical exam and labs, including CBC, Chemistries with 
LFTs and TSH (for patients on Arm 2)
2
Toxicity Assessment
3
Radiographic tumor measurement
4
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
Monthly for 3 months after discontinuation of tremelimumab.
3
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.
4
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 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.

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TREATMENT PLAN/REGIMEN DESCRIPTION
Treatment Plan
Protocol treatment should begin within 7 days of registration.
ARM 1
Olaparib 300 mg (2 x 150 mg tablets) PO twice daily until disease progression or adverse 
events prohibit further treatment
ARM 2
Olaparib 300 mg (2 x 150 mg tablets) PO twice daily until disease progression or adverse 
events prohibit further treatment
Tremelimumab 750 mg* IV over 60 minutes on Day 1 every 4 weeks for 4 cycles, then 
every 12 weeks for up to 2 years total.  
*If a patient’s weight falls to ≤ 30 kg, the patient should receive weight-based dosing 
equivalent to 10 mg/kg of tremelimumab every 4 weeks.  These adjustments apply to all 
cycles until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of tremelimumab, 750 mg every 4 weeks. (24-APR-2020)
ONE CYCLE = 4 weeks
Safety Lead-In Components:  Two safety lead-in components are included in this study 
as detailed in section 13.6.2.  If the study is deemed safe after each component following 
review by the Data Safety Monitoring Board, it will continue to accrue patients for 
assessment of the primary endpoints of the phase II trial.  Importantly, all patients 
enrolled in the safety-lead in portions of the study will be included in the assessment of 
primary endpoints for this trial.
5.1.1
Administration of Olaparib
•
For Arm 2, Olaparib will be started concomitantly with the first dose of 
Tremelimumab.
•
Treatment will be administered on an outpatient basis.
•
No premedications are required, however standard of care anti-emetics are permitted 
if clinically indicated.
•
Pills should not be chewed, dissolved or crushed.  Pills may be taken with food.
•
Olaparib should be taken twice daily, with 12 hours between doses. Missed doses 
should be made up within 2 hours; otherwise they should be skipped.

 
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5.1.2 Administration of Tremelimumab 
Patients will have their blood pressure and pulse measured before, during, and after every 
infusion at the following times (based on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In the 60 minute observation period post-infusion for cycle 1: 30 and 60 minutes 
after the infusion (i.e., 90 and 120 minutes from the start of the infusion) (±5 
minutes) – for the first infusion only and then for subsequent infusions as 
clinically indicated. If the infusion takes longer than 60 minutes, then blood 
pressure and pulse measurements should follow the principles as described above 
or more frequently if clinically indicated. 
 
Tremelimumab is administered intravenously. Possible risks associated with IV 
administration of tremelimumab are infection, redness, swelling, pain, and induration at 
the administration site as well as infusion related reactions such as cytokine release 
syndrome, cytokine storm, anaphylactic and anaphylactoid reactions, and drug 
hypersensitivity.  Management of infusion reactions will include the following:  
 
• In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study 
drug may be decreased by 50% or interrupted until resolution of the event and re-
initiated at 50% of the initial rate until completion of the infusion.  For patients 
with a ≤Grade 2 infusion-related reaction, subsequent infusions may be 
administered at 50% of the initial rate.  Acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) or equivalent medications per institutional standard may 
be administered at the discretion of the investigator. 
 
• If the infusion-related reaction is ≥Grade 3 in severity, study drug will be 
discontinued and managed as follows: 
▪ Immediate interruption of the infusion. 
▪ Immediate IV administration of diphenhydramine, ranitidine or famotidine, 
and corticosteroids for the treatment of cytokine release syndrome.  
▪ In patients suspected of demonstrating anaphylaxis or those with infusion 
reactions which do not respond to the above measures the use of IV/IM 
epinephrine should be considered. 
▪ If epinephrine is required for anaphylaxis or to control an infusion-related 
reaction, discontinue the infusion permanently.  Patients experiencing > Grade 
3 infusion reaction should not receive any additional tremelimumab.  If 
tremelimumab is discontinued due to toxicity, patients may continue treatment 
with olaparib monotherapy. 
 
NOTE: As with any antibody, allergic reactions to dose administration are possible.  
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.  The study site must have immediate access to emergency resuscitation 
teams and equipment in addition to the ability to admit patients to an intensive care unit if 

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necessary.
General Concomitant Medication and Supportive Care Guidelines
5.2.1
Permitted Supportive/Ancillary Care and Concomitant Medications
All standard of care anti-emetics, anti-diarrheals, and antibiotics are permitted if 
clinically indicated.
5.2.1.1 Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications identified 
as “prohibited,” as listed in Section 5.2.2.
To be administered as 
prescribed by the 
Investigator
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc])
Should be used, when 
necessary, for all patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
5.2.2
Prohibited Therapies
Based on in vitro data and clinical exposure data olaparib is considered unlikely to cause 
clinically significant drug interactions through inhibition or induction of CYP enzyme 
activity. In vitro data have shown that the principal enzyme responsible for the formation 
of the 3 main metabolites of olaparib is CYP3A and in vivo data have shown that 
metabolism is an important route of clearance in humans. Consequently, to ensure patient 
safety the following potent inhibitors of CYP3A must not be used by any patient 
receiving olaparib. While this is not an exhaustive list, it covers the known potent 
inhibitors that have most often previously been reported to be associated with clinically 
significant drug interactions: ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, 
telithromycin, clarithromycin and nelfinavir (wash-out period 1 week). 
In addition, to avoid potential reductions in exposure due to drug interactions and, 
therefore, a potential reduction in efficacy, the following CYP3A4 inducers should be 
discontinued prior to starting study treatment: phenytoin, rifampicin, rifapentin, rifabutin, 
carbamazepine, phenobarbitone, nevirapine, modafinil and St John’s Wort (Hypericum 
perforatum). 

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5.2.2.1 Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any concurrent anticancer drugs other than 
those under investigation in this study
Should not be given concomitantly while the patient 
is on study treatment. 
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding [10 mg/day] of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to tremelimumab infusions. The 
following are allowed exceptions:
•
Use of immunosuppressive medications for 
the management of IP-related AEs, 
•
Use in patients with contrast allergies. 
•
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (e.g., chronic 
obstructive pulmonary disease, nausea, etc.).
Drugs with laxative properties and herbal or 
natural remedies for constipation
Should be used with caution through to 90 days after 
the last dose of tremelimumab during the study
Live attenuated vaccines
Should not be given through 30 days after the last 
dose of IP (including SoC)
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless approved 
by the Study Chair
5.2.3
Participation in Other Trials
Patients are not to participate in other therapeutic trials.  However, trials that do not add 
experimental agents are allowed (e.g., imaging trials, quality of life).
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in Section 5.1 or until one of the following criteria applies:
▪
Disease progression.
▪
Intercurrent illness that prevents further administration of treatment,
▪
Grade >3 infusion reaction.
▪
Unacceptable adverse event(s), as described in Section 6.
▪
Patient decides to withdraw consent for participation in the study, or
▪
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator.
▪
Patient non-compliance.
▪
Initiation of alternative anticancer therapy including another investigational agent
▪
Pregnancy or intent to become pregnant in women of child-bearing potential.

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▪
All women of child-bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation.
▪
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study (See section 7.5.4).
▪
Termination of the study by the sponsor.
▪
The drug manufacturer can no longer provide the study agent.
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and 
the corresponding dates must be documented in the Case Report Form (CRF).
TREATMENT MODIFICATIONS/MANAGEMENT
NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5 is used for this 
study.  Any toxicity observed during the course of the study should be managed by 
interruption of the dose of study treatment if deemed appropriate by the investigator. 
Repeat dose interruptions are allowed as required, for a maximum of 14 days on each 
occasion.  If the interruption is any longer, the study team must be informed. Study 
treatment must be interrupted until the patient recovers completely or the toxicity reverts 
to the National Cancer Institute (NCI) CTCAE v.5 Grade 1 or less. 
Dose Re-escalation is Not permitted.
Olaparib Dose Modifications
Olaparib starting dose
Dose reduction 1
Dose reduction 2
300 mg BID 
(2 x 150 mg tablets)
200 mg BID
(2 x 100 mg tablets)
150 mg BID
(1 150mg tablet)
6.1.1
Management of anemia (see table below): 
•
Adverse events of anemia CTCAE Grade 1 or 2 (Hb ≥8 g/dl) should be investigated 
taking into account previous history of anemia. Common treatable causes of anemia 
(e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) should be 
excluded. 
•
The first occurrence of anemia with Hb < 10 and > 8g/dl will be managed based on 
the investigator’s judgement. Patients may receive transfusion or olaparib may be 
held for a maximum of 14 days. 
•
Repeat occurrence of anemia with Hb < 10 and > 8 requires a 1-level dose reduction 
to 200mg twice daily. 
•
An additional dose reduction to 150mg twice daily may be required if anemia 
persists (see table below).

 
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• If a patient has been treated for anemia with multiple blood transfusions without 
study treatment interruptions and becomes blood transfusion dependent as judged by 
investigator, study treatment should be interrupted for up to a maximum of 14 days to 
allow for bone marrow recovery. Study treatment should be restarted at a reduced 
dose. 
 
 
Hemoglobin  
Action to be taken  
Hb < 10 but ≥ 8 g/dl  
(CTCAE Grade 2)  
Give appropriate supportive treatment and 
investigate causality.  
 
Investigator judgement to continue olaparib with 
supportive treatment (e.g. transfusion) or interrupt 
dose for a maximum of 14 days.  
 
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for 
max of 14 days) until Hb ≥ 10 g/dl. Upon recovery, 
treatment may resume at the full dose.  Alternately, 
a dose reduction to 200 mg twice daily as a first 
step and to 150 mg twice daily as a second step may 
be considered based on the assessment of the 
treating physician.  
 
Hb < 8 g/dl  
(CTCAE Grade 3)  
Give appropriate supportive treatment (e.g. 
transfusion) and investigate causality.  
 
Interrupt Olaparib for a maximum of 14 days until 
improved to Hb ≥ 10 g/dl.  
 
Upon recovery, dose reduce to 200 mg twice daily 
is required.  Additional dose reduction to 150 mg 
twice daily is required in the case of repeat Hb 
decrease <10g/dl.  
 
 
6.1.2 Management of neutropenia and leukopenia: (see table below) 
• Study treatment can be restarted at the same dose if an AE of neutropenia or 
leukopenia has resolved to CTCAE Grade < 1 (ANC ≥1,500 mcl). Growth factor 
support is not recommended for routine use with olaparib.  If administered, it should 
be stopped at least 24h before restarting study drug (7 days for pegylated G-CSF). 
Any subsequent interruptions will require study treatment dose reductions.  
• If toxicity reoccurs following re-challenge with olaparib, and if further dose 
interruptions are considered inadequate for management of toxicity, then the patient 
should be considered for dose reduction or must permanently discontinue study 
treatment.  

 
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• Treatment must be interrupted if any NCI-CTCAE Grade 3 or 4 AE occurs which the 
investigator considers to be related to administration of study treatment  
 
 
 
Hematological Toxicity Dose Reductions for Olaparib  
 
ANC 1 
Platelets  
Action  
≥ 
1,500/mcl  
100,000/ mcl  
None.  
1000-
1499/mcl  
75,000-99,000/mcl  
-1st Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Do not replace missed doses. 
Restart next treatment at the full dose.  
 
-2nd Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Do not replace missed doses. 
Restart next treatment at 200mg PO BID. 
  
-3rd Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Do not replace missed doses. 
Restart next treatment at 150mg PO BID. 
  
-4th Occurrence or a delay in treatment > 28 
days: Discontinue olaparib 
 
500-
999/mcl  
50,000-74,000/mcl  
-1st Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Do not replace missed doses. 
Restart next treatment at 200mg PO BID. 
  
-2nd Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Do not replace missed doses. 
Restart next treatment at 150 mg PO BID.  
 
-3rd Occurrence or delay in treatment >14 
days: Discontinue olaparib 
 
<500/mcl  
<50,000/mcl  
-1st Occurrence: Hold current dose until 
ANC ≥ 1,500/mcl and platelets ≥ 
100,000/mcl. Restart next treatment at 
200mg PO BID.  
 

 
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-2nd Occurrence or delay in treatment >14 
days: Discontinue olaparib 
 
Note: G-CSF (Filgrastim) or other growth factors are not recommended for routine 
use with olaparib.  If administered at the treating physician’s discretion in the event 
of febrile neutropenia, G-CSF should be stopped at least 24h before restarting study 
drug. 
 
6.1.3 Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as:  
 
• ≥14 day interruption/delay in study treatment due to CTCAE Grade 3 or worse 
anemia and/or development of blood transfusion dependence  
 
• ≥14 day interruption/delay in study treatment due to CTCAE Grade 3 or worse 
neutropenia (ANC <1,000/mcl)  
 
• ≥14 day interruption/delay in study treatment due to CTCAE Grade 3 or worse 
thrombocytopenia (Platelets <50,000/mcl)  
 
Then weekly differential blood counts including reticulocytes, reticulocyte index and 
peripheral blood smear should be performed. If any blood parameters remain clinically 
abnormal after 4 weeks of dose interruption, the patient should be referred to a 
hematologist for further investigations. Bone marrow analysis and/or blood cytogenetic 
analysis should be considered at this stage according to standard hematological practice.  
 
Development of a confirmed MDS or other clonal blood disorder should be reported as 
an SAE and full reports must be provided by the investigator. Olaparib treatment should 
be permanently discontinued if patient’s diagnosis of MDS and or AML is confirmed. 
 
6.1.4 Management of non-hematologic toxicities 
 
 
Olaparib  
Non-hematological Toxicity Dose Reductions  
 
Event  
Action  
 
Nausea  
Grade 1  
Administer anti-emetics  
 
Grade 2  
Administer anti-emetics. Hold treatment until toxicity resolves to < 
Grade 1. No change from original starting dose  
 

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Grade 3 
Administer anti-emetics. Hold treatment until toxicity resolves to < 
Grade 1, then reduce to 200mg BID. 
If patients experience > Grade 2 nausea at the 200mg BID dose, 
further reduce dose to 150mg BID. 
Grade 4 
Discontinue therapy 
Fatigue 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then reduce to 200mg BID. If 
patients experience > Grade 2 fatigue at the 200mg BID dose, 
further reduce dose to 150mg BID. 
6.1.5
Criteria to Resume Treatment with Olaparib
•
Treatment may resume when the AE(s) resolve(s) to Grade 1 or baseline value. 
•
Olaparib may be restarted or continued even if a patient has experienced a SAE that 
requires permanent discontinuation of Tremelimumab (see Section 6.2 for guidelines 
regarding tremelimumab treatment).
6.1.6
Rules for Permanent Discontinuation of Olaparib: 
•
Any Grade 4 toxicity or Grade 3 toxicity attributed to olaparib that does not resolve to 
< Grade 1 within 14 days after dose reduction. 
•
No patient should be re-started on olaparib if, in the judgment of the treating 
investigator, this would be clinically contraindicated (e.g., due to the severity of the 
antecedent toxicity, or to the patient’s medical condition) 
•
Patients in Arm 2 who discontinue treatment with olaparib and who recover from 
olaparib-induced toxicity within 4 weeks of discontinuing treatment may be 
considered for ongoing treatment with Tremelimumab monotherapy after consultation 
with the Study PI. 
Tremelimumab Dose Modifications
Patients should be thoroughly evaluated and appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin, or other etiologic causes of suspected 
immune related adverse events ( irAE, see Section 6.2.1). Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis.  In 
the absence of a clear alternative etiology, events should be considered potentially 
immune related. Based on the mechanism of action of tremelimumab, no dose reductions 
will be permitted. Emergent immune-related toxicity will be managed with dose delays 
based on the severity of the event.
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines (see 
Section 6.2.1) will be applied.  The results of the full diagnostic workup (including high-

 
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resolution computed tomography (HRCT), blood and sputum culture, hematological 
parameters, etc.) will be captured in the eCRF.  It is strongly recommended to perform a 
full diagnostic workup, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed.  
 
Pneumonitis (ILD) investigation 
 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis.  The results of 
the assessment will be collected. 
 
• 
Physical examination 
o Signs and symptoms (cough, shortness of breath and pyrexia, etc.) including 
auscultation for lung field will be assessed. 
 
• 
SpO2 
o Saturation of peripheral oxygen (SpO2) 
 
• 
Other items 
o When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible: 
▪ ILD Markers (KL-6, SP-D) and β-D-glucan 
▪ Tumor markers: Particular tumor markers which are related to disease 
progression.  
 
o Additional Clinical chemistry: CRP, LDH 
 
See Section 6.2.1 for further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s law. 
 
Tremelimumab dose reductions are not permitted.  Dose may be delayed or 
permanently discontinued as directed by Dosing Modification Table below.   In case 
of doubt, the Investigator should consult with the Study PI. 
 
6.2.1 Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune-Mediated Reactions  
 
General Considerations 
General guidelines for treatment modifications: Treatment modifications will be made to manage 
potential immune-related AEs (irAEs) based on severity of treatment-emergent toxicities graded per 
NCI CTCAE v5.0. 
 
In addition to the criteria for permanent discontinuation of study drugs as described in the table below, 
permanent discontinuation of tremelimumab is also required for the following conditions: 

 
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General Considerations 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or equivalent) 
within 12 weeks after last dose of study drug/study regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of 
dosing 
 
 
AE Grade: 
Grade 1 
No dose modification 
Grade 2 
Hold tremelimumab dose until Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Tremelimumab can be resumed once event stabilizes to Grade ≤1 after completion of 
steroid taper. 
Patients with endocrinopathies who may require prolonged or continued steroid 
replacement can be retreated with tremelimumab on the following conditions: 
1. The event stabilizes and is controlled. 
2. The patient is clinically stable as per investigator or treating physician’s clinical 
judgement. 
3. Doses of prednisone of ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, tremelimumab may be permanently discontinued. 
Please refer to guidelines below. 
Grade 4 
Permanently discontinue tremelimumab. 
 
Note: There are some exceptions to permanent discontinuation of tremelimumab for Grade 4 events 
(i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).   
 
Note: tremelimumab should be permanently discontinued in Grade 2 or grade 3 events with high 
likelihood for morbidity or mortality – e.g., myocarditis, or other similar events even if they are not 
currently noted in the guidelines.   
 
Note:  subjects who discontinue tremelimumab due to irAE are eligible to continue treatment with 
olaparib monotherapy. 
 
 
Toxicity Management – general guidelines 
It is recommended that management of irAEs follows the guidelines presented in this table: 
− Adverse events with an inflammatory or immune mediated mechanism could occur in all organs, 
not all of which are noted specifically in these guidelines. 
− Patients should be thoroughly evaluated to rule out alternative etiology (e.g., disease progression, 
concomitant medications, and infections) to a possible immune-mediated event. In the absence of 
a clear alternative etiology, all such events should be managed as if they were immune related. 
General recommendations follow. 
o Symptomatic and topical therapy should be considered for low-grade (Grade 1 or 2, 
unless otherwise specified) events.  
o For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) events, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
o Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if not currently noted in the guidelines -  
Initiate high dose IV corticosteroids (methylprednisolone at 2 to 4 mg/kg/day) even if 
the event is Grade 2 when clinical suspicion is high or there has been clinical 

 
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General Considerations 
confirmation.  Consider, as necessary, discussing with the study chairs and promptly 
pursue specialist consultation. 
o Steroid tapering should be gradual over at least 4 weeks.  If symptoms recur or 
worsen during tapering, increase the corticosteroid dose (prednisone dose [e.g., up to 2 
to 4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of symptoms, 
then resume corticosteroid tapering at a slower rate (>28 days of taper). 
o If no improvement after steroids, consider more potent immunosuppressives such as 
TNF inhibitors (e.g., infliximab) (also refer to the individual sections of the imAEs for 
specific type of immunosuppressive).  Progression to use of more potent 
immunosuppressives should proceed more rapidly in events with high likelihood for 
morbidity or mortality – e.g., myocarditis, or other similar events even if not currently 
noted in the guidelines. 
o With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii 
pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring (refer to 
current NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation])a 
− Discontinuation of tremelimumab is not mandated for Grade 3/4 inflammatory reactions 
attributed to local tumor response (e.g., inflammatory reaction at sites of metastatic disease and 
lymph nodes).  Continuation of tremelimumab in this situation should be based upon a benefit-
risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for 
Adverse Events; irAE Immune-mediated adverse event; IV intravenous; NCI National Cancer 
Institute; PO By mouth. 

 
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 Dose Delay Treatment modifications for Specific Immune-Mediated Reactions 
Adverse Events 
Grade of the 
Event (NCI 
CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ 
Interstitial 
Lung Disease 
(ILD) 
General Guidance:  
− Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough).  Patients should be evaluated with imaging 
and pulmonary function tests, including other diagnostic procedures as described 
below. 
− Initial workup may include clinical evaluation, monitoring of oxygenation via pulse 
oximetry (resting and exertion), laboratory workup, and high- resolution CT scan. 
Grade 1 
(asymptomat
ic, clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated) 
No dose 
modifications 
required.  However, 
consider holding 
tremelimumab as 
clinically appropriate 
pending workup for 
other etiologies. 
For Grade 1 (radiographic changes only): 
− Monitor and closely follow up in 2 to 4 
days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory workup and then as clinically 
indicated. 
− Consider Pulmonary and Infectious 
disease consult. 
Grade 2 
(symptomati
c; medical 
intervention 
indicated; 
limiting 
instrumental 
ADL) 
Hold tremelimumab 
until resolution to 
Grade ≤1. 
• If toxicity worsens, 
treat as Grade 3/4 
• If toxicity improves 
to Grade ≤1, then 
the decision to 
retreat will be based 
upon treating 
physician’s 
discretion and after 
completion of 
steroid taper. 
For Grade 2 (mild to moderate new 
symptoms): 
− Monitor symptoms daily and consider 
hospitalization. 
− Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
− Reimage as clinically indicated. 
− If no improvement within 3 to 5 days, 
additional workup should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day  
− If still no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start additional 
immunosuppressive agent such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 
2 weeks).  Caution: It is important to rule 
out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or 
anti-PJP treatment Consider pulmonary and 
infectious disease consult. 
− Consider, as necessary, discussing with 
study physician. 
Grade 3 or 
4 
Permanently 
discontinue 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening): 

 
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(Grade 3: 
severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated) 
 
(Grade 4: 
life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated 
[e.g., 
tracheostomy 
or 
intubation]) 
tremelimumab. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent. 
− Obtain Pulmonary and Infectious disease 
consult; consider, as necessary, 
discussing with study physician. 
− Hospitalize the patient and Supportive 
care 
− If no improvement within 3 to 5 days, 
additional workup should be considered 
and prompt treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks’ dose) started.  Caution: 
rule out sepsis and refer to infliximab 
label for general guidance before using 
infliximab. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days  
− Refer to General Guidelines for PCP 
prophylactics for prolonged use of 
steroids or immunesuppressanta 
Diarrhea/ Colitis For Any Grade: 
− Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal 
pain, cramping, or changes in bowel habits such as increased frequency over 
baseline or blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, or infections), including testing 
for clostridium difficile toxin, etc. 
− Steroids should be considered in the absence of clear alternative etiology, even 
for low-grade events, in order to prevent potential progression to higher grade 
event. 
− Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis. 
Grade 1 
(Diarrhea: 
stool 
frequency of 
<4 over 
baseline per 
day) 
Colitis: 
asymptomatic;
clinical or 
diagnostic 
observations 
only) 
No dose 
modifications. 
For Grade 1: 
− Monitor closely for worsening symptoms. 
− Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic 
Association colitis diet), and loperamide.  
Use probiotics as per treating physician’s 
clinical judgment. 
Grade 2 
(Diarrhea: 
stool 
Hold tremelimumab 
until resolution to 
Grade ≤1 
For Grade 2: 
− Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 

 
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frequency of 
4 to 6 over 
baseline per 
day) 
(Colitis: 
abdominal 
pain; mucus 
or blood in 
stool) 
• If toxicity worsens, 
then treat as Grade 
3 or Grade 4. 
• If toxicity improves 
to Grade ≤1, then 
tremelimumab can 
be resumed after 
completion of 
steroid taper. 
changes (e.g., American Dietetic 
Association colitis diet), and loperamide 
and/or budesonide. 
− Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− If event is not responsive within 3 to 5 days 
or worsens, obtain GI consult for 
consideration of further workup, such as 
imaging and/or colonoscopy, to confirm 
colitis and rule out perforation.  Promptly 
start IV methylprednisolone 2 to 4 
mg/kg/day. 
− If still no improvement within 3 to 5 days 
despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as infliximab at 
5 mg/kg once every 2 weeksa.  Caution: it 
is important to rule out bowel perforation 
and refer to infliximab label for general 
guidance before using infliximab. 
− Consider, as necessary, discussing with 
study physician if no resolution to Grade 
≤1 in 3 to 4 days. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and  
− Refer to General Guidelines for PCP 
prophylactics for prolonged use of steroids 
or immunesuppressanta 
Grade 3 or 
4 
(Grade 3 
diarrhea: 
stool 
frequency of 
≥7 over 
baseline per 
day; 
 
Grade 4 
diarrhea: life 
threatening 
consequences) 
(Grade 3 
colitis:  severe 
abdominal 
pain, change 
in bowel 
habits, 
medical 
intervention 
indicated, 
Grade 3 
Permanently 
discontinue 
tremelimumab for 
Grade 3 if toxicity 
does not improve to 
Grade ≤1 within 
14 days; 
tremelimumab can be 
resumed after 
completion of steroid 
taper. 
 
Grade 4 
Permanently 
discontinue  
tremelimumab 
For Grade 3 or 4: 
− Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent. 
− Monitor stool frequency and volume and 
maintain hydration. 
− Urgent GI consult and imaging and/or 
colonoscopy as appropriate. 
− If still no improvement within 3 to 5 days 
of IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent, promptly start further 
immunosuppressives (e.g., infliximab at 5 
mg/kg once every 2 weeks).  Caution: 
Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days 
− Refer to General Guidelines for infection 
and PCP prophylactics for prolonged use of 
steroids or immunesuppressanta 

 
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peritoneal 
signs; Grade 4 
colitis:  life-
threatening 
consequences, 
urgent 
intervention 
indicated) 
Hepatitis 
(elevated LFTs) 
Infliximab 
should not be 
used for 
management of 
immune-related 
hepatitis. 
 
 
 
General Guidance For Any Grade: 
− Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
− Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications). 
Grade 1 
(Based on 
ULN 
regardless of 
baseline 
LFT) 
(AST or ALT 
>ULN and 
≤3.0×ULN 
and/or TB > 
ULN and  
≤1.5×ULN) 
• No dose 
modifications. 
• If it worsens, then 
treat as Grade 2 
event. 
For Grade 1: 
− Continue LFT monitoring per 
protocol. 
Grade 2 
(Based on 
ULN 
regardless of 
baseline 
LFT) 
(AST or ALT 
>3.0×ULN 
and 
≤5.0×ULN 
and/or TB 
>1.5×ULN 
and  
≤3.0×ULN) 
• Hold tremelimumab 
dose until resolution 
to Grade ≤1. 
• If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• If toxicity improves 
to Grade ≤1 or 
baseline, resume 
tremelimumab after 
completion of steroid 
taper. 
For Grade 2: 
− Regular and frequent checking of LFTs 
(e.g., every 1 to 2 days) until 
improvement or resolution. 
− If no resolution to Grade ≤1 in 1 to 2 
days, consider, as necessary, discussing 
with study physician. 
− If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− If still no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional workup and start 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start 
further immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss with 
study physician if mycophenolate 
mofetil is not available.  Infliximab 
should NOT be used. 
− Once the patient is improving, 
gradually taper steroids over ≥28 days 

 
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and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
Grade 3 or 4 
(Based on 
ULN 
regardless of 
baseline 
LFT) 
(Grade 3: 
AST or ALT 
>5.0×ULN 
and 
≤20.0×ULN 
and/or TB 
>3.0×ULN 
and  
≤10.0×ULN) 
 
(Grade 4: 
AST or ALT 
>20×ULN 
and/or TB 
>10×ULN) 
For Grade 3: 
For transaminases 
elevations ≤8 × ULN, 
or bilirubin  elevations 
≤5 × ULN: 
• Hold tremelimumab 
until resolution to 
Grade ≤1 or baseline 
• Resume 
tremelimumab if 
LFT elevations 
resolve to Grade ≤1 
or baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue 
tremelimumab if no 
resolution within 
14 days 
 
Permanently 
discontinue 
tremelimumab for: 
• Transaminases 
elevation >8 × ULN 
or bilirubin >5 × 
ULN. 
• Any case meeting 
Hy’s law criteria 
(AST or ALT >3 × 
ULN + bilirubin >2 × 
ULN without initial 
findings of 
cholestasis (i.e., 
elevated alkaline P04) 
and in the absence of 
any alternative 
cause.b 
 
For Grade 4: 
Permanently 
discontinue 
tremelimumab. 
For Grade 3 or 4: 
− Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day 
or equivalent. 
− If still no improvement within 3 to 5 
days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil).  Discuss with 
study physician if mycophenolate is not 
available.  Infliximab should NOT be 
used. 
− Perform hepatology consult, abdominal 
workup, and imaging as appropriate. 
− Once the patient is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Nephritis or 
renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade: 
− Consult with nephrologist. 
− Monitor for signs and symptoms that may be related to changes in renal function 
(e.g., routine urinalysis, elevated serum BUN and creatinine, decreased creatinine 
clearance, electrolyte imbalance, decrease in urine output, or proteinuria). 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression or infections). 
− Steroids should be considered in the absence of clear alternative etiology even for 
low-grade events (Grade 2), in order to prevent potential progression to higher grade 
event. 
Grade 1 
(Serum 
creatinine > 1 
to 1.5 × 
baseline; > 
ULN to 1.5 × 
ULN) 
No dose 
modifications. 
For Grade 1: 
− Monitor serum creatinine weekly and any 
accompanying symptoms. 
• If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
• If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− Consider symptomatic treatment, including 
hydration, electrolyte replacement, and 
diuretics. 
Grade 2 
(serum 
creatinine 
>1.5 to 3.0 × 
baseline; >1.5 
to 3.0 × ULN) 
Hold 
tremelimumab 
until resolution 
to Grade ≤1 or 
baseline.  
• If toxicity 
worsens, then 
treat as Grade 
3 or 4. 
• If improvement 
to Grade ≤1 or 
baseline, 
resume 
tremelimumab 
after 
completion of 
steroid taper. 
For Grade 2: 
− Consider symptomatic treatment, including 
hydration, electrolyte replacement, and 
diuretics. 
− Carefully monitor serum creatinine every 2 to 
3 days and as clinically warranted. 
− Consult nephrologist and consider renal 
biopsy if clinically indicated. 
− If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− If event is not responsive within 3 to 5 days 
or worsens despite prednisone at 1 to 2 
mg/kg/day PO/IV equivalent, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone at 2 to 
4 mg/kg/day started. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
−  
Grade 3 or 4 
(Grade 3: 
serum 
creatinine 
>3.0 × baselin
e; >3.0 to 
Permanently 
discontinue 
tremelimumab. 
For Grade 3 or 4: 
− Carefully monitor serum creatinine on daily 
basis. 
− Consult nephrologist and consider renal 
biopsy if clinically indicated. 
− Promptly start prednisone 1 to 2 mg/kg/day 

 
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6.0 × ULN; 
 
Grade 4: 
serum 
creatinine 
>6.0 × ULN) 
PO or IV equivalent. 
− If event is not responsive within 3 to 5 days 
or worsens despite prednisone at 1 to 2 
mg/kg/day PO/IV equivalent, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2 to 
4 mg/kg/day started. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Rash 
(excluding 
bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE v5.0 for definition of severity/grade depending on type of skin 
rash) 
General Guidance 
For Any Grade: 
− Monitor for signs and symptoms of dermatitis (rash and pruritus). 
− IF THERE IS ANY BULLOUS FORMATION, THE STUDY PHYSICIAN 
SHOULD BE CONTACTED AND TREMELIMUMAB DISCONTINUED. 
Grade 1 
No dose 
modifications. 
For Grade 1: 
− Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., urea 
cream). 
Grade 2 
For persistent (>1 
to 2 weeks) Grade 2 
events, hold 
tremelimumab until 
resolution to Grade 
≤1 or baseline. 
• If toxicity 
worsens, treat as 
Grade 3. 
• If toxicity 
improves to 
Grade ≤1 or 
baseline, resume 
tremelimumab 
after completion 
of steroid taper. 
For Grade 2: 
− Obtain dermatology consult. 
− Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., urea 
cream). 
− Consider moderate-strength topical steroid. 
− If no improvement of rash/skin lesions occurs 
within 3 to 5 days or is worsening despite 
symptomatic treatment and/or use of moderate 
strength topical steroid, consider, as necessary, 
discussing with study physician and promptly 
start systemic steroids such as prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− Consider skin biopsy if the event is persistent 
for >1 to 2 weeks or recurs 
Grade 3 or 
4 
Grade 3: 
Hold tremelimumab 
until resolution to 
Grade ≤1 or 
baseline. 
 
If no improvement 
within 30 days, 
For Grade 3 or 4: 
− Consult dermatology. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent. 
− Consider hospitalization. 
− Monitor extent of rash [Rule of Nines]. 
− Consider skin biopsy (preferably more than 1) 

 
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permanently 
discontinue 
tremelimumab. 
 
Grade 4: 
Permanently 
discontinue 
tremelimumab 
as clinically feasible. 
− Once the patient is improving, gradually taper 
steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
− Consider, as necessary, discussing with study 
physician. 
Endocrinopathy 
(e.g., hyperthyro
idism, Type 1 
diabetes mellitus 
hypophysitis, 
hypothyroidism, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event 
of 
amylase/lipase 
increased also 
included in this 
section) 
Any Grade 
(depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE v5.0 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− Consider consulting an endocrinologist for endocrine events. 
− Consider, as necessary, discussing with study physician. 
− Monitor patients for signs and symptoms of endocrinopathies.  
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c) 
− For modest asymptomatic elevations in serum amylase and 
lipase, corticosteroid treatment is not indicated as long as 
there are no other signs or symptoms of pancreatic 
inflammation. 
− If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing. 
Grade 1 
No dose 
modifications. 
For Grade 1 (including asymptomatic TSH 
elevation): 
− Monitor patient with appropriate endocrine 
function tests. 
− For suspected hypophysitis/hypopituitarism, 
consider consultation of an endocrinologist to 
guide assessment of early-morning ACTH, 
cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test 
(though it may not be useful in diagnosing 
early secondary adrenal insufficiency). 
− If TSH < 0.5 × LLN, or TSH >2 × ULN or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist. 

 
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Grade 2 
For Grade 2 
endocrinopathy 
other than 
hypothyroidism and 
Type 1 diabetes 
mellitus, hold 
tremelimumab until 
patient is clinically 
stable. 
- If toxicity 
worsens, treat as 
Grade 3/4. 
- Tremelimumab 
can be resumed 
once event 
stabilizes and 
after completion 
of steroid taper. 
Patients with 
endocrinopathies 
who may require 
prolonged steroid 
replacement can 
resume 
tremelimumab on 
the following 
conditions: 
1. The event 
stabilizes and is 
controlled. 
2. The patient is 
clinically stable 
as per 
investigator’s 
clinical 
judgement. 
3. Doses of 
prednisone are 
≤10 mg/day or 
equivalent. 
For Grade 2 (including symptomatic 
endocrinopathy): 
− Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− For all patients with abnormal endocrine 
workup, except those with isolated 
hypothyroidism or Type 1 diabetes mellitus, 
and as guided by an  endocrinologist, consider 
short-term corticosteroids (e.g., 1 to 
2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment 
with relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
− Isolated hypothyroidism may be treated with 
replacement therapy, without tremelimumab 
interruption, and without corticosteroids. 
− Isolated Type 1 diabetes mellitus (DM) may 
be treated with appropriate diabetic therapy, 
without tremelimumab interruption, and 
without corticosteroids. 
− Once patients on steroids are improving, 
gradually taper immunosuppressive steroids 
(as appropriate and with guidance of 
endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
− For patients with normal endocrine workup 
(laboratory assessment or MRI scans), repeat 
laboratory assessments/MRI as clinically 
indicated initiate hormone replacement as 
needed for management. 
Grade 3 or 
4 
For Grade 3 or 4 
endocrinopathy 
other than 
hypothyroidism and 
Type 1 diabetes 
mellitus, hold 
tremelimumab until 
endocrinopathy 
symptom(s) are 
controlled.  
For Grade 3 or 4: 
− Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended. 
− For all patients with abnormal endocrine 
workup, except those with isolated 
hypothyroidism or Type 1 diabetes mellitus, 
and as guided by an endocrinologist, promptly 

 
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Tremelimumab can 
be resumed once 
event stabilizes and 
after completion of 
steroid taper. 
 
Patients with 
endocrinopathies 
who may require 
prolonged steroid 
replacement (e.g., 
adrenal 
insufficiency) can 
resume 
tremelimumab on 
the following 
conditions: 
1. The event 
stabilizes and is 
controlled. 
2. The patient is 
clinically stable 
as per 
investigator’s 
clinical 
judgement. 
3. Doses of 
prednisone are 
≤10 mg/day or 
equivalent. 
initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent, as well as relevant 
hormone replacement (e.g., hydrocortisone, 
sex hormones).or Type 1 DM, and as guided 
by an  endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as relevant 
hormone replacement (e.g., hydrocortisone, 
sex hormones). 
− For adrenal crisis, severe dehydration, 
hypotension, or shock, immediately initiate IV 
corticosteroids with mineralocorticoid 
activity. 
− Isolated hypothyroidism may be treated with 
replacement therapy, without tremelimumab 
interruption, and without corticosteroids. 
− Isolated Type 1 diabetes mellitus may be 
treated with appropriate diabetic therapy, 
without tremelimumab interruption, and 
without corticosteroids. 
− Once patients on steroids are improving, 
gradually taper immunosuppressive steroids 
(as appropriate and with guidance of 
endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
. 
Neurotoxicity 
(to include but 
not be limited to 
limbic 
encephalitis and 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre 
Any Grade  
(depending on the type of neurotoxicity, refer to NCI CTCAE v5.0 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes, or medications). 
− Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, 
or weakness). 
− Consider appropriate diagnostic testing (e.g., electromyogram and nerve conduction 
investigations). 
− Perform symptomatic treatment with neurological consult as appropriate. 
Grade 1 
No dose modifications. For Grade 1: 
− See “Any Grade” recommendations 
above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold 
tremelimumab dose 
until resolution to 
Grade ≤1. 
For Grade 2: 
− Consider, as necessary, discussing with the 
study physician. 
− Obtain neurology consult. 
− Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 

 
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For sensory 
neuropathy/neuropathi
c pain, consider 
holding tremelimumab 
dose until resolution to 
Grade ≤1. 
• If toxicity worsens, 
treat as Grade 3 or 
4. 
Tremelimumab can be 
resumed after 
improvement to Grade 
≤1 and after 
completion of steroid 
taper. 
(e.g., gabapentin or duloxetine). 
− Promptly start systemic steroids prednisone 
1 to 2 mg/kg/day PO or IV equivalent. 
− If no improvement within 3 to 5 days despite 
1 to 2 mg/kg/day prednisone PO or IV 
equivalent, consider additional workup and 
promptly treat with additional 
immunosuppressive therapy (e.g., IV IG). 
Grade 3 or 
4 
For Grade 3: 
Hold tremelimumab 
dose until resolution to 
Grade ≤1. 
 
Permanently 
discontinue 
tremelimumab if 
Grade 3 irAE does not 
resolve to Grade ≤1 
within 30 days. 
 
For Grade 4: 
Permanently 
discontinue 
tremelimumab. 
For Grade 3 or 4: 
− Consider, as necessary, discussing with 
study physician. 
− Obtain neurology consult. 
− Consider hospitalization. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− If no improvement within 3 to 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat with 
additional immunosuppressants (e.g., IV 
IG). 
− Once stable, gradually taper steroids over 
≥28 days. 
Peripheral 
neuromotor 
syndromes 
(such as 
Guillain-Barre 
and myasthenia 
gravis) 
For Any Grade: 
− The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is 
important, since certain patients may unpredictably experience acute 
decompensations that can result in substantial morbidity or in the worst case, 
death.  Special care should be taken for certain sentinel symptoms that may 
predict a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or autonomic 
instability. 
− Patients should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes or medications).  It should be 
noted that the diagnosis of immune-mediated peripheral neuromotor syndromes 
can be particularly challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its treatments) throughout 
the neuraxis.  Given the importance of prompt and accurate diagnosis, it is 
essential to have a low threshold to obtain a neurological consult. 
− Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and “repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon suspicion of such conditions and may 
be best facilitated by means of a neurology consultation. 

 
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− It is important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective.  Patients requiring 
treatment should be started with IV IG and followed by plasmapheresis if not 
responsive to IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− Consider, as necessary, discussing with 
the study physician. 
− Care should be taken to monitor patients 
for sentinel symptoms of a potential 
decompensation as described above. 
− Obtain a neurology consult unless the 
symptoms are very minor and stable. 
Grade 2 
Hold tremelimumab until 
resolution to Grade ≤1. 
Permanently 
discontinue 
tremelimumab if it does 
not resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency or 
autonomic instability. 
For Grade 2: 
− Consider, as necessary, discussing with 
the study physician. 
− Care should be taken to monitor patients 
for sentinel symptoms of a potential 
decompensation as described above. 
− Obtain a neurology consult 
− Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used to 
treat myasthenia gravis.  It is important 
to consider that steroid therapy 
(especially with high doses) may result 
in transient worsening of myasthenia 
and should typically be administered in 
a monitored setting under supervision of 
a consulting neurologist. 
o Patients unable to tolerate steroids may 
be candidates for treatment with 
plasmapheresis or IV IG. Such decisions 
are best made in consultation with a 
neurologist, taking into account the 
unique needs of each patient. 
o If myasthenia gravis-like neurotoxicity 
is present, consider starting AChE 
inhibitor therapy in addition to steroids. 
Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o It is important to consider here that the 
use of steroids as the primary treatment 
of Guillain-Barre is not typically 
considered effective. 
o Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV 

 
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IG. 
Grade 3 or 
4 
For Grade 3: 
Hold tremelimumab dose 
until resolution to Grade 
≤1. 
Permanently discontinue 
tremelimumab if Grade 3 
irAE does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability. 
 
For Grade 4: 
Permanently discontinue 
tremelimumab. 
For Grade 3 or 4 (severe or life-
threatening events): 
− Consider, as necessary, discussing with 
study physician. 
− Recommend hospitalization. 
− Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used to 
treat myasthenia gravis. They should 
typically be administered in a 
monitored setting under supervision 
of a consulting neurologist. 
o Patients unable to tolerate steroids 
may be candidates for treatment with 
plasmapheresis or IV IG. 
o If myasthenia gravis-like 
neurotoxicity present, consider 
starting AChE inhibitor therapy in 
addition to steroids. Such therapy, if 
successful, can also serve to reinforce 
the diagnosis. 
 
GUILLAIN-BARRE: 
o It is important to consider here that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective. 
o Patients requiring treatment should be 
started with IV IG and followed by 
plasmapheresis if not responsive to IV 
IG. 
Cardiac* 
 
Includes CHF, 
LV dysfunction, 
myocarditis, 
arrhythmia, 
conduction 
disorder and 
others) 
General Guidance for Any Grade: 
− The prompt diagnosis of immune-mediated myocarditis is important, 
particularly in patients with baseline cardiopulmonary disease and reduced 
cardiac function.  
− Consider, as necessary, discussing with the study physician. 
− Monitor patients for signs and symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, shortness of breath, peripheral edema). As 
some symptoms can overlap with lung toxicities, simultaneously evaluate for 
and rule out pulmonary toxicity as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt assessment of 
whether and when to complete a cardiac biopsy, including any other diagnostic 
procedures. 
− Initial workup should include clinical evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry 
(resting and exertion), and additional laboratory workup as indicated. Spiral CT 
or cardiac MRI can complement ECHO to assess wall motion abnormalities 
when needed. 

 
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− Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, or infections) 
− Discontinue tremelimumab permanently if biopsy-proven immune-
mediated myocarditis regardless of grade 
 
Grade 1 cardiac 
AE 
(asymptomatic 
with laboratory 
(e.g., BNP, EKG, 
troponin)  
No dose modifications 
required unless clinical 
suspicion is high for 
myocarditis, in which case 
hold tremelimumab during 
diagnostic workup.  
- If myocarditis is excluded, 
resume after complete 
resolution to Grade 0. 
- If myocarditis is 
diagnosed, permanently 
discontinue tremelimumab 
For Grade 1 (no definitive 
findings): 
- 
Monitor and closely follow up 
in 2 to 4 days for clinical 
symptoms, BNP, cardiac 
enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), 
and laboratory workup as 
clinically indicated. 
- 
Consider using steroids if 
clinical suspicion is high. 
 
Grade 2, 3 or 4 
cardiac AE or 
suspected 
myocarditis 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
 
(Grade 3: Severe 
with symptoms at 
rest or with 
minimal activity 
or exertion; 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support) 
For Grade 2:  
- Hold tremelimumab 
- If toxicity rapidly 
improves to Grade 0 and 
no evidence for 
myocarditis, then the 
decision to reinitiate 
tremelimumab is based 
upon treating physician’s 
clinical judgment and 
after completion of steroid 
taper.  
- If toxicity does not rapidly 
improve, permanently 
discontinue tremelimumab 
- If myocarditis is 
diagnosed, permanently 
discontinue tremelimumab 
regardless of timeline of 
recovery. 
- If Grade 3-4, permanently 
discontinue 
tremelimumab.  
For Grade 2-4: 
− Monitor symptoms daily, 
hospitalize if myocarditis is 
suspected. 
− Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent after 
Cardiology consultation has 
determined whether and when 
to complete diagnostic 
procedures including a cardiac 
biopsy. 
− Supportive care (e.g., oxygen). 
− If no improvement within 3 to 
5 days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy 
such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is 
important to rule out sepsis and 
refer to infliximab label for 
general guidance before using 
infliximab. 
− Once the patient is improving, 
gradually taper steroids over 
≥28 days and consider 
prophylactic antibiotics, 
antifungals, or anti-PJP 
treatment (refer to current 
NCCN guidelines for treatment 
of cancer-related infections 
[Category 2B 
recommendation]).a 

 
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Myositis/Polymy
ositis 
(“Poly/myositis”) 
For Any Grade: 
− Monitor patients for signs and symptoms of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles including upper arms, thighs, shoulders, 
hips, neck and back, but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur and progress rapidly. 
Increased general feelings of tiredness and fatigue may occur, and there can be new-
onset falling, difficulty getting up from a fall, and trouble climbing stairs, standing 
up from a seated position, and/or reaching up. 
− If poly/myositis is suspected, a Neurology consultation should be obtained early, 
with prompt guidance on diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. Given breathing complications, 
refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) autoimmune disorder, 
consider Rheumatology consultation. 
− Consider, as necessary, discussing with the study physician. 
− Initial workup should include clinical evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory workup as indicated, including a number of 
possible rheumatological/antibody tests (i.e., consider whether a rheumatologist 
consultation is indicated and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal-
recognition particle antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of the muscles, and/or a muscle 
biopsy. Consider Barium swallow for evaluation of dysphagia or dysphonia. 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose 
modifications. 
For Grade 1: 
− Monitor and closely follow up in 2 to 4 days 
for clinical symptoms and initiate evaluation 
as clinically indicated. 
− Consider Neurology consult. 
− Consider, as necessary, discussing with the 
study physician. 
 
Grade 2 
(moderate 
pain 
associated 
with 
weakness; 
pain 
limiting 
instrument
al activities 
of daily 
living 
[ADLs]) 
Hold tremelimumab 
dose until 
resolution to Grade 
≤1. 
Permanently 
discontinue 
tremelimumab if it 
does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
For Grade 2: 
− Monitor symptoms daily and consider 
hospitalization. 
− Obtain Neurology consult, and initiate 
evaluation. 
− Consider, as necessary, discussing with the 
study physician. 
− If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input 
from Neurology consultant  
− If clinical course is not rapidly progressive, 
start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent); if no 
improvement within 3 to 5 days, continue 

 
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additional workup and start treatment with 
IV methylprednisolone 2 to 4 mg/kg/day 
− If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
3 to 5 days, consider start of 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg every 
2 weeks). Caution: It is important to rule out 
sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Grade 3 or 
4 
(pain 
associated 
with severe 
weakness; 
limiting 
self-care 
ADLs) 
For Grade 3: 
Hold tremelimumab 
dose until 
resolution to Grade 
≤1. 
Permanently 
discontinue 
tremelimumab if 
Grade 3 irAE does 
not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
 
For Grade 4: 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− Monitor symptoms closely; hospitalization 
recommended. 
− Obtain Neurology consult, and complete 
full evaluation. 
− Consider, as necessary, discussing with the 
study physician. 
− Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with 
receiving input from Neurology 
consultant. 
− If not improvement within 3-5 days after 
IV methylprednisolone at 2 to 
4 mg/kg/day, consider start of 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important to 
rule out sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− Consider whether patient may require IV 
IG, plasmapheresis. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by 
Michael Postow, MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing 
Clinical Evaluation. 

 
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AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline 
phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea 
nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD 
Interstitial lung disease; irAE Immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI 
Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; 
NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis 
jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; 
T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-
stimulating hormone; ULN Upper limit of normal. 
 
Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related reactions (e.g., fever 
and/or shaking chills, flushing and/or itching, alterations in heart rate and blood 
pressure, dyspnea or chest discomfort, or skin rashes) and anaphylaxis 
(e.g., generalized urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of tremelimumab may 
be decreased by 50% or temporarily 
interrupted until resolution of the event. 
For Grade 2: 
The infusion rate of tremelimumab 
should be decreased 50% or temporarily 
interrupted until resolution of the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines 
may be administered per institutional 
standard at the discretion of the 
investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue tremelimumab 
For Grade 3 or 4: 
− 
Manage severe infusion-related 
reactions per institutional standards 
(e.g., IM epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV 
glucocorticoid). 

 
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Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity 
Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat 
accordingly, as 
per institutional 
standard. 
Grade 1 
No dose modifications. 
Treat 
accordingly, as 
per institutional 
standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat 
accordingly, as 
per institutional 
standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat 
accordingly, as 
per institutional 
standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat 
accordingly, as 
per institutional 
standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal 
to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
6.2.2 Rules for permanent discontinuation of tremelimumab: 
 
• Persistent grade 2 toxicity that does not resolve to grade 1 within 14 days with 
adequate corticosteroid treatment. 
 
• Any symptomatic grade 3-4 toxicity, including any of the following: 
▪ Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more over baseline), stool incontinence, need for intravenous 
hydration for more than 24 hours, gastrointestinal hemorrhage, or 
gastrointestinal perforation.  
▪ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >8 
times the upper limit of normal or total bilirubin >3 times the upper limit of 
normal. 
▪ Evidence of incipient Stevens-Johnson syndrome, toxic epidermal necrolysis, 
or rash complicated by full thickness dermal ulceration, or necrotic, bullous, 
or hemorrhagic manifestations.  
▪ Motor or sensory neuropathy (interfering with daily activity) such as Guillain-

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Barre like syndrome, or myasthenia gravis. 
▪
Clinically significant immune-mediated reactions involving any organ system 
(e.g., nephritis, pneumonitis, pancreatitis, non-infectious myocarditis).
▪
Clinically significant immune-mediated ocular disease (uveitis, conjunctivitis, 
blepharitis, episcleritis, scleritis) that is unresponsive to topical 
immunosuppressive therapy.
•
Any of the above toxicities will be managed by stopping both tremelimumab and 
olaparib and initiating treatment with corticosteroids until the toxicity is resolved 
to Grade 1 or less. Olaparib will then be restarted as a single agent.
If tremelimumab is permanently discontinued due to immune related toxicity, subjects 
may continue treatment on study with olaparib monotherapy.
ADVERSE EVENTS REPORTING REQUIREMENTS
Protocol Agents
Investigational Agents
The investigational agents administered in NRG-GY021 are olaparib and tremelimumab, 
which are being made available under an IND sponsored by DCTD, NCI.   For 
determination of whether an adverse event meets expedited reporting criteria, see the 
reporting table in section 7.5.1.1 of the protocol.
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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Comprehensive Adverse Events and Potential Risks list (CAEPR) for Olaparib 
(AZD2281, NSC 747856) (27-AUG-2021)
Comprehensive Adverse Events and Potential Risks list (CAEPR)
for
Olaparib (AZD2281, NSC 747856)
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 3449 patients. Below is the CAEPR for Olaparib 
(AZD2281).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.
Version 2.5, July 1, 20211
Adverse Events with Possible 
Relationship to Olaparib (AZD2281)
(CTCAE 5.0 Term)
[n= 3449]
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 4)
Febrile neutropenia
GASTROINTESTINAL DISORDERS
Abdominal distension
Abdominal pain
Abdominal pain (Gr 3)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 3)
Dyspepsia
Dyspepsia (Gr 2)
                                                    
Mucositis oral
Nausea
Nausea (Gr 3)
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Edema limbs
Fatigue
Fatigue (Gr 3)
IMMUNE SYSTEM DISORDERS
Allergic reaction
INFECTIONS AND INFESTATIONS
Upper respiratory infection
Urinary tract infection
INVESTIGATIONS

 
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 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Creatinine increased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
 
Platelet count decreased 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (erythema 
nodosum) 
  
 
NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in all cases, 
including documented BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents. Most are 
not attributed to olaparib. 
 
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. 
 
 

 
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Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that olaparib (AZD2281) caused the adverse 
event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; 
Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (gastrointestinal hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); 
Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal perforation; Obstruction gastric; 
Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; Malaise; 
Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Gastrointestinal anastomotic leak; Injury, poisoning and procedural complications - Other (vena cava 
injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; GGT increased; Hemoglobin increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle weakness lower limb; Muscle weakness upper limb; Neck pain; 
Rotator cuff injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(decreased glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
 
Note: Olaparib (AZD2281) 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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Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Tremelimumab (CP-675,206, NSC #744483)
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 1642 patients. Below is the CAEPR for 
Tremelimumab (CP-675,206).
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 2.1, March 25, 20191
Adverse Events with Possible 
Relationship to Tremelimumab (CP-675,206)
(CTCAE 5.0 Term)
[n= 1642]
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia2
Anemia2 (Gr 2)
CARDIAC DISORDERS
Myocarditis3
ENDOCRINE DISORDERS
Adrenal insufficiency2
Endocrine disorders - Other 
(thyroiditis)2
Hyperthyroidism2
Hypophysitis2
Hypothyroidism2
EYE DISORDERS
Uveitis
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr 2)
Colitis2
Diarrhea
Diarrhea (Gr 2)
Enterocolitis2
Gastrointestinal disorders -
Other (intestinal perforation)2
Nausea
Nausea (Gr 2)
Pancreatitis2
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Edema limbs
Edema limbs (Gr 2)

 
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 Adverse Events with Possible  
 Relationship to Tremelimumab (CP-675,206) 
 (CTCAE 5.0 Term) 
[n= 1642] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (autoimmune 
hepatitis)2  
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
 Alanine aminotransferase 
increased2 (Gr 2) 
 
Aspartate aminotransferase 
increased2 
 
 Aspartate aminotransferase 
increased2 (Gr 2) 
 
Lipase increased2 
 
 Lipase increased2 (Gr 2) 
 
Lymphocyte count decreased2 
 
 Lymphocyte count decreased2 (Gr 
2) 
 
Neutrophil count decreased2 
 
 Neutrophil count decreased2 (Gr 2) 
 
Platelet count decreased2 
 
 Platelet count decreased2 (Gr 2) 
 
Serum amylase increased2 
 
 Serum amylase increased2 (Gr 2) 
 
White blood cell decreased2 
 
 White blood cell decreased2 (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypokalemia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  
 
 
Musculoskeletal and 
connective tissue disorders - 
Other (Sjogren's syndrome) 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
Headache2 
 
  
 
 
Myasthenia gravis2,4  
  
 
 
Nervous system disorders - 
Other (encephalitis)2 
  
 
Peripheral motor neuropathy2 
 
  
 
Peripheral sensory neuropathy2 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
  
Nephrotic syndrome2 
  

 
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 Adverse Events with Possible  
 Relationship to Tremelimumab (CP-675,206) 
 (CTCAE 5.0 Term) 
[n= 1642] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Pneumonitis2 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(interstitial lung disease)2  
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin2 
 
 Dry skin2 (Gr 2) 
Pruritus 
 
 
 Pruritus (Gr 2) 
Rash maculo-papular2 
 
 
 Rash maculo-papular2 (Gr 2) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(cutaneous scleroderma-like 
syndrome) 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(Grover's disease) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vascular disorders - Other 
(giant cell temporal arteritis)2 
  
 
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-related adverse events may occur in any organs including but not limited to the events listed in 
CAEPR table. 
 
3Myocarditis has been reported with other anti-CTLA4 agents; however, it has not yet been observed in 
clinical trials of tremelimumab (CP-675,206). 
 
4Myasthenia gravis was observed in trials of tremelimumab in combination with durvalumab. 
 
Adverse events reported on tremelimumab (CP-675,206) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that tremelimumab (CP-675,206) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Graves' disease with ophthalmopathy) 

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GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Gastritis; Gastrointestinal disorders -
Other (diverticulitis); Ileus; Mucositis oral; Rectal hemorrhage
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Pain; Sudden death 
NOS
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (oral herpes); 
Lung infection; Sepsis
INVESTIGATIONS - GGT increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized muscle 
weakness; Myalgia
NERVOUS SYSTEM DISORDERS - Dizziness; Syncope
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pleural effusion; Respiratory, thoracic 
and mediastinal disorders - Other (asthma)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Rash acneiform
VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other 
(hemorrhage); Vasculitis
Note: Tremelimumab (CP-675,206) 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.
Expedited Reporting of Adverse Events
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site, 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting.
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. 
•
Supporting source documentation is requested by the IND Sponsor for this study 
(CTEP/DCTD) and NRG as needed to complete adverse event review. Supporting 
source documentation should include the protocol number, patient ID number, and 
CTEP-AERS ticket number on each page, and fax supporting documentation to CTEP 
at 301-230-0159 and to NRG Regulatory Affairs at 215-854-0716.
•
A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 

 
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submission of all reports regardless of the results of the assessment.  
 
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 
 

 
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7.5.2 Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 
 
Tremelimumab AESIs should be reported through the CTEP Adverse Event Reporting 
System (CTEP-ARES) 
 
AESIs are of scientific and medical interest specific to understanding of the 
Investigational Product and may require close monitoring and rapid communication by 
the investigator to the sponsor.  An AESI may be serious or non-serious.  The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the use of this investigational product. 
 
An irAE is defined as an AESI that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate 
etiology.  Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be 
used to support an irAE diagnosis.  Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.  
 
AESIs observed with tremelimumab requiring reporting through CTEP AERS include: 
 
• Pneumonitis / ILD any grade / ALT/AST increases / hepatitis / hepatotoxicity - Hy’s 
Law:  
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 
× ULN may need to be reported as SAEs 
• Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré, and myasthenia gravis) 
• Endocrinopathies (i.e., events of hypophysitis, hypopituitarism adrenal insufficiency, 
diabetes insipidus, hyper- and hypothyroidism and type I diabetes mellitus) 
• Myocarditis, pericarditis, and uveitis. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
7.5.4 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 

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http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP. 
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 
AE reporting unless otherwise specified.
8.
REGISTRATION AND STUDY ENTRY PROCEDURES (24-APR-2020)
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
RCR utilizes five person registration types.
•
IVR — MD, DO, or international equivalent;
•
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD);
•
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, activing 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.

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RCR requires the following registration documents:
Documentation Required
IVR
NPIVR
AP
A
AB
FDA Form 1572
✔
✔
Financial Disclosure Form
✔
✔
✔
NCI Biosketch (education, training, 
employment, license, and certification)
✔
✔
✔
GCP training
✔
✔
✔
Agent Shipment Form (if applicable)
✔
CV (optional)
✔
✔
✔
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following:
•
Addition to a site roster;
•
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN;Act 
as the site-protocol Principal Investigator (PI) on the IRB approval.
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, 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.
Cancer Trials Support Unit (CTSU) Registration Procedures
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 

 
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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). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an active CTEP status; 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional 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); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
8.1.1 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 based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a Protocol Organization (PO) on the protocol. One way to serach for a 
protocol is listed below: 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number 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 
Oncology and protocol number NRG-GY021. 

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•
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU 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 at 1-866-651-2878 in order to 
receive further instruction and support.
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 sties 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.
Patient Enrollment
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.  
8.2.1
Oncology Patient Enrollment Network (OPEN)
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave.
Requirements for OPEN access:  

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•
A valid CTEP-IAM account;
•
To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type;
•
Have an approved site registration for the protocol prior to patient enrollment.
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
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 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.
Patient enrollment during the 1st safety lead-in of this study will be facilitated using the 
Slot Reservation System in conjunction with the registration system in OPEN. Prior to 
discussing protocol entry with the patient, all site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available to the patient. Once a 
slot reservation confirmation is obtained, site staff may then proceed to enroll the patient 
to this study. 
Data Submission / Data Reporting
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. 
Requirements to access Rave via iMedidata:
•
A valid CTEP-IAM account; and 
•
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
Rave role requirements:
o
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type;

 
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o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page. 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 link in the upper right 
pane of the iMedidata screen. If an eLearning is required and has not yet been taken, the 
link to the eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; 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 display under the study 
name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.  
 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of post-baseline 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.    
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period and used to collect AEs that start during the period or persist from the 
previous reporting period. The CRA will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS 
integration. AEs that occur prior to enrollment must begin and end on the baseline 
Adverse Events form and should not be included on the standard Adverse Events 
form that is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rule’s evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 

 
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• 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 evaluation by completing the Expedited Reporting Evaluation 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. 
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> Education and Promotion; 
and   
• Expedited Safety Reporting Rules Evaluation user guide: 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/aeg
uidelines.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 and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
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Rave Home, DQP Queries, and DQP Delinquent Forms modules.
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
Agent Ordering and Agent Accountability
8.4.1
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead participating 
investigator at that institution.
Sites can order study agents in OAOP when a patient is enrolled to treatment. Agent 
orders can be expedited overnight Monday-Thursday when sites provide expedited 
courier information.
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.  
8.4.2
Investigator Brochure Availability
The current versions of the Olaparib and Tremelimumab IBs will be accessible to site 
investigators and research staff through the PMB OAOP application. Access to OAOP 
requires the establishment of a CTEP IAM account and the maintenance of an “active” 
account status, a “current” password and active person registration status.  Questions 
about IB access may be directed to the PMB IB Coordinator via email.
8.4.3
Agent Accountability
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  
Store and maintain separate NCI Investigational Agent Accountability Records for each 
study participant and ordering investigator on this protocol.
8.4.4
PMB Useful Links and Contacts
•
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/
•
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  

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•
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
•
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
•
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/
•
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)
DRUG INFORMATION 
9.1
Investigational Study Agent: Olaparib (AZD2281) (NSC # 747856) (24-APR-2020)
9.1.1
Chemical Name: 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one
Other Names: AZD2281; KU-0059436; CO-CE 42
Classification:  PARP inhibitor
CAS Registry Number: 763113-22-0
Molecular Formula:
C24H23FN4O3
M.W.: 434.46
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient 
in the homologous recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and 
genomic instability. Olaparib may also enhance the effects of DNA damage caused by 
ionizing radiation and chemotherapy. 
9.1.2
Description: crystalline solid
9.1.3
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, 
film-coated tablets in 100 mg and 150 mg strengths. 
•
100 mg tablets are 14.5 mm x 7.25 mm oval-shaped
•
150 mg are 14.5 mm x 7.25 mm oval-shaped
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant. 

 
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Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, 
iron oxide yellow and iron oxide black. 
  
 
Availability: Olaparib is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Tremelimumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix VIII). 
 
9.1.4 Storage: Store in a secure location below 30° C (86° F).  
 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to 
room temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
9.1.5 Stability: Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. 
Once the bottle is opened, olaparib tablets must be used within 3 months of the opening 
date; unused tablets should be discarded. Instruct patients not to open a bottle until they 
are ready to use it. 
 
9.1.6 
Route and Method of Administration: Oral. Take tablets without regard to meals. 
 
9.1.7 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4. Therefore, avoid concomitant administration of sensitive 
substrates, particularly those with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 

 
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caution when given concomitantly with olaparib. 
 
9.1.8 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryofetal survival and development. Therefore, women of child-bearing potential and 
their partners should agree to use two (2) highly effective forms of contraception throughout 
study participation and for at least six (6) months after the last dose of olaparib.  The study 
investigator should discuss the most appropriate forms of highly effective contraceptive 
methods for each patient.  
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious 
adverse reactions in breastfed infants. Advise lactating women to not breastfeed during 
study treatment and for one (1) month after receiving the last dose of olaparib.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and 
dizziness, patients should be advised to use caution while driving or using machinery. 
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, 
olaparib treatment should be stopped at least 3 days prior to planned surgery. After 
surgery olaparib can be restarted when the wound has healed. No stoppage of olaparib is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient 
undergoes therapeutic or palliative radiation treatment. Study treatment should be 
restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
 
9.1.9 Adverse Events: Please see Section 7.3 for the Olaparib CAEPR. 
9.2 
Investigational Study Agent: Tremelimumab (NSC # 744483) (24-APR-2020) 
9.2.1 Other Names: CP-675,206 
 
Classification: Anti-CTLA-4 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Tremelimumab is specific for human cytotoxic T lymphocyte-
associated antigen 4 (CTLA-4), a cell surface receptor that is expressed primarily on 
activated T cells.  CTLA-4 delivers a negative regulatory signal to T cells upon binding 
of CD80 or CD86 ligands on antigen-presenting cells.  Tremelimumab blocks the 
inhibitory signal resulting from CTLA-4 binding to CD80/86, leading to prolongation and 
enhancement of T-cell activation and expansion. 
 
9.2.2 Description: Tremelimumab is a human immunoglobulin G2 kappa (IgG2κ) monoclonal 
antibody. 
9.2.3 
How Supplied: Tremelimumab is supplied by AstraZeneca, and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 400 mg/vial 
solution for infusion (20 mg/mL).  Tremelimumab solution for infusion is formulated in 
20 mM histidine/histidine-HCl, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, 
and 0.27 mM disodium edetate dihydrate, pH 5.5. 

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Availability: Tremelimumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI.
Tremelimumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix VIII).
9.2.4
Preparation: Tremelimumab solution for infusion must be diluted prior to administration.  
Allow the required number of vials to equilibrate to room temperature for 30 minutes.  Do 
not shake the vials.  To prepare the infusion solution add the dose volume of tremelimumab 
to an infusion bag containing 0.9% Sodium Chloride Injection or Dextrose 5% in Water 
Injection, USP and mix by gentle inversion to ensure homogeneity of the dose in the bag.  
The final concentration must be between 0.10 mg/mL to 10 mg/mL.
Infusion bags must be latex-free and can be made of polyvinyl chloride (PVC) or 
polyolefins (eg, polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or 
DEHP free.
9.2.5
Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze.
If a storage temperature excursion is identified, promptly return tremelimumab 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.
9.2.6
Stability: Stability testing of the intact vials is on-going.  
Total in-use storage time from needle puncture of tremelimumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-
46°F).  If there are interruptions during infusion, the total allowed time should not exceed 
4 hours at room temperature. In the event that either preparation time or infusion time 
exceeds the time limits, a new dose must be prepared from new vials.
9.2.7
Route of Administration: IV infusion
Method of Administration: Infuse over approximately 60 minutes using IV infusion lines 
made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or polyethylene or 
polyurethane.  All DEHP-containing or DEHP-free lines are acceptable.  IV lines should 
contain a 0.22 or 0.2 μm in-line filter.  The in-line filter can be made of polyethersulfone 
or polyvinylidine fluoride. IV lines containing cellulose-based filters should not be used 
with tremelimumab.  Flush the IV line with a volume of normal saline equal to the 
priming volume of the infusion set used at the completion of infusion.  Do not co-
administer other drugs through the same infusion line.
9.2.8
Adverse Events: Please see Section 7.4 for the Tremelimumab CAEPR.
PATHOLOGY/BIOSPECIMEN (27-AUG-2021)
Note: The final biomarker assays and analyses at CIMAC-CIDC will be based on the 
“Proposal Intake Form for Investigators Using the CIMAC-CIDC Network” for this 

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trial. The Intake Form will be reviewed and approved by NCI and the CIMAC-CIDC 
coordination center before testing of banked biospecimens.
Central Pathology Review Guidelines 
Not applicable.
Biospecimen Selection for Integral Biomarker Testing
Not applicable.
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
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below.
Required Biospecimen (Biospecimen Code)
Collection Time Point
Sites Ship Biospecimens To
FFPE TUMOR TISSUE (Submit one of the following – listed in order of preference)
FFPE Recurrent Primary (FRP01) or Metastatic 
(FRM01) Tumor1
Block must be submitted2
Prior to study treatment
NRG Oncology BB -
Columbus within 8 weeks of 
registration3
FFPE Persistent Primary (FPP01) or Metastatic 
(FPM01) Tumor1
Block must be submitted2
FFPE Neoadjuvant Primary (FPT01) or Metastatic 
(FMT01) Tumor1
Block must be submitted2
After patient received 
neoadjuvant treatment; 
prior to study treatment
FFPE Primary (FP01) or Metastatic (FM01) Tumor1
Block must be submitted2
Prior to all treatment
BLOOD BIOSPECIMENS
Pre-cycle 1
Pre-cycle 1 T Cell Whole Blood (WB01)
30mL drawn into green top sodium heparin (NaHep) 
tube(s)
Prior to starting cycle 1 
of study treatment
NRG Oncology BB -
Columbus the day the 
biospecimen is collected3
Pre-cycle 1 TCR Whole Blood (WB02)
2mL drawn into a purple top (EDTA) tub
Pre-cycle 1 cfDNA Whole Blood (WB03)
10mL drawn into a Streck (cell-free DNA) tube
Pre-cycle 3
Pre-cycle 3 T Cell Whole Blood (WB04)
30mL drawn into green top sodium heparin (NaHep) 
tube(s)
Prior to starting cycle 3 
of study treatment
NRG Oncology BB -
Columbus the day the 
biospecimen is collected3
Pre-cycle 3 TCR Whole Blood (WB05)
2mL drawn into a purple top (EDTA) tub
Pre-cycle 3 cfDNA Whole Blood (WB06)

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10mL drawn into a Streck (cell-free DNA) tube
Final
Final T Cell Whole Blood (WB07)
30mL drawn into green top sodium heparin (NaHep) 
tube(s)
Prior to starting cycle 6 
of study treatment or at 
the time patient 
progresses or goes off-
study (if prior to cycle 6)
NRG Oncology BB -
Columbus the day the 
biospecimen is collected3
Final TCR Whole Blood (WB08)
2mL drawn into a purple top (EDTA) tub
Final cfDNA Whole Blood (WB09)
10mL drawn into a Streck (cell-free DNA) tube
1 All tissue biospecimens sent to the NRG BB-Columbus must be shipped with a copy of the corresponding 
pathology report and a completed copy of the FFPE Materials Verification Form (Appendix VII).  The FFPE 
Materials Verification Form should be provided to your Pathology Department when FFPE materials are 
requested and must be completed by the person providing the FFPE materials. 
2 Only blocks will be accepted. Please provide Appendix IX to your pathologist.
3 NRG Oncology BB-Columbus / Protocol NRG-GY021, Nationwide Children’s Hospital, 700 Children’s Drive, 
WA1340, Columbus, OH 43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: 
BPCBank@nationwidechildrens.org
10.4.2 Optional Biospecimen Submissions
Not applicable.
10.5
Exploratory Biomarker Testing (27-AUG-2021)
Note: The final biomarker assays and analyses at CIMAC-CIDC will be based on the 
“Proposal Intake Form for Investigators Using the CIMAC-CIDC Network” for this 
trial. The Intake Form will be reviewed and approved by NCI and the CIMAC-CIDC 
coordination center before testing of banked biospecimens.
Tumor tissue and blood will be used for the CIMAC assays outlined below. All assays 
will be done at a CIMAC laboratory using standardized CIMAC testing procedures.
Biospecimen (quantity)
CIMAC Assay
Pre-Cycle 1
Pre-Cycle 3
Final
Tissue
FFPE Tissue Blocks
IHC/IF
Archival
NA
NA
RNA-Seq
Archival
NA
NA
WES
Archival
NA
NA
Blood
Sodium Heparin (30 mL total)
CyTOF (PBMCs)
X
X
X
Olink (plasma)
X
X
X
Streck Cell-Free DNA (10 mL)
cfDNA
X
X
X
EDTA (2mL)
TCR-Seq
X
X
X
WES
X
NA
NA
ASSESSMENT OF EFFECT 
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).  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. 

 
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11.1.1 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT 
scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in 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 

 
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short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
  
11.1.2 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 

 
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scanner and follow the baseline imaging protocol as closely as possible. If possible, body 
scans should be performed with breath-hold scanning techniques. 
 
NRG Oncology will not allow PET-CT use for RECIST 1.1 response criteria.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA125 cannot be 
used to assess response or progression in this study. If CA125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical 
response. Specific guidelines for CA-125 response (in recurrent ovarian cancer) have 
been published [JNCI 96:487-488, 2004]. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria that are to be integrated with objective tumor 
assessment for use only in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology: 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. 
  
11.1.3 Response Criteria  
Determination of response should take into consideration all target and non-target lesions 
and, if appropriate, biomarkers. 
 
11.1.3.1  Evaluation of Target Lesions (24-APR-2020) 
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 

 
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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.  
 
11.1.3.2  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). 
  
Note: If CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response. 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) Progressive 
Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not 
normally trump target lesion status. It must be representative of overall disease status 
change, not a single lesion increase. 
  
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). 
  
11.1.3.3 
Evaluation of Biomarkers  
If serum CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response.  
 
Progression cannot be based upon biomarkers, including serum CA-125 and HE4 for 
this study. 
  
11.1.3.4 
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) 
 

 
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*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. 
 
***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 randomized trials (phase II or III), confirmation of response is not required since 
it will not add value to the interpretation of results. 
 
For this study, the minimum criteria for SD duration is 12 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. 
 
11.1.4 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. 
 
Target 
Lesions 
Non-Target 
Lesions 
Biomarker 
CA-125 
New 
Lesions* 
Time Point 
Response 
CR
*** 
CR 
Within 
normal limits 
No 
CR 
CR 
Non-CR/Non-PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
Yes 
PD 

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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.
11.1.5 Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression per RECIST criteria or death due to any cause, whichever occurs 
first. Individuals who are progression free at the time of their last assessment will be 
censored on the date of their last radiographic assessment.  
11.1.6 Survival
Survival is defined as the duration of time from study entry to the date of death.  For 
those individuals who are alive, their survival duration is censored on the date last known 
to be alive.  
11.1.7 Dose Limiting Toxicity
Since immune-related adverse events are not classically dose-dependent, no provision is 
made for a dose reduction of tremelimumab, only treatment delays are permitted.  For the 
purposes of the safety lead-in, a dose-limiting toxicity is a treatment-related adverse 
event requiring permanent discontinuation of tremelimumab prior to the completion of 
cycle 3 of treatment.  Dose reductions for olaparib are permitted, however if persistent 
toxicity following olaparib dose-reduction requires a treatment delay of >30 days, then 
this will also be counted as a DLT.
DATA AND RECORDS
Data Management/Collection
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave, the 
site user must have an active CTEP-IAM account and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
rosters at the enrolling site.
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings) and will be listed in the 
upper right pane of the iMedidata screen.
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation 

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instructions are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com.
NRG Data Management Forms
Refer to the CTSU member website for the table of Required Forms and Materials.
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 and 7.5.1.1 for information about expedited 
and routine reporting.  
Global Reporting/Monitoring (24-APR-2020)
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 (http://ctep.cancer.gov/reporting/cdus.html).
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, 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 CTEP-AERS.
STATISTICAL CONSIDERATIONS
Study Design
Treatment Assignment
A web-based enrollment procedure will be used to register patients onto the study.  
Immediately after an individual has been successfully enrolled, one of the study regimens 
will be randomly assigned (for this study the date of enrollment is equivalent to the date 
of randomization).  The study regimens: Olaparib with Tremelimumab (OT) or Olaparib-
alone (O) will be assigned in a 1:1 ratio within stratum determined by germline and/or 
somatic BRCA status (mutation vs no mutation or unknown mutation status) and prior 
treatment with a PARP inhibitor among BRCAm patients (yes vs no).  Patients with 
unknown BRCA status will be stratified as BRCA wild-type.  The study treatments will 
be sequentially drawn from pre-allocated blocks of randomly permuted treatments, which 
are created for each stratum.  The treatment assignment will remain concealed until after 

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the individual has been successfully enrolled onto the trial, and the interim and final 
reports will include an accounting of all enrolled individuals.
Study Endpoints
Primary Endpoint
•
The primary endpoint of this study is progression free survival (PFS).  PFS is 
defined in Section 11.1.5. The primary endpoints for the initial safety/efficacy lead-
in study will be dose-limiting toxicity (DLT, see Section 11.1.7) and RECIST 1.1 
response (Section 11.1.3), respectively.
Secondary Endpoints 
• The categories of responses (OR) are defined in section 11.1.3.  The objective 
response rate is the percentage of subjects with a best overall complete response 
(CR) or partial response (PR) among those with target lesions at the time of 
enrollment. The duration of response is defined in Section 11.1.4.
• Overall survival (OS) defined as the time from enrollment and randomization to the 
date of death due to any cause. A subject who has not died will be censored on the 
date that they were last known to be alive. OS will be followed regularly in 
accordance with the schedules presented in sections 4.2 and 4.3.  Following 
discontinuation of study treatment, subjects will be evaluated every 3 months via in-
person or phone contact for two years and then every 6 months for 3 additional 
years.
Safety data will be summarized for all treated subjects. All adverse events, 
including severe adverse events (SAEs) and treatment-related adverse events, will 
be categorized and graded for severity according to NCI CTCAE v 5.0. 
Primary Objectives Study Design
13.3.1 Primary Hypothesis 
The primary null hypothesis (H0) is that the O+T regimen does not increase the duration 
of progression-free survival compared to olaparib alone.  The primary aim of this study is 
to assess this hypothesis in the target population.  
13.3.2 How Primary Endpoints Will Be Analyzed
The logrank procedure will be used to test the primary study hypothesis.   The logrank 
procedure will be stratified by germline and/or somatic BRCA status (mutation vs no or 
unknown mutation status) and prior treatment with a PARP-inhibitor (yes vs no).  All 
patients enrolled onto the study will be included in the interim and final analyses of the 
primary objective regardless of their eligibility or study treatment compliance.  The 
following conditions will censor an individual’s PFS duration: 1) In the event that an 
individual initiates an anticancer therapy that is not prescribed by the protocol, her PFS
duration will be censored on the date her last assessment was done prior to beginning that 
therapy, 2)the PFS duration for an individual who misses 2 consecutive assessments will 
be censored on the date of her last assessment prior to missing two consecutive 

 
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assessments, 3)the PFS duration for those individuals who have no post-enrollment 
assessments done will be censored 1 day after enrollment. 
 
Interim Analyses: 
After at least 58 PFS events (50% information time) have been reported, an interim 
analysis will be conducted.  The purpose of the interim analysis is to assess futility of 
rejecting H0 at the time of the final analysis.  If the estimated relative hazard from a 
proportional hazards model, adjusted for germline and/or somatic BRCA status and prior 
PARP-inhibitor treatment, indicates that the hazard of first progression or death (PFS) is 
greater among those allocated to the O+T treatment group, compared to O, then the Data 
Monitoring Committee (DMC) will have the option to stop the study early, release the 
study results and conclude that it is very unlikely that the alternative hypothesis, Ha, is 
true.  
 
Final Analysis: 
The analysis of the primary objective will be conducted on an intention-to-treat basis.  A 
logrank test stratified by BRCA mutation status and prior PARPi use will be used to 
assess the primary hypothesis.  The study will be considered sufficiently mature for 
assessing the primary objective when at least 115 PFS events occur among all of the 
enrolled patients.  Assuming that the accrual is interrupted for three months at the end of 
each safety component, this study is expected to mature approximately 2.3 years after the 
first patient is enrolled.  
 
A proportional hazards model will be used to estimate the treatment hazard ratio and 
corresponding confidence interval, after adjusting for the patients’ BRCA status and prior 
PARPi usage.  Also, an exploratory analysis will be conducted to assess whether the 
proportional hazards assumption is supported by the study data.  A product-limit method 
will be used to estimate the cumulative distribution of PFS duration for each of the study 
treatments used in this population.   
 
Descriptive statistics will be used to summarize adverse events (AEs).  These analyses 
will focus on the individuals who initiated their assigned study treatment and summarize 
maximum grade of adverse events occurring during treatment classified by CTC 
category.  The primary summary of AEs will present counts and percentages, regardless 
of whether the AE was attributed to any of the study agents. 
 
13.3.3 Sample Size and Power Calculations:  
 
The targeted accrual for this study is 170 eligible individuals, including those enrolled 
during the safety lead-in components and follow-up of these individuals will continue 
until at least 115 have experienced either disease progression or death.  This sample size 
provides 80% power for detecting a hazard ratio of 0.625 (Ha) when type I error is set to 
0.05 for a one-tail test of H0 (EAST ver 6.4, accounting for the interim analysis of PFS 
described above).  If the true median duration of PFS for patients in this population 
treated with olaparib is 8 months, then a HR of 0.625, assuming proportional hazards, is 
comparable to increasing the expected percent of patients alive and progression free for at 
least 8 months from 50% to 64.8%.  Assuming a constant hazard this is comparable to 

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increasing the median PFS duration from 8 months to 12.9 months.
Study Monitoring of Primary Objectives
Interim Analysis for the DMC
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis. The stopping boundaries described above provide prospective 
guidelines based on statistical rationale for early study termination.  These guidelines are 
non-binding and the DMC may use additional ethical, clinical or statistical criteria to 
recommend early termination of the study.
Accrual/Study Duration Considerations
The targeted enrollment for this study is 170 eligible patients.  During the first safety 
lead-in, accrual will be limited to NRG’s Safety Lead-in institutions and the accrual rate 
is expected to be about 10 patients per month.  Once this component has been completed 
it is conservatively estimated that at least 20 patients per month will be available for this 
study.  Allowing for a 3 month interruption in accrual following each safety lead-in sub-
study (described below), the time from first-patient-in to last-patient-in is expected to be 
about 1.5 years.  The expected time from first-patient-in until data maturity for final 
analysis is approximately 2.4 years.
Secondary or Exploratory Endpoints 
13.6.1 Definitions of Secondary Endpoints and How These Will Be Analyzed
Overall Survival:  The overall survival endpoint is defined in Section 11.1.6. Kaplan-
Meier procedures will be used to estimate the cumulative distribution of survival times 
for each treatment in this population.  A proportional hazards model stratified by BRCA 
status and prior PARPi treatment will be used to estimate the treatment hazard ratio and 
the corresponding confidence interval.
RECIST Response: The criteria for assessing objective response is defined in Section 
11.1.3 and the definition of response duration is defined in section 11.1.4.  A logistic 
model will be used to estimate the relative odds of responding (CR+PR) to O+T relative 
to O after adjusting for BRCA mutation status and prior PARPi usage.  Assuming 90% of 
these patients have measurable disease, the proposed sample size provides 85% power for 
detecting a relative odds of 2.5 when type I error is limited to 0.05 for a one-tail test.  
Assuming the true probability of response to olaparib monotherapy is about 50%, a 
relative odds of 2.5 is comparable to expecting the true probability of response to 
increase 21.4% on O+T (i.e. increase from 50% to 71%).
13.6.2 Interim Analysis for All Other Endpoints (Goals): 
Two Embedded Safety Lead-in Components of this Study:
In order to limit the number of patients who could be exposed to an excessively toxic 
treatment regimen, this study includes two embedded safety assessments.  
Initial Safety Lead-In: The study treatments will be randomly allocated (1:1) to each 

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individual enrolled during this component of the study.  Enrollment will proceed until 
there are at least 25 patients treated with O+T regimen.  Enrollment during this phase of 
the study will be limited to institutions that are members of the NRG’s Phase I Group.  
These clinics are experienced in conducting phase I trials, and they are adequately staffed 
and committed to expedited reporting procedures. Once 25 patients have received at least 
3 cycles of O+T, the cumulative toxicity data will be reviewed by the Safety Review 
Committee.  Provided no more than 6 of these 25 patients experience dose-limiting 
toxicities (DLT, see Section 11.1.7 for definition of DLT) during the first 3 cycles of 
treatment, the O+T regimen will be considered sufficiently safe to continue enrollment 
onto the second safety assessment component of this study.  If the number of patients 
experiencing a DLT exceeds 6 at any time before the targeted enrollment for the safety 
lead-in has been completed, then the study’s conclusion will be considered ineluctable 
and the enrollment will be stopped.
If the true probability of a DLT is 0.15 in this population then this decision rule provides 
a 93% chance of advancing to the next study component.  On the other hand, if the true 
probability of a DLT is 0.35, then there is an 83% chance of stopping the study during or 
immediately following the first safety lead-in.  
Second Safety Lead-in: If the O+T regimen is deemed sufficiently safe following the 
initial safety lead-in, then enrollment will be opened to all approved NRG sites.
Enrollment will continue until at least 45 patients have been randomized and treated on 
O+T (including those enrolled during the first safety lead-in). Following review by the 
Safety Review Committee, if there are more than 11 DLTs observed among the 45 
patients enrolled onto and treated with the O+T regimen then the O+T regimen will be 
deemed too toxic to warrant further evaluation.  In the event that more than 11 DLTs are 
observed before completing enrollment onto this component of the study, then the study’s 
conclusion will be considered ineluctable and the enrollment will be stopped.  
If the true probability of a DLT is 0.15 then the decision rules from the first and second 
safety assessments provide 92% chance of continuing the study to the completion of its 
primary objective.  However, if the true probability of a DLT is 35%, then these rules 
provide a 93.5% chance of stopping the study early; that is, during or immediately 
following one of the two scheduled safety assessments.  If the study regimen is deemed to 
be safe based on this assessment, the protocol will be amended to allow participation of 
NCTN sites and activation of the full phase II trial.
Gender/Ethnicity/Race Distribution
Racial Categories
DOMESTIC PLANNED ENROLLMENT REPORT
Ethnic Categories
Not Hispanic or 
Latino
Hispanic or Latino
Total
Female
Male
Female
Male
American Indian/Alaska 
Native
3
0
0
3
Asian
12
0
0
0
12

 
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Native Hawaiian or Other 
Pacific Islander 
1 
0 
0 
0 
1 
Black or African 
American 
7 
0 
1 
0 
8 
White  
141 
0 
5 
0 
146 
More Than One Race 
0 
0 
0 
0 
0 
Total 
164 
0 
6 
0 
170 
 
 
 
 
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 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White  
0 
0 
0 
0 
0 
More Than One Race 
0 
0 
0 
0 
0 
Total 
0 
0 
0 
0 
0 
 
 
 

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Minn AJ, Interferons and the immunogenic effects of cancer therapy.  Trends in Immunol 
2015; 36(11): 725-37. 
 
Minn AJ and Wherry EJ.  Combination cancer therapies with immune checkpoint 
blockade: convergence on interferon signaling.  Cell 2016; 165: 272-5. 
 
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-
sensitive, recurrent ovarian cancer.  New Engl J Med 2016 Dec 1; 375(22):2154-64. 
 
Moore K, Colombo N, Scambia G, et al.  Maintenance olaparib in patients with newly 
diagnosed advanced ovarian cancer.  N Engl J Med 2018 Dec 27; 379(26):  2495-505. 
 

 
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Ott, P.A., F.S. Hodi, and C. Robert, CTLA-4 and PD-1/PD-L1 blockade: new 
immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin 
Cancer Res, 2013. 19(19): p. 5300-9. 
 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
reviews Cancer 2012;12(4):252-64. 
 
Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, Hawkins RE, 
Thistlethwaite FC. Modulation of lymphocyte regulation for cancer therapy: a phase II 
trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer 
Res. 2010 Mar 1;16(5):1662-72. 
 
Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, 
Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P, Lasarte JJ, Pérez-Gracia JL, Melero I, Prieto 
J.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular 
carcinoma and chronic hepatitis C.J Hepatol. 2013 Jul;59(1):81-8. 
 
Swisher EM, Lin KK, Oza Am, et al.  Rucaparib in relapsed, platinum-sensitive high-
grade ovarian carcinoma (ARIEL2 Part 1): an international, multicenter, open-label, 
phase 2 trial.  Lancet Oncol Jan 2017: (18): 75-87. 
 
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T 
lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with 
advanced cancers.  Exper Opin Biol Ther. 2008 Oct 8 (10):1583-93. 
 
Topalian, S.L., C.G. Drake, and D.M. Pardoll. Immune checkpoint blockade: a common 
denominator approach to cancer therapy. Cancer Cell, 2015. 27(4): p. 450-61. 
 
Warrener P, Kim S, Williams SMG, et al.  Synthetic lethality of PARP inhibition in 
BRCA-network disrupted tumor cells is associated with interferon pathway activation 
and enhanced by interferon-g. Apoptosis 2012; 17: 691-701. 
 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 
1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24. 
 
Zhang L, Conejo-Garcia JR, Katsaros D, et al.  Intratumoral T cells, recurrence and 
survival in ovarian cancer.  N Engl J Med 2003 Jan 16; 348(3): 203-13. 
 
 
 

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

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

 
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APPENDIX II – 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 – GENERAL THERAPY GUIDELINES  
 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of 
chemotherapy delayed up to 7 days (without this being considered to be 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 or 28 day 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). 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to 
be delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can 
be delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given 
on Day 14, Day 15, or Day 16. 
• 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 required 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. 
APPENDIX IV: PATIENT DRUG INTERACTIONS HANDOUT AND PATIENT DRUG 
INTERACTIONS WALLET CARD - OLAPARIB 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:  
      
Trial #: 
      
Study 
Doctor: 
      
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
      
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  

 
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These are the things that your healthcare providers need to know: 
Olaparib interacts with a specific enzyme in your liver and transport proteins.  It must be used 
very carefully with other medicines. 
 
 
Explanation 
CYP 
isoenzymes  
The enzymes in question are CYP3A4/5, CYP1A2, 2B6, 3A4,  and UGT1A1  
“Olaparib is broken down by CYP3A4/5 and may be affected by other drugs 
that inhibit or induce these enzymes.  Olaparib inhibits CYP3A4/5 and induces 
CYP1A2, 2B6, and UGT1A1 which may affect other drugs that are broken 
down by these enzymes.” 
 
Protein 
transporters  
The proteins in question are P-gp, OATP1B1, OCT1, OCT2, OAT3, 
MATE1MATE2K and BCRP. “Olaparib is moved in and out of cells/organs by 
P-gp transport protein and may be affected by inhibitors or inducers of P-gp.  
Olaparib inhibits P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2K 
and BCRP which may affect how other drugs are moved in and out of cells in 
the body.”  
 
These are the things that you need to know: 
The study drug Olaparib may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your doctors about all your medicines, including:  (a) 
medicines you are taking before this clinical trial, (b) medicines you start or stop taking during 
this study, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals 
or supplements (e.g. St. John’s Wort).  It is helpful to bring your medication bottles or an 
updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP3A4/5 and Pgp. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
o Avoid St. John’s Wort (Hypericum perforatum). 
• Make sure your doctor knows to avoid certain prescription medications.  
o Phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbitone, 
nevirapine, modafinil. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
 
 
PATIENT DRUG INTERACTION WALLET CARD (24-APR-2020) 
 
 

 
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EMERGENCY INFORMATION 
 
DRUG INTERACTIONS  
Show this card to all of your 
healthcare providers. Keep 
it with you in case you go to 
the emergency room. 
Tell your doctors before you 
start or stop any medicines. 
Check with your doctor or 
pharmacist if you need to use 
an over-the-counter medicine 
or herbal supplement! 
Carry this card with you at all times   
Olaparib interacts with a specific enzyme in your liver and transport 
proteins.  It must be used very carefully with other medicines. 
 
 
Patient Name:       
Use caution and avoid the 
following drugs if possible:  
 
Phenytoin, rifampicin, rifapentin, 
rifabutin, carbamazepine, 
phenobarbitone, nevirapine, 
modafinil, St. John’s Wort 
(Hypericum perforatum) or other 
herbal supplements.   
 
 
Your healthcare providers should be aware of any medicines that 
are strong or moderate inducers/inhibitors of CY3A4/5 and Pgp.  
Olaparib inhibits “CYP 3A4, UGT1A1 and transport proteins Pgp, 
OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2K and BCRP 
and induces CYP 1A2, 2B6, 3A4, 2C9, 2C19 .” It may change how 
other medicine works in your body 
 
Diagnosis:       
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:       
Before prescribing new medicines, your health care provider 
should check a frequently-updated medical reference for a list of 
drugs to avoid or contact your study doctor. 
Study Drug(S):  Olaparib  
 
 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
For more information: 1-800-4-
CANCER 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 
cancer.gov | clinicaltrials.gov 

 
 
 
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APPENDIX V: PATIENT DRUG DIARY: OLAPARIB 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name _______________________________________ 
 
1. Complete one form for each cycle (28 days) 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment 
4. Do not chew, dissolve, or crush medications.  DO NOT make up vomited doses. 
5. If you miss a dose, you have up to 2 hours to make this dose up.  Otherwise, write “missed” where you 
would normally write the time of your dose. 
6. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
OLAPARIB 
Take _____ (number) ______ mg and _____ (number) _____ mg tablets twice a day 12 hours apart. 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/19 
2 
0 
8:00 
8:00 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: _________________________________    Date: __________________ 
 
Physician/Nurse/Data Manager’s Signature: _________________________   Date: _____________ 

 
 
 
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APPENDIX VI – TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES 
 
1. Obtaining a Bank ID for Translational Science Biospecimens 
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 Support if you need assistance (Email: support@nrgoncology.org). 
 
2. Requesting Translational Science Biospecimen Kits  
Upon request, a biospecimen kit including a Streck tube and ambient shipper will be provided for 
the collection and shipment of cfDNA whole blood biospecimens. A separate kit is needed for 
each cfDNA whole blood biospecimen. 
 
Sites can order kits online via the Kit Management system (https://kits.bpc-apps.nchri.org/) (27-
AUG-2021). . Each site may order two kit types per protocol per day (daily max = 6 kits).  
 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Supplies will not be provided for the collection or shipment of whole blood collected in 
sodium heparin (NaHep) or EDTA tubes. 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits should 
arrive within 3-5 business days. 
 
3. FFPE Tissue Shipped to the NRG BB-Columbus 
Only one block may be submitted per tissue type. All tissue biospecimens sent to the NRG BB-
Columbus must be shipped with a copy of the corresponding pathology report (all PHI must be 
redacted) and a completed copy of the FFPE Materials Verification Form (Appendix VII) should 
be provided to your Pathology Department when FFPE materials are requested and must be 
completed by the person providing the FFPE materials. 
 
3.1  
FFPE Biospecimen Requirement 
3.1.1 Tumor Tissue Type 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
required type: 
• Recurrent (FRP01) or persistent (FPP01) primary and recurrent (FRM01) or persistent 
(FPM01) metastatic tumor should be collected prior to the study treatment and is the 
preferred tumor type. 
• Neoadjuvant primary (FPT01) or metastatic (FMT01) tumor should be collected after the 
patient received neoadjuvant tumor, but prior to the study treatment. 
• Primary (FP01) or metastatic (FM01) tumor should be collected prior to all treatment. 

 
 
 
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3.1.2 FFPE Type 
Only blocks will be accepted. Please provide Appendix IX to your pathologist. 
 
3.1.3 Labeling FFPE Biospecimens 
A waterproof permanent marker or printed label should be used to label each translational 
science FFPE 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. 
3.1.4 
Completing Form TR for FFPE Biospecimens 
The type of biospecimen (block) should be specified on Form TR. 
 
The time the tissue was in formalin (i.e., fixation time) should be entered as Estimated 
Processing Time. 
 
4. Whole Blood Biospecimens Shipped to the NRG BB-Columbus 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label should be used to label each 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. 
 
4.1 
T Cell Whole Blood 

 
 
 
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4.1.1 
Collection Time Points 
T cell whole blood should be collected as per section 10.4.1. 
4.1.2 
Collecting T Cell Whole Blood 
1.  Label the green top sodium heparin (NaHep) collection tube(s) as described above. Multiple 
tubes may be used to collect the required amount. Do not use glass blood collection tubes. 
2. Draw 30mL of blood into the labeled green top tube(s). 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and sodium 
heparin. 
4. Whole blood specimens should be kept at room temperature until the specimens can be 
shipped. Whole blood must be shipped to the NRG BB-Columbus the day the specimen is 
collected. If the specimen cannot be shipped the day it is collected, it should be discarded. 
 
4.2 
T Cell Repertoire (TCR) Whole Blood 
4.2.1 
Collection Time Points 
T cell repertoire (TCR) whole blood should be collected as per section 10.4.1. 
4.2.2 
Collecting T Cell Repertoire (TCR) Whole Blood 
1.  Label the lavender/purple top (EDTA) collection tube as described above. Do not use glass 
blood collection tubes. 
2. Draw 2mL of blood into the labeled lavender/purple top tube. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA. 
4. Whole blood specimens should be kept at room temperature until the specimens can be 
shipped. Whole blood must be shipped to the NRG BB-Columbus the day the specimen is 
collected. If the specimen cannot be shipped the day it is collected, it should be discarded. 
 
 
4.3 
Cell-Free DNA (cfDNA) Whole Blood 
4.3.1 
Collection Time Points 
Cell-free DNA (cfDNA) whole blood should be collected as per section 10.4.1. 
4.3.2 
Special Notes Regarding the Collection of Blood in Streck (cf DNA) Tubes 
• Heparin should be avoided in pre-collection flush procedures. 
• All other blood biospecimens should be drawn before the Streck (cell-free DNA) tube when 
multiple blood biospecimens are collected on the same day. 
• Over or under filling a Streck (cell-free DNA) tube will result in an incorrect blood-to-
additive ratio. 
• No other tube may be substituted for a Streck (cell-free DNA) tube. 
4.3.3 
Collecting Streck (Cell-Free DNA) Whole Blood 
1.  Label the Streck (cell-free DNA) collection tube as described below. 
2. Draw 10mL of blood into the labeled tube. 
3.  Immediately after collection, gently invert the tube 5-10 times. 
4. Ship whole blood to the NRG BB-Columbus the day the biospecimen is collected. If the 
whole blood absolutely cannot be shipped the day it is collected, the tube must remain at 
room temperature until shipment. 
 
5. Submitting Biospecimen Transmittal Forms 
A biospecimen transmittal form 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. 

 
 
 
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An electronically (i.e., Rave) completed copy of the biospecimen transmittal form 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. 
 
Biospecimen transmittal forms 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). 
 
6.  Shipping Translational Science Biospecimens 
• Translational science biospecimens should not be shipped until after patient registration and 
Bank ID assignment. 
• An electronically completed copy of the biospecimen transmittal form must be included for 
each translational science biospecimen. 
• All translational science biospecimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG-GY021 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
6.1 
FFPE Tissue Shipped to the NRG BB-Columbus 
FFPE tissue, a copy of the corresponding pathology report, and a competed copy of the FFPE 
Materials Verification Form (Appendix VII) 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. 
 
6.2 
Whole Blood Shipped to the NRG BB-Columbus 
• Whole blood biospecimens can be shipped to the NRG BB-Columbus Monday through 
Friday for Tuesday through Saturday delivery. Do not ship whole blood the day before a 
holiday. Ship biospecimens via FedEx priority overnight. 
• When shipping whole blood biospecimens, your site must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the NRG BB-
Columbus at BPCBank@nationwidechildrens.org or by phoning 866-464-2262.  

 
 
 
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6.2.1 
Whole Blood Collected in Sodium Heparin (NaHep) and EDTA Tubes 
To ship whole blood collected in Sodium Heparin (NaHep) and EDTA tubes you will need (1) a 
sturdy shipping container (e.g., a cardboard or styrofoam box), (2) a leak proof biohazard 
envelope with absorbent material*, (3) a puncture and pressure resistant envelope (e.g. Tyvek 
envelope), (4) an Exempt Human Specimen sticker, and (5) a pre-paid FedEx air bill. 
  
*If you will be shipping both whole blood collected in sodium heparin (NaHep) and EDTA, 
please put each biospecimen in a separate plastic zip-lock bag before placing the biospecimens 
in the shipping bag.  
 
If you do not have these materials available at your site, you may order them from any supplier 
(e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
6.2.1.1 Shipping Whole Blood  in Sodium Heparin (NaHep) and EDTA Tubes 
1. Ship whole blood collected in sodium heparin (NaHep) or EDTA tubes using your own 
shipping container and supplies. 
2. Place the whole blood biospecimens in a biohazard envelope containing absorbent material. 
Expel as much air as possible before sealing the bag. 
3. Wrap the biohazard envelope in bubble wrap or another padded material. 
4. Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing 
the envelope. 
5. Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
6. Insert a copy of the Blood Biospecimen Submission Form for each biospecimen.  
7. Attach an Exempt Human Specimen sticker to the outside of the shipping container. 
8. Print a pre-paid FedEx air bill using the Kit Management link.  (https://kits.bpc-
apps.nchri.org/). (27-AUG-2021). Attach the air bill. 
9. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-
238-5355. 
 
6.2.2 
Whole Blood Collected in Streck Tubes 
To ship whole blood collected in Streck tubes you will need a Streck Cell-Free DNA Ambient 
Shipper. Refer to Section 2 of this appendix for details. 
 
6.2.2.1 Shipping Whole Blood Using a Streck Cell-Free DNA Ambient Shipper 
1. Before packaging cfDNA whole blood biospecimens, verify that each biospecimen is labeled 
according to the instructions above.   
2. Prepare the SAF-T-TEMP Gel Pak for shipment. Note: If contents of the Pak are crunchy, 
place Pak in a warm water bath until gel is smooth. Do not refrigerate, freeze, or 
microwave.  
3. Place the SAF-T-TEMP Pak in bottom of insulated chest. Note: The insulated chest must be 
shipped inside the provided cardboard box.  
4. Place the blood collection tube in zip-lock bags.   
5. Next, place zip-lock bag into a biohazard envelope with absorbent material. Expel as much 
air as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible and seal 

 
 
 
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securely. 
7. Place packaged Streck blood collection tube and a completed copy of the Blood Biospecimen 
Submission Form on top of SAF-T-TEMP Gel Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container. 
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Print a pre-paid FedEx air bill using the Kit Management link (https://kits.bpc-
apps.nchri.org/). (27-AUG-2021). Attach the air bill. 
13. Make arrangements for FedEx pick-up through your site’s usual procedure or by calling 800-
238-5355. 
 
7. Banking Translational Science Biospecimens for Future Research 
Biospecimens will remain in the NRG BB-Columbus and made available for approved research 
projects if the patient has provided permission for the use of her biospecimens for future health 
research. 
 
Note: The final biomarker assays and analyses at CIMAC-CIDC will be based on the “Proposal 
Intake Form for Investigators Using the CIMAC-CIDC Network” for this trial. The Intake Form 
will be reviewed and approved by NCI and the CIMAC-CIDC coordination center before testing 
of banked biospecimens. (27-AUG-2021) 
 
The patient’s biospecimen consent choices will be recorded on the signed informed consent 
document and electronically via the Specimen Consent form. At the time of biospecimen 
selection for project distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any 
time if the patient changes her mind. 
 
If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy 
or return any remaining biospecimens. The patient’s biospecimens will not be used for any 
further research; however, any biospecimens distributed for research prior to revoking consent 
cannot be returned or destroyed. In addition, the patient cannot be removed from any research 
that has been done with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense. 
 
 

 
 
 
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APPENDIX VII - BIOSPECIMEN BANK-COLUMBUS PATHOLOGY MATERIALS 
VERIFICATION FORM (24-APR-2020) 
 
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): 
• recurrent (FRP01) or metastatic (FRM01) – i.e., collected prior to study treatment; 
• persistent primary (FPP01) or metastatic (FPM01) – i.e., collected prior to study 
treatment; 
• neoadjuvant primary (FPT01) or metastatic (FMT01) – i.e., collected after neoadjuvant 
treatment, but prior to study treatment; or 
• primary (FP01) or metastatic (FM01) tumor – i.e., collected prior to any treatment. 
  
Only blocks will be accepted. Please provide Appendix IX to your pathologist. 
  
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: 
□ Recurrent Primary (FRP01) 
□ Recurrent Metastatic (FRM01) 
□ Persistent Primary (FPP01) 
□ Persistent Metastatic (FPM01) 
□ Neoadjuvant Primary (FPT01) □ Neoadjuvant Metastatic (FMT01) 
□ Primary (FP01) 
 
□ Metastatic (FM01) 
 
Site: 
 
□ Ovary 
 
 
□ Other, specify ___________________ 
 
Materials Prepared  
Number Provided 
 
Thickness (μm) 
Block 
 
 
Not Applicable 
 
 
_________________________________________ 
 
________________________ 
Name of person preparing materials 
 
 
Date 
 
 

 
 
 
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APPENDIX VIII – COLLABORATIVE AGREEMENT 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 

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

 
 
 
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APPENDIX IX – LETTER TO PATHOLOGISTS 
 
Dear Pathologist, 
 
Your site is a participant in NRG GY021, “A phase II randomized trial of olaparib versus 
olaparib plus tremelimumab in platinum-sensitive recurrent ovarian cancer.” 
 
This study includes exploratory biomarker testing to be done in collaboration with the NCI 
Cancer Immune Monitoring and Analysis Centers (CIMACs). 
 
CIMAC testing requirements mandate that all slides used must be fresh cut. 
 
Given the biospecimen requirements for this biomarker testing, NRG GY021 requires all sites 
submit FFPE blocks only (i.e., unstained slides will not be accepted). Blocks may be 
submitted on a permanent or temporary basis. 
 
 
If submitted on a temporary basis, blocks will be returned after completion of the CIMAC 
biomarker testing. 
 
If return of the block is requested, the NRG BB-Columbus will contact your institution for 
a Fed Ex Account number and shipping address after completion of the integral and 
integrated biomarker testing. 
 
If you should have any questions, please do not hesitate to contact Drs. Sarah Adams (PI) and 
Heather Lankes (Translational Research Scientist). 
 
We thank you in advance for your participation in this trial and your commitment to the 
successful completion of this study’s objectives. 
 
Sincerely, 
 
Sarah Adams, MD 
Heather A Lankes, PhD, MPH