A Randomized Phase II Trial of Triplet Therapy (A PD-L1 Inhibitor Durvalumab (MEDI4736) in Combination With Olaparib and Cediranib) Compared to Olaparib and Cediranib or Durvalumab (MEDI4736) and Cediranib or Standard of Care Chemotherapy in Women With Platinum-Resistant Recurrent Epithelial Ovarian Cancer, Primary Peritoneal or Fallopian Cancer Who Have Received Prior Bevacizumab
Phase: PHASE2
Conditions: Fallopian Tube Mucinous Adenocarcinoma, Ovarian Seromucinous Carcinoma, Platinum-Refractory Fallopian Tube Carcinoma, Platinum-Refractory Ovarian Carcinoma, Platinum-Refractory Primary Peritoneal Carcinoma, Recurrent Fallopian Tube Clear Cell Adenocarcinoma, Recurrent Fallopian Tube Endometrioid Adenocarcinoma, Recurrent Fallopian Tube High Grade Serous Adenocarcinoma, Recurrent Fallopian Tube Mucinous Adenocarcinoma, Recurrent Fallopian Tube Transitional Cell Carcinoma, Recurrent Fallopian Tube Undifferentiated Carcinoma, Recurrent Low Grade Fallopian Tube Serous Adenocarcinoma, Recurrent Ovarian Clear Cell Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Ovarian High Grade Serous Adenocarcinoma, Recurrent Ovarian Low Grade Serous Adenocarcinoma, Recurrent Ovarian Mucinous Adenocarcinoma, Recurrent Ovarian Seromucinous Carcinoma, Recurrent Ovarian Transitional Cell Carcinoma, Recurrent Ovarian Undifferentiated Carcinoma, Recurrent Platinum-Resistant Fallopian Tube Carcinoma, Recurrent Platinum-Resistant Ovarian Carcinoma, Recurrent Platinum-Resistant Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Clear Cell Adenocarcinoma, Recurrent Primary Peritoneal Endometrioid Adenocarcinoma, Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma, Recurrent Primary Peritoneal Low Grade Serous Adenocarcinoma, Recurrent Primary Peritoneal Transitional Cell Carcinoma, Recurrent Primary Peritoneal Undifferentiated Carcinoma, Refractory Fallopian Tube Clear Cell Adenocarcinoma, Refractory Fallopian Tube Endometrioid Adenocarcinoma, Refractory Fallopian Tube High Grade Serous Adenocarcinoma, Refractory Fallopian Tube Mucinous Adenocarcinoma, Refractory Fallopian Tube Transitional Cell Carcinoma, Refractory Fallopian Tube Undifferentiated Carcinoma, Refractory Low Grade Fallopian Tube Serous Adenocarcinoma, Refractory Ovarian Clear Cell Adenocarcinoma, Refractory Ovarian Endometrioid Adenocarcinoma, Refractory Ovarian High Grade Serous Adenocarcinoma, Refractory Ovarian Low Grade Serous Adenocarcinoma, Refractory Ovarian Mucinous Adenocarcinoma, Refractory Ovarian Seromucinous Carcinoma, Refractory Ovarian Transitional Cell Carcinoma, Refractory Ovarian Undifferentiated Carcinoma, Refractory Primary Peritoneal Clear Cell Adenocarcinoma, Refractory Primary Peritoneal Endometrioid Adenocarcinoma, Refractory Primary Peritoneal High Grade Serous Adenocarcinoma, Refractory Primary Peritoneal Low Grade Serous Adenocarcinoma, Refractory Primary Peritoneal Transitional Cell Carcinoma, Refractory Primary Peritoneal Undifferentiated Carcinoma
Sponsor: National Cancer Institute (NCI)

            
 
- 1 -  
 
 
For Protocol Amendment #3 to: NRG-GY023 
 
NCI Protocol #: NRG-GY023 
Local Protocol #: NRG-GY023 
 
NCI Protocol Version Date: July 25, 2023 
 
 
This amendment is being submitted in response to an RRA received by Dr. S. Percy Ivy 
(ivy.p@ctep.nci.nih.gov) received on 7/6/2023. 
 
Section 
Comment 
7.4 
The CAEPR for Olaparib has been updated to version 2.6, June 5, 2023: 
x 
Added New Risk:  
x 
Rare but Serious: Vascular disorders - Other (venous 
thromboembolism) 
 
ICD 
Please see the ICD for additional changes. 
  
 
Changes made in addition to RRA: 
 
Section 
Comment 
Title Page 
x The NCI version date is now July 25, 2023 
x CTSU language has been updated to agree with current template 
language 
8 
x CTSU language has been updated to agree with current template 
language 
8.1 
x CTSU language has been updated to agree with current template 
language 
8.2 
x CTSU language has been updated to agree with current template 
language 
13.1 
x CTSU language has been updated to agree with current template 
language 

            
 
- 1 -  
 
 
NRG-GY023: A RANDOMIZED PHASE II TRIAL OF TRIPLET 
THERAPY (A PD-L1 INHIBITOR DURVALUMAB (MEDI4736) IN 
COMBINATION WITH OLAPARIB AND CEDIRANIB) COMPARED TO 
OLAPARIB AND CEDIRANIB OR DURVALUMAB (MEDI4736) AND 
CEDIRANIB OR STANDARD OF CARE CHEMOTHERAPY IN WOMEN 
WITH PLATINUM-RESISTANT RECURRENT EPITHELIAL OVARIAN 
CANCER, PRIMARY PERITONEAL OR FALLOPIAN CANCER WHO 
HAVE RECEIVED PRIOR BEVACIZUMAB 
 
ClinicalTrials.gov Identifier NCT #04739800 
 
NCI Version Date: July 25, 2023  
 
 
Principal Investigator: 
Jung-Min Lee, MD 
Center for Cancer Research, NCI 
10 Center Drive, Bldg. 10, Room 4B54 
 
 
Bethesda, MD 
240-760-6128 
leej6@mail.nih.gov 
 
Participating Organizations 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
 
Participating Sites  
 U.S. 
 Canada  
 Approved International Member Sites 
 Limited Participation  
 
This protocol was designed and developed by NRG Oncology. It is intended to be used only in 
conjunction with IRB approval for study entry. No other use or reproduction is authorized by NRG 
Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this protocol. 
 
 
 
 
 
 
 
 
 

NRG-GY023 
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Version Date: July 25, 2023 
Protocol Agents: 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Durvalumab 
CTEP 
778709 
 
 
 
DCTD, NCI 
Olaparib 
CTEP 
747856 
DCTD, NCI 
Cediranib  
CTEP 
732208 
DCTD, NCI 
Paclitaxel 
Commercial 
673089 
N/A 
N/A 
Topotecan 
Commercial 
609699 
N/A 
N/A 
Pegylated Liposomal 
Doxorubicin (PLD) 
Commercial 
712227 
N/A 
N/A 
 
 
Document History 
Initial 
April 01, 2021 
Amendment 1 
August 27, 2021 
Amendment 2 
August 23, 2022 
Amendment 3 
July 25, 2023 
 
 
STUDY TEAM  
PRINCIPAL INVESTIGATOR 
STATISTICIAN 
Principal Investigator/Medical Oncologist 
Jung-Min Lee, MD 
Center for Cancer Research, NCI 
Bethesda, MD 
240-760-6128 
leej6@mail.nih.gov  
 
Austin Miller, PhD 
NRG Oncology Statistics and Data Management 
Center-Buffalo  
Buffalo, NY 
716-845-5702 
millera@nrgoncology.org  
 
MODALITY CHAIRS 
Medical Oncology  
Joyce F. Liu, MD 
Dana-Farber Cancer Institute 
Boston, MA 
617-632-8927 
Joyce_liu@dfci.harvard.edu 
Translational Scientist 
Heather Lankes, PhD, MPH 
NRG Oncology 
Philadelphia, PA 
215-854-0770 
lankesh@nrgoncology.org  
 
Research Nurse 
Erin Villanueva, RN 
Center for Cancer Research, NCI 
Bethesda, MD 
240-760-6131 
erin.villanueva@nih.gov 
 
 
 
 
 

NRG-GY023 
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Version Date: July 25, 2023 
STUDY-SPECIFIC CONTACTS AND RESOURCES 
For questions/comments related to:                               Contact:  
Protocol Document, informed consent 
documents and amendments 
 
Leah Madden, Protocol Coordinator 
NRG Oncology  
215-854-0770 
maddenl@nrgoncology.org  
 
Data Management 
Including submission, eligibility  
 
 
Dolores Kirschner, MPH 
NRG Oncology Statistics and Data Management Center-
Pittsburgh 
412-383-4912 
kirschnerd@nrgoncology.org 
 
Biospecimen Collection 
 
NRG Oncology Biobank Columbus 
866-464-2262 
bpcbank@nationwidechildrens.org  
Regulatory 
NRG-GY-Regulatory@nrgoncology.org  
NRG Oncology Gynecologic Oncology Chair  
 
Carol Aghajanian, MD 
Memorial Sloan Kettering Cancer Center 
New York, NY 
646-888-4217 
 
Aghajanc@mskcc.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NRG-GY023 
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Version Date: July 25, 2023 
 
CONTACT INFORMATION (23-AUG-2022)(25-JUL-2023) 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trial Support Unit 
(CTSU) via the Regulatory 
Submission Portal. (Sign in at 
https://www.ctsu.org, and 
select Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878) , or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN). 
OPEN is accessed at 
https://www.ctsu.org/OPEN_
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 on the CTSU members’ website 
(https://www.ctsu.org).   
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the Roster Maintenance application and in 
most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the CTSU members’ website. 
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of 
the Lead Protocol Organization. 
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.  
 
 

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Version Date: July 25, 2023 
TABLE OF CONTENTS 
 
1. 
OBJECTIVES ................................................................................................................. - 9 - 
1.1 
Primary Objective ............................................................................................... - 9 - 
1.2 
Secondary Objectives .......................................................................................... - 9 - 
2. 
BACKGROUND ............................................................................................................ - 9 - 
2.1 
Platinum-resistant recurrent ovarian cancer ........................................................ - 9 - 
2.2 
Immunotherapy and targeted agent combinations as a novel therapeutic 
strategy .............................................................................................................. - 10 - 
2.3 
Phase I/II single arm study of the PD-L1 inhibitor, durvalumab 
(MEDI4736) in combination with olaparib and cediranib in recurrent 
ovarian cancer (NCT0248440) ......................................................................... - 12 - 
2.4 
Phase II single arm study of olaparib and cediranib in recurrent ovarian 
cancer ................................................................................................................ - 14 - 
2.5 
Translational Science Background ................................................................... - 15 - 
2.6 
Rationale for trial design ................................................................................... - 16 - 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..................................................... - 18 - 
3.1 
Eligibility Criteria ............................................................................................. - 18 - 
3.2 
Ineligibility Criteria .......................................................................................... - 20 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 25 - 
4.1 
Pre-Treatment Assessments (27-AUG-2021) ................................................... - 25 - 
4.2 
Assessments During Treatment ........................................................................ - 26 - 
4.3 
Assessments in Follow-up ................................................................................ - 28 - 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION ..................................................... - 28 - 
5.1 
Treatment Plan .................................................................................................. - 29 - 
5.2 
General Concomitant Medication and Supportive Care Guidelines ................. - 31 - 
5.3 
Duration of Therapy (27-AUG-2021) ............................................................... - 31 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................ - 32 - 
6.1 
Arm I (Reference regimen) ............................................................................... - 33 - 
6.2 
Arms II [durvalumab (MEDI4736) plus olaparib and cediranib], III 
durvalumab (MEDI4736) plus cediranib alone], and IV [olaparib and 
cediranib] .......................................................................................................... - 34 - 
6.3 
Cediranib-related adverse events ...................................................................... - 55 - 
6.4 
Olaparib-related AEs ........................................................................................ - 61 - 
6.5 
Management of durvalumab, Olaparib, or Cediranib for 
Surgery/Procedure............................................................................................. - 62 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 63 - 
7.1 
Protocol Agents ................................................................................................. - 63 - 
7.2 
Adverse Events and Serious Adverse Events ................................................... - 63 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 

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Study Agents ..................................................................................................... - 64 - 
7.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ................. - 68 - 
7.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ................. - 70 - 
7.6 
Adverse Events for Commercial Study Agents ................................................ - 74 - 
7.7 
Expedited Reporting of Adverse Events ........................................................... - 74 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES ........................................ - 77 - 
8.1 
Cancer Trials Support Unit Registration Procedures (23-AUG-2022) ............. - 79 - 
8.2 
Patient Enrollment (23-AUG-2022) ................................................................. - 81 - 
9. 
DRUG INFORMATION .............................................................................................. - 82 - 
9.1 
Investigational Study Agent: Durvalumab (MEDI4736) (NSC# 778709) ....... - 82 - 
9.2 
Olaparib (AZD2281) (NSC# 747856) .............................................................. - 83 - 
9.3 
Cediranib (NSC# 732208) ................................................................................ - 86 - 
9.4 
Commercial Agent—Paclitaxel (NSC# 673089) .............................................. - 88 - 
9.5 
Commercial Agent: Topotecan (NSC# 609699) ............................................... - 89 - 
9.6 
Commercial Agent: Pegylated Lipomosal Doxorubicin (PLD) ........................ - 90 - 
9.7 
Agent Ordering and Agent Accountability ....................................................... - 92 - 
10. 
PATHOLOGY/BIOSPECIMEN .................................................................................. - 93 - 
10.1 
Central Pathology Review Guidelines .............................................................. - 93 - 
10.2 
Biospecimen Selection for Integral Biomarker Testing .................................... - 94 - 
10.3 
Biospecimen Selection for Integrated Biomarker testing ................................. - 94 - 
10.4 
Biospecimen Submission Tables ...................................................................... - 94 - 
10.5 
Biospecimen Selection for Exploratory Biomarker Testing ............................. - 94 - 
10.6 
Banking Biospecimens for Future Research ..................................................... - 95 - 
11. 
SPECIAL STUDIES (Non-Tissue) ............................................................................... - 95 - 
12. 
ASSESSMENT OF EFFECT ....................................................................................... - 95 - 
12.1 
Antitumor Effect – Solid Tumors ..................................................................... - 95 - 
12.2 
Response Criteria .............................................................................................. - 98 - 
12.3 
Duration of Response ...................................................................................... - 101 - 
12.4 
Progression-Free Survival ............................................................................... - 102 - 
12.5 
Overall Survival .............................................................................................. - 102 - 
13. 
DATA AND RECORDS ............................................................................................ - 102 - 
13.1 
Data Submission/Data Reporting (23_AUG-2022) ........................................ - 102 - 
13.2 
NRG Data Management Forms ...................................................................... - 105 - 
13.3 
Summary of Data Submission ........................................................................ - 105 - 
14. 
STATISTICAL CONSIDERATIONS........................................................................ - 105 - 
14.1 
Study Design ................................................................................................... - 105 - 
14.2 
Study Endpoints .............................................................................................. - 106 - 
14.3 
Primary Objectives Study Design ................................................................... - 106 - 
14.4 
Study Monitoring of Primary Objectives ........................................................ - 108 - 
14.5 
Accrual/Study Duration Considerations ......................................................... - 109 - 

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14.6 
Gender/Ethnicity/Race Distribution ................................................................ - 109 - 
15. 
REFERENCES ........................................................................................................... - 111 - 
APPENDIX I-PERFORMANCE STATUS CRITERIA ........................................................ - 118 - 
APPENDIX II – NYHA CLASSIFICATION ........................................................................ - 119 - 
APPENDIX III-GENERAL THERAPY GUIDELINES........................................................ - 120 - 
APPENDIX IV-CTEP COLLABORATIVE AGREEMENTS LANGUAGE ....................... - 121 - 
APPENDIX V-DURVALUMAB (MEDI4736) ClINCAL TRIAL WALLET CARD .......... - 123 - 
APPENDIX VI- CEDIRANIB PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD .................................................................................................................... - 124 - 
APPENDIX VII- OLAPARIB PATIENT CLINICAL TRIAL WALLET CARD ................ - 127 - 
APPENDIX VIII-ARM 2 CEDIRANIB AND OLAPARIB PATIENT DRUG DIARY ...... - 128 - 
APPENDIX IX-ARM 3 CEDIRANIB PATIENT DRUG DIARY ........................................ - 129 - 
APPENDIX X-ARM 4 CEDIRANIB AND OLAPARIB PATIENT DRUG DIARY .......... - 130 - 
APPENDIX XI- PATIENT BLOOD PRESSURE DIARY ................................................... - 131 - 
APPENDIX XII- ORAL ANTIHYPERTENSIVE MEDICATIONS. ................................... - 132 - 
APPENDIX XIII– TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES ........ - 134 - 
APPENDIX XIV-BIOSPECIMEN BANK-COLUMBUS PATHOLOGY MATERIALS ... - 139 - 
APPENDIX XV– LETTER TO PATHOLOGISTS ............................................................... - 140 - 
 
 
 
 
 

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NRG-GY023  
SCHEMA 
 
 
*Non-platinum single agent chemotherapy includes weekly paclitaxel, topotecan or pegylated 
liposomal doxorubicin (PLD). There can be no deviance from the prescribed regimens, e.g. 
addition of bevacizumab or other agents. 
 
Randomization is 1:2:2:2 
 
 
 

NRG-GY023 
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Version Date: July 25, 2023 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objective 
1.1.1 To assess the efficacy of the combinations durvalumab (MEDI4736) plus olaparib and 
cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as 
measured by progression-free survival (PFS), as compared to physician's choice standard 
of care chemotherapy, in patients with recurrent platinum-resistant ovarian, primary 
peritoneal or fallopian tube cancer who had prior bevacizumab. 
 
1.2 
Secondary Objectives 
1.2.1 To assess the efficacy of the combinations durvalumab (MEDI4736)) plus olaparib and 
cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as 
measured by overall response rate (ORR) by RECIST version 1.1 criteria, as compared to 
physician's choice standard of care chemotherapy, in patients with recurrent platinum-
resistant ovarian, primary peritoneal or fallopian tube cancer who had prior bevacizumab. 
 
1.2.2 To assess the efficacy of the combinations durvalumab (MEDI4736) plus olaparib and 
cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as 
measured by overall survival (OS), as compared to physician's choice standard of care 
chemotherapy, in patients with recurrent platinum-resistant ovarian, primary peritoneal or 
fallopian tube cancer who had prior bevacizumab. 
 
2. 
BACKGROUND 
   
2.1 
Platinum-resistant recurrent ovarian cancer  
 
Ovarian cancer is the deadliest gynecologic malignancy in the United States (Seigel, 
2018). The majority of women with epithelial ovarian cancer present at advanced stage, 
and recurrence is nearly universal leading to incurable disease with limited treatment 
options (Torre, 2018). There are clear unmet needs for novel treatment approaches for 
recurrent ovarian cancer. 
 
Platinum resistance is associated with a poor prognosis for women with ovarian cancer 
and almost all patients with recurrent disease ultimately develop resistance to platinum-
based therapy (Naumann, 2011, Tomao, 2017). Several chemotherapeutic options exist 
for the treatment of recurrent platinum-resistant ovarian cancer, including weekly 
paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and 
etoposide. The use of single agent cytotoxic chemotherapy or targeted agent historically 
resulted in outcome of a median progression-free survival (PFS) of 3-4 months and 
median overall survival of about 12 months (Tomao, 2017). Added PFS benefit was 
observed with the addition of bevacizumab to chemotherapy (PLD, weekly paclitaxel, or 
topotecan) in platinum-resistant recurrent ovarian cancer patients (Cortez, 2018). The 
combination of bevacizumab and chemotherapy showed improved PFS and objective 
response rate (RR) compared to chemotherapy alone; RR of 30.9% and a median PFS of 
6.7 months vs. RR of 12.6% and a median PFS of 3.4 months (HR 0.48, 95% CI 0.38–

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Version Date: July 25, 2023 
0.60, p<0.001) in bevacizumab-naïve population. Bevacizumab in combination with 
chemotherapy is now an FDA-approved treatment regimen for patients with platinum-
resistant recurrent ovarian cancer who have received no more than two previous lines of 
chemotherapy. However, patients ultimately acquire resistance to bevacizumab and a 
critical need remains for new therapeutic strategies for those who progressed on 
bevacizumab. 
 
VEGF-C and/or VEGF-D mediated activation of VEGFR-2 has been proposed as a 
potential resistance mechanism following inhibition of VEGF-A by bevacizumab (van 
der Bilt, 2012).  Also, VEGF-C and its receptor VEGFR-3 are shown to be elevated in 
serum and ascites fluid isolated from ovarian cancer patients and high serum or tumor 
VEGF-C levels/expression are associated with poor prognosis in ovarian cancer (Cheng, 
2013, Nishida, 2004).  Similar findings are reported for the related ligand VEGF-D, 
which also activates VEGFR-3 (Yokoyama, 2003). Thus, it is hypothesized that targeting 
all 3 VEGFRs (VEGFR-1, -2, -3) activated by different ligands (VEGF-A, -B, -C, -D) 
can comprehensively suppress the VEGF/VEGFR axis for the treatment of ovarian 
cancer patients who developed resistance to bevacizumab. A phase II single arm olaparib 
and cediranib study is now ongoing to test this hypothesis clinically for recurrent 
platinum-resistant ovarian cancer patients who had prior bevacizumab (NCT02889900; 
Lee, 2020). Separately, two NRG Oncology phase III studies (GY004 and GY005) are 
currently ongoing in recurrent ovarian cancer based on the findings from the randomized 
Phase II study of olaparib and cediranib in platinum-sensitive recurrent ovarian cancer 
(Liu, 2014). These NRG studies evaluate the combination of olaparib and cediranib 
compared to standard of care treatment, one in recurrent platinum-resistant ovarian 
cancer (NRG GY005, NCT02502266) and another in recurrent platinum-sensitive 
ovarian cancer (NRG GY004, NCT02446600).  
 
2.2 
Immunotherapy and targeted agent combinations as a novel therapeutic strategy  
 
Immunotherapy has emerged as a major therapeutic modality in oncology and 
demonstrated durable long-term response in subsets of ovarian cancer patients. Yet, the 
majority of patients with recurrent ovarian cancer do not derive benefit from immune 
checkpoint blockade monotherapy as demonstrated in early clinical trials (RR of 9.6% 
with avelumab monotherapy (Disis, 2019) [JAVELIN Solid Tumor Trial] and RRs of 
7.4-9.9% with pembrolizumab monotherapy (Matulonis, 2019) [KEYNOTE-100], 
leaving the need to test combination approaches to increase the effectiveness of immune 
checkpoint inhibitors (Lee, 2018, Mouw, 2018, Mouw, 2017). Other active therapeutic 
targets in ovarian cancer include the DNA repair and vascular endothelial growth factor 
(VEGF)/VEGF receptor (VEGFR) pathways (Lee, 2016).   
 
It has been hypothesized that DNA repair inhibition (e.g., PARP inhibition) may 
modulate the immune response by increasing DNA damage and tumor mutational burden 
(TMB). Increased DNA damage promotes local antigen release resulting in systemic anti-
tumor immune responses after tumor exposure to radiation or DNA damaging agents 
(Galluzzi, 2012, Wu, 2014, Gameiro, 2014, Kroemer, 2013). Potential neoantigen 
expression and associated TMB increase have been correlated with clinical response to 

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immune checkpoint inhibition in solid tumors, though TMB as a predictive biomarker is 
still being investigated (Brill, 2017, Hellman, 2018, Lampert 2020). Another possible 
mechanism of immune modulation by increased DNA damage is constitutive activation 
of an innate immune STING (stimulator of interferon genes) pathway. PARP inhibition 
blocks DNA repair, resulting in DNA breaks (Lord, 2017). Fragments of these DNA 
breaks enter the cytoplasm and bind to cyclic GMP-AMP synthase (cGAS) upregulating 
the cGAS-STING pathway within the tumor microenvironment, a potent activator of a 
type I interferons and other immunomodulatory molecules (Chen, 2016). Thus, increased 
DNA damage from the PARP inhibitor exposure could yield greater TMB, potentially 
increasing neoantigens (Gajewski, 2013), and affect the immune microenvironment, thus 
complementing the clinical benefit of immune checkpoint blockade in subsets of 
recurrent ovarian cancer (Lee, 2017, Lampert 2020). Additionally, results from 3 PARP 
inhibitor and PD-1/PD-L1 blockade combination trials showed early clinical activity in 
subsets of recurrent ovarian cancer; 18% RR and 65% disease control rate (DCR, defined 
by CR+PR+SD) of niraparib and pembrolizumab in platinum-resistant ovarian cancer 
(TOPACIO) (Konstantinopoulos, 2019), 14% RR and 71% DCR of olaparib and 
durvalumab (MEDI4736) in heavily-pretreated recurrent ovarian cancer (Lampert, 2020) 
and 72% RR of durvalumab (MEDI4736) and olaparib in PARP inhibitor-naïve germline 
BRCA mutant platinum-sensitive ovarian cancer patients (MEDIOLA) (Drew, 2018). 
These findings suggest potential added benefit of PARP inhibition to PD-1/PD-L1 
blockade although additional biomarkers of efficacy are needed.    
 
There are emerging pre-clinical and clinical evidence suggesting synergy between 
immune checkpoint blockade and VEGF/VEGFR pathway inhibition. VEGF reduces the 
antitumor immune responses in preclinical models including ovarian cancer models, by 
suppression of dendritic cell maturation (Sondak, 2011, Ohm, 2001), inhibition of T cell 
responses (Terme, 2013, Gavalas, 2012), increases in Treg proliferation, and increases in 
immunosuppressive activity of myeloid-derived suppressor cells  (MDSCs) and tumor-
associated macrophages (Huang, 2013, Terme, 2012). VEGF also suppresses lymphocyte 
trafficking across endothelia into tumor deposits and sites of inflammation to promote 
vessel growth (Kandalaft, 2011, Tartour, 2011). Wallin et al. reported intra-tumoral 
CD8+ T cells increase (median 5-fold) following combination treatment with 
bevacizumab and a PD-L1 inhibitor, atezolizumab, in metastatic renal cell carcinoma 
(RCC) patients (Wallin, 2016), suggesting that the anti-VEGF and anti-PD-L1 
combination improves antigen-specific T cell migration. Consistent with these preclinical 
evidences, axitinib, an oral VEGFR- tyrosine kinase inhibitor (TKI) and pembrolizumab 
combination is approved by FDA as a front-line therapy in patients with advanced RCC, 
independent of PD-L1 status. Also, lenvatinib, another oral VEGFR TKI, and 
pembrolizumab was recently FDA-approved in advanced endometrial cancer, 
independent of mismatch repair instability (MSI) status (Makker, 2019). In recurrent 
ovarian cancer, Liu and colleagues reported phase II single arm study of bevacizumab 
and nivolumab which demonstrated a median PFS of 9.4 months (RR of 40% and clinical 
benefit rate [CBR] of 75% defined by CR+PR+SD> 6months) in platinum-sensitive 
patients (20 patients)  and a median PFS of 5.3 months (RR of 16.7% and CBR of 55.3%) 
in platinum-resistant patients (18 patients) (Liu, 2019).  
 

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Further, angiogenesis pathways interact with both immune activity and DNA repair 
mechanisms. Tumor hypoxia induces downregulation of genes involved in DNA repair, 
e.g., RAD51 and BRCA1, leading to further DNA damage, genomic instability, and cell 
death (Hegen, 2010). These data support VEGFR TKI as an optimal drug for the immune 
checkpoint blockade and/or PARP inhibitor combination therapy in ovarian cancer. As 
such, it has been hypothesized that 3-pathway (DNA repair, angiogenesis and immune 
checkpoints) modulation would enhance the anti-tumor activity of PD-1/PD-L1 inhibitor, 
by creating higher mutational loads and a more immunogenic microenvironment in 
recurrent platinum-resistant patients. 
 
2.3 
Phase I/II single arm study of the PD-L1 inhibitor, durvalumab (MEDI4736) in 
combination with olaparib and cediranib in recurrent ovarian cancer 
(NCT0248440) 
 
Preclinical data suggest potential synergy between the PARP inhibitor or anti-angiogenic 
agents with immune checkpoint inhibition in breast, lung and renal cell carcinoma models 
(Jiao, 2017, Pircher, 2017). durvalumab (MEDI4736) is a human immunoglobulin G1κ 
monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 (B7.1) (Lee, 2017). A 
phase I/II study is currently evaluating activity signal by combining durvalumab 
(MEDI4736) with olaparib and cediranib for recurrent ovarian cancer patients at the NCI 
Clinical Center (NCT0248440). Evaluation of toxicity and early clinical activity of the 
two durvalumab (MEDI4736) doublets [durvalumab (MEDI4736) plus olaparib or 
cediranib] was conducted prior to launching the durvalumab (MEDI4736) triplet 
[durvalumab (MEDI4736) plus olaparib and cediranib because there were anticipated 
overlapping toxicities such as diarrhea and fatigue. Durvalumab (MEDI4736) was given 
intravenously monthly with olaparib and/or cediranib until disease progression, patient 
withdrawal of consent, or intolerable toxicities.  
 
Lee et al. reported that durvalumab (MEDI4736) and olaparib combination was tolerable 
and yielded durable response in recurrent women’s cancer patients (Lee, 2017). Adverse 
events (AEs) were mostly grade 1 and 2, including fatigue, nausea, and rash. There were 
no reports of colitis of any grade in the durvalumab (MEDI4736) and olaparib or 
durvalumab (MEDI4736) and intermittent cediranib combinations. In contrast, daily 
cediranib dosing scheduling was not tolerable due to recurrent grade 2 and non-dose 
limiting toxicities (DLT) grade 3 and 4 AEs of fatigue and dyspnea. Preplanned 
pharmacokinetic analysis identified exposure to durvalumab (MEDI4736) increased 
cediranib exposure including area under the curve [AUC] and maximum plasma 
concentration (Cmax) on the daily scheduling due to decreased clearance of cediranib. This 
led to the protocol amendment modifying the dose schedule of cediranib daily to an 
intermittent (5 days on/2 days off) schedule. An intermittent cediranib schedule was 
found to be tolerable and did not increase AUC or Cmax of cediranib after durvalumab 
(MEDI4736) infusion.  It is important to note that lower dose (20mg 5days on/2days off 
schedule) did not attenuate clinical activity when combined with durvalumab 
(MEDI4736) (Lee, 2017).  
 
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(MEDI4736) plus olaparib and cediranib) was also reported (Zimmer, 2019). These 
established doses and schedules durvalumab (MEDI4736) 1,500mg every 4 weeks with 
olaparib tablets 300mg BID and/or cediranib 20 mg daily 5 days on/2 days off) are now 
being used in ongoing single arm phase II studies for recurrent ovarian cancer at the NCI 
Clinical Center (NCT0248440). In the triplet therapy durvalumab (MEDI4736) plus 
olaparib and cediranib) phase I study, 9 patients were enrolled (Table 1) and most AEs 
were grade 1 or 2, including fatigue, nausea, diarrhea, hypertension. Grade 3/4 adverse 
events included hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No grade 4 AEs 
were observed.  
 
Patient Characteristics 
Durvalumab (MEDI4736) plus olaparib 
and cediranib 
Phase I study (n=9) 
Age: median (range) 
59 years (44-73) 
Tumor types 
     Ovarian cancer (platinum-resistant/-sensitive 
recurrent disease) 
     Endometrioid endometrial cancer (MSI-low) 
     Triple negative breast cancer 
 
7 (5/2) 
 
1 
1 
Number of prior treatment regimens: median (range) 
     Prior PARP inhibitor  
     Prior bevacizumab  
2 (2-6) 
None 
2 
 
Four patients had PR (44%) and 3 had SD lasting  > 6 months, yielding a 67% CBR 
(Figure 1). All patients were BRCA wild type (BRCAwt) except one patient with 
platinum-sensitive disease and PR of 9 months (BRCA1 187delAG). Three of 5 platinum-
resistant patients had durable clinical benefit >1.5 year without unanticipated new AEs. 
Additionally, pharmacokinetic data showed no significant changes of olaparib AUC or 
Cmax when durvalumab (MEDI4736) was given to the patients with steady-state exposure 
to olaparib and cediranib. The presence of durvalumab (MEDI4736) also did not 
 
 
Figure 1. Spider plot and waterfall plot of durvalumab (MEDI4736) plus olaparib and cediranib phase I study. Triplet 
combination resulted in durable long-term response in heavily pretreated women’s cancer patients, mostly platinum-resistant 
recurrent ovarian cancer. R: platinum-resistant recurrent ovarian cancer, S: platinum-sensitive recurrent ovarian cancer. One 
endometrial cancer patient who achieved PR had MSI-low tumor. 
 

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significantly affect cediranib PK, consistent with the previous report (Lee, 2017), where 
demonstrated the lack of a drug interaction between durvalumab (MEDI4736) and 
cediranib alone when cediranib was given on the intermittent schedule.   
 
2.4 
Phase II single arm study of olaparib and cediranib in recurrent ovarian cancer 
 
patients who had prior anti-angiogenic agents (NCT0248440).  
CONCERTO (Cediranib maleate and Olaparib or staNdard Chemotherapy in treating 
patients with rEcurrent platinum-ResistanT or -refractory Ovarian, fallopian tube, or 
primary peritoneal cancer) is a single arm multi-center phase II study evaluating the 
activity of the olaparib and cediranib combination in platinum-resistant recurrent ovarian 
cancer patients who have no germline BRCA mutation. Eligibility includes at least 3 prior 
lines of chemotherapy and exposure to prior antiangiogenics, e.g., bevacizumab. This 
eligibility criteria represent the difficult-to-treat patient population in the platinum-
resistant disease setting. The primary endpoint is objective RR (ORR) by Independent 
Central Review using RECIST 1.1 criteria.   
 
The study findings were recently presented at the 2020 ASCO virtual meeting (Lee, 
2020). 60 women were enrolled and received olaparib and cediranib. Although olaparib 
and cediranib combination did not meet the target of 20% confirmed ORR, the 
combination treatment showed the evidence of antitumor activity in this heavily-
pretreated (≥4 lines of chemotherapy), non-gBRCAm platinum-resistant ovarian cancer 
patients, with 88.3% of the patients already exposed to a VEGF inhibitor, bevacizumab. 
ORR was 15.3% including 1 CR and 8 PR and a total of 4/9 responders had a measurable 
response for more than 9 months. Furthermore, 14 out of 59 patients evaluable for 
response remained in disease control at 6 months; median overall survival was 13.2 
months and median PFS was 5.1 months (Figure 2). Overall, the safety findings of this 
study were consistent with the known safety profiles of olaparib and cediranib.  
 
Biomarker studies were also presented. % global loss of heterozygosity (gLOH) 
 
 
Figure 2. Kaplan-Meier PFS curves in patients treated on olaparib and cediranib in Phase II 
CONCERTO trial  

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measured at Foundation Medicine was available for 47 patients in the evaluable for 
response set. Of these, 15 had a tumor BRCAm and/or gLOH score ≥16% (gLOHhigh) and 
32 had a gLOH score <16% (gLOHlow). The ORR was 26.7% (4/15; 95% CI 7.8–55.1%) 
in the gLOHhigh group and 12.5% (4/32; 95% CI 3.5–29.0%) in the gLOHlow group, 
requiring further investigation.  
 
2.5 
Translational Science Background 
 
2.5.1.  Tumor PD-L1 and tumor infiltrating lymphocytes (TIL) 
 
The expression of PD-L1 and presence of CD8+ TILs have been previously characterized 
as prognostic biomarkers in ovarian cancer.  In certain settings across different tumor 
types, tumor PD-L1 expression has been described as potential predictive biomarkers for 
response to immune checkpoint blockade (Topalian 2012; Garon 2015; Motzer 2015 (1); 
Rosenberg 2016).  However, in other studies, no association has been reported (Brahmer 
2015; Motzer 2015 (2)).  In ovarian cancer, associations between PD-L1 expression and 
response to immune checkpoint therapy have been limited.  In the Phase II study of 
avelumab in ovarian cancer, PD-L1 expression did not clearly correlate with activity of 
the drug (Disis 2019).  In contrast, in the KEYNOTE-100 study, a higher RR was 
reported for ovarian cancer tumors with higher PD-L1 expression as measured by a 
combined positive score (CPS) of ≥10 (Matulonis 2019).   
 
Immune checkpoint blockade activity is thought to be in part mediated by re-activating a 
tumor immune response; as such, it has been hypothesized that the presence of TILs 
could also be a predictive biomarker of response.  Tumors that are “immune-inflamed” 
with the presence of both CD8+ and CD4+ TILs have been reported to experience a 
better response to immune checkpoint blockade (Herbst 2014; Tumeh 2014; Lee 2017).  
The significance of PD-L1 and TILs as potential predictive biomarkers in ovarian cancer 
when immune checkpoint inhibitors are combined with other agents remains unclear.  In 
JAVELIN Ovarian 200, the performance of avelumab together with liposomal 
doxorubicin appeared to be more robust compared to liposomal doxorubicin alone in 
patients who were PD-L1+ (Pujade-Lauraine 2018). However, this was a subgroup 
analysis, and the activity of the avelumab and liposomal doxorubicin combination was 
similar in both the PD-L1+ and PD-L1- cohorts; rather, the activity of liposomal 
doxorubicin was slightly decreased in the PD-L1- tumors.  In JAVELIN Ovarian 100, in 
newly diagnosed ovarian cancer, neither PD-L1 nor CD8 status appeared to be a 
predictive biomarker for activity of combined chemotherapy and avelumab (Ledermann 
2020). In this study, PD-L1 and TILs in archival tissue samples will be evaluated to 
correlate with responses to the treatment. 
 
2.5.2.  Homologous recombination deficiency (HRD) assessment 
 
Homologous recombination (HR) is a DNA damage repair pathway responsible for 
repairing double-strand DNA breaks.  Key proteins that are intrinsic to proper function of 
this pathway include BRCA1, BRCA2, and other members of the Fanconi anemia 
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perform double-strand break repair via HR; as a consequence, they can be more sensitive 
to the effects of drugs such as PARP inhibitors and platinum. 
 
In the clinical setting, assessment of HRD status has been primarily performed by 
evaluation of patterns of “genomic scarring”, which occurs as cells lacking HR acquire 
specific patterns of mutations and structural aberrations of chromosomes.  Three separate 
types of genomic scarring patterns have been described to be associated with HRD:  loss 
of heterozygosity (LOH), large-scale state transitions (LST), and telomeric-allelic 
imbalance (TAI) (Abkevich 2012; Popova 2012; Birkbak 2012).  Various assays to assess 
these genomic instability patterns exist, including measurement of percent genomic LOH, 
which is utilized by the FoundationFocus CDx BRCA LOH test, and a composite score 
with measurement of LOH, LST, and TAI, which is utilized in the Myriad MyChoice 
CDx test. 
 
The presence of HRD has been associated with activity of PARP inhibitors in ovarian 
cancer.  The strongest association of PARP inhibitor activity has been with the presence 
of a BRCA1/2 mutation, as seen in both monotherapy studies of PARP inhibitors for 
treatment of relapsed disease (Gelmon 2011; Swisher 2017; Moore 2019), and trials of 
PARP inhibitor maintenance therapy (Ledermann 2014; Mirza 2016; Coleman 2017; 
Gonzalez-Martin 2019; Coleman 2019; Ray-Coquard 2019).  In non-mutated BRCA 
tumor populations within these trials, exploratory analyses have suggested that assays of 
HRD provide some additional information regarding the likelihood of deriving benefit 
from PARP inhibitor therapy, although these assays do not clearly differentiate 
populations that will or will not derive benefit (Mirza 2016; Coleman 2017; Gozalez-
Martin 2019; Ray-Coquard 2019), and in one study, no difference was seen with regards 
to PARP inhibitor activity in BRCA wild-type tumors that were deemed HRD on the 
Myriad MyChoice assay and those that did not (Coleman 2019, Swisher 2020).  In 
studies of combined olaparib and cediranib, higher RRs have been reported in those 
patients with platinum-resistant tumors where the LOH score was more elevated, 
although these are small studies and require further validation (Liu 2019; Lee 2020). 
Other mechanisms of HRD may be a functional biomarker for response. As such, it is 
important to identify which ovarian cancer patients have germline or somatic mutations 
in HRD genes and to examine their potential as predictive biomarkers. 
 
2.6 
Rationale for trial design  
 
Patients with recurrent platinum-resistant ovarian cancer who had prior bevacizumab 
remain a patient population with significant unmet needs. There are no effective 
therapeutic options currently available for this population. Single agent olaparib has 
shown limited activity in patients with non-BRCA mutant platinum-resistant ovarian 
cancer with RR of 4% (1/26) (Gelmon, 2011).  Single agent cediranib has shown an 
objective RR of 17% and a median PFS of 5.2 months in patients with platinum-resistant 
ovarian cancer, treated in 2nd or 3rd line setting (Matulonis, 2009).  Given the limited 
activity of single agent olaparib or cediranib in platinum resistant recurrent ovarian 
cancer patients who do not carry a deleterious or suspected deleterious BRCA mutation, 
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and without durvalumab, a PD-L1 inhibitor in this population. The proposed study will 
identify potential benefit of the 3-pathway modulation for recurrent platinum-resistant 
ovarian cancer patients who had prior bevacizumab.  
 
More importantly, given that the number of patients exposed to immune checkpoint 
inhibitors and/or PARP inhibitors has significantly increased over the past few years, this 
study will provide insights on the optimal use of a triplet therapy in patients who 
previously received these therapies by stratifying them based on the prior immune 
checkpoint inhibitors and/or PARP inhibitors. Also, given that PARP inhibitors are now 
widely used in various clinical settings for ovarian cancer patients, it is important to test 
whether the combination of durvalumab (MEDI4736) and cediranib without olaparib 
yields a similar clinical activity to the triplet therapy in this population. Furthermore, the 
activities of these combinations compared to standard of care chemotherapy need to be 
defined in this previously unstudied population.  
 
Women with recurrent platinum-resistant ovarian cancers, who had prior bevacizumab 
and/or PARP inhibitors are the enriched patient population with unmet medical needs. 
There is an urgent need for the development of targeted therapies for this patient 
population. The results of this randomized phase II trial could lead to future randomized 
phase III trials, and potentially produce practice-changing results, given the limited 
options for therapy in recurrent platinum-resistant ovarian cancer who had prior 
bevacizumab. Additionally, if positive, the results of this trial may provide a non-
chemotherapy treatment alternative for patients, with the potential for increased 
tolerability. 
 
The purpose of this phase II randomized study is to test the hypothesis that olaparib and 
cediranib in combination with durvalumab, or durvalumab (MEDI4736) plus cediranib, 
or olaparib plus cediranib may result in greater clinical benefit for women with recurrent 
platinum-resistant ovarian cancer who previously received bevacizumab compared to 
standard of care chemotherapy. Preliminary clinical data of a triplet therapy showed 
potential durable anti-tumor activity in a subset of heavily pretreated recurrent ovarian 
cancer patients (Zimmer 2019).  It was thus hypothesized that creating a more 
immunogenic milieu via increased DNA damage and reduced VEGF signaling would 
complement the anti-tumor activity of an immune checkpoint inhibitor in this difficult-to-
treat population. 
 
Rationale for a fixed dosing of durvalumab (MEDI4736):  
 
A population PK model was developed for durvalumab (MEDI4736) using monotherapy 
data from a Phase I study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg 
Q3W; solid tumors). Population PK analysis indicated only minor impact of body weight 
(WT) on the PK of MEDI4736 (coefficient of ≤0.5). The impact of body WT-based (10 
mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab (MEDI4736) was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 95th 
percentiles) using the population PK model. A fixed dose of 750 mg was selected to 
approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 patients 

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were simulated using body WT distribution of 40–120 kg. Simulation results demonstrate 
that body WT-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-patient variability with fixed dosing 
regimen. Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, 
Zhang et al 2012, Narwal et al 2013). Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed 
dosing being better for 7 of 12 antibodies (Wang et al 2009)]. In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed 
better for 12 of 18 in terms of reducing the between-patient variability in 
pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012). A fixed dosing 
approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, it 
was considered feasible to switch to fixed dosing regimens. Based on average body WT 
of 75 kg, a fixed dose of 1500 mg Q4W MEDI4736 (equivalent to 20 mg/kg Q4W) is 
included in the current study 
 
3. 
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. 
 
3.1.1 Women with recurrent/persistent platinum-resistant ovarian, primary peritoneal, or 
fallopian tube cancers; platinum-resistant disease is defined as progression within < 6 
months from completion of platinum based therapy.  The date should be calculated from 
the last administered dose of platinum therapy.  
 
3.1.2 Patients must have histologically or cytologically confirmed ovarian cancer, peritoneal 
cancer or fallopian tube cancer and must have a histological diagnosis of high grade 
serous, grade 3 endometrioid or clear cell carcinoma based on local histopathological 
findings.  
 
Patients with low grade serous, grade 1 or 2 endometrioid, mixed epithelial, 
undifferentiated carcinoma, or mucinous carcinoma histologies are also eligible, provided 
that the patient has a known deleterious BRCA1 or BRCA2 mutation identified through 
testing at a clinical laboratory.  
 
Histologic confirmation of the original primary tumor is required via the pathology report 
(upload of report required). 
 
Confirmation of BRCA1 and BRCA2 germline and/or somatic mutation status and HR 
status is required for all entered patients (if available) via testing report (upload of 

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report[s] required). (27-AUG-2021) 
 
3.1.3 Evaluable disease – defined as RECIST 1.1 measurable disease OR non-measurable 
disease (defined as solid and/or cystic abnormalities on radiographic imaging that do not 
meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural effusion that has 
been pathologically demonstrated to be disease-related in the setting of a CA125 ≥ 2x 
upper limit of normal (ULN)). 
 
3.1.4 Prior therapy:  
 
x At least two prior treatment regimens (including primary therapy) but up to 5 
lines of systemic anticancer therapy. Hormonal therapy (such as tamoxifen, 
aromatase inhibitors) will not count as a previous treatment regimen. 
x Prior use of bevacizumab in the upfront or recurrent setting is required. 
x Prior use of PARP inhibitor is allowed.  
x Prior use of immune checkpoint blockade (e.g., a PD-L1/PD-1inhibitor or a 
CTLA-4 inhibitor) is allowed.  
 
3.1.5 ECOG Performance Status of 0, 1, or 2 (see Appendix I). 
 
3.1.6 Patients must have adequate organ and marrow function as defined below  
 
x Absolute neutrophil count (ANC) ≥ 1,500/mcL 
x Hemoglobin > 10 g/dL  
x Platelets ≥ 100,000/mcL 
x Creatinine clearance (CrCL) or estimated Glomerular filtration rate (eGFR) of >50 
mL/min estimated using either the Cockcroft-Gault equation, the Modification of 
Diet in Renal Disease Study, or as reported in the comprehensive metabolic 
panel/basic metabolic panel (eGFR). (27-AUG-2021) 
x Urine protein: creatinine ratio (UPC) of ≤1  
x Total serum bilirubin level ≤ 1.5 x ULN (patients with known Gilbert’s disease who 
have bilirubin level ≤ 3 x ULN may be enrolled) 
x AST and ALT ≤ 3 x ULN  
 
3.1.7  Age ≥ 18 years. 
 
 
3.1.8 Body weight > 30 kg 
 
3.1.9  Adequately controlled blood pressure (SBP < 140; DBP < 90 mmHg) on a maximum of 
three antihypertensive medications. Patients must have a BP of ≤ 140/90 mmHg taken in 
the clinic setting by a medical professional within 2 weeks prior to study registration.  
It is strongly recommended that patients who are on three antihypertensive medications 
be followed by a cardiologist or a primary care physician for management of BP while on 
protocol. Patients must be willing and able to check and record daily blood pressure 
readings. BP cuffs will be provided to patients randomized to the cediranib-containing 
arms (Appendix X). 

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3.1.10 Adequately controlled thyroid dysfunction with no symptoms of thyroid dysfunction and 
normal TSH. If TSH is not within normal range despite no symptoms of thyroid 
dysfunction, normal free T4 level is required. 
 
3.1.11 Able to swallow and retain oral medications and no GI illnesses that would preclude 
absorption of olaparib and cediranib as judged by treating physician. 
 
3.1.12 Toxicities of prior therapy (excepting alopecia and vitiligo), should be resolved to less 
than or equal to Grade 1 as per CTCAE v5.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   
 
3.1.13  Women of childbearing potential (WOCBP) must agree to use two forms of birth control 
(hormonal or barrier method of birth control; abstinence). 
 
Note: Definition of women of no longer having childbearing potential:  
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to 
start of study treatment.   
 
Postmenopausal is defined as: Age ≥60 years, or 
Age <60 with any one or more of the conditions below: 
x Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal 
treatments, 
x Luteinizing hormone and/or Follicle stimulating hormone and/or estradiol levels 
in the post-menopausal range, 
x Radiation-induced oophorectomy with last menses >1 year ago, 
x Chemotherapy-induced menopause with >1 year interval since last menses, 
x Surgical sterilization (bilateral oophorectomy or hysterectomy). 
 
3.1.14 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry and 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. Primary platinum-refractory disease defined as progression during first-line platinum-
based chemotherapy. 
 
3.2.2 Rising CA-125 only without RECIST 1.1 evaluable disease. 
 
3.2.3    Prior therapy:  
 
x Patients who have had chemotherapy, investigational drugs or radiotherapy within 
3 weeks prior to study registration or those who have not recovered from adverse 

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events due to agents administered more than 3 weeks earlier.  
x Patients may not have had hormonal therapy within 2 weeks of study registration. 
Patients receiving raloxifene for bone health as per FDA indication may remain on 
raloxifene absent other drug interactions.  
x Prior use of concurrent olaparib and cediranib combination.  
x Patients who have experienced immune-mediated adverse events requiring dose 
modification or discontinuation. (23-AUG-2022) 
x For patients who have received prior PARP inhibitor: 
o Patients who have required dose modification or dose reduction of 
olaparib will not be eligible, as they will not be able to start this study at 
full dose. 
o Patients who have required dose reduction of non-olaparib PARP 
inhibitors for hematologic adverse events will not be eligible (Note: 
niraparib that is initiated at 200mg daily per weight and platelet guidelines 
is not considered a dose reduction). 
o Patients who required dose-reduction of non-olaparib PARP inhibitors for 
non-hematologic adverse events may be eligible after discussion with the 
Study Chair if the treating investigator feels that they could appropriately 
receive olaparib at full dose. (23-AUG-2022) 
 
3.2.4 History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 3 months prior to study registration. 
 
3.2.5 Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel 
obstruction within 3 months of study registration except temporary (<24hr) improved with 
medical management, within last 3 months. 
 
3.2.6    Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous  
immunotherapy agent, or any unresolved irAE > grade 1.  
 
3.2.7    Dependency on IV hydration or TPN. 
 
3.2.8 Pregnant women. Because there is an unknown but potential risk of adverse events in 
nursing infants secondary to treatment of the mother with these drugs, breastfeeding 
should be discontinued. These potential risks may also apply to other agents used in this 
study. 
 
3.2.9 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.2.10  Patients with untreated brain metastases, spinal cord compression, or evidence of 
symptomatic brain metastases or leptomeningeal disease as noted on CT or MRI scans 
should not be included on this study, since neurologic dysfunction may confound the 
evaluation of neurologic and other adverse events. Patients with treated brain metastases 
and resolution of any associated symptoms must demonstrate stable post-therapeutic 

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imaging for at least 6 months following therapy prior to starting study registration. 
 
3.2.11 Patients who have the following clinical conditions are considered to be at increased risk 
for cardiac toxicities. Patients with any cardiac history of the following conditions:  
x History of myocardial infarction or myocarditis within six months of study 
registration 
x Unstable angina 
x Resting ECG with clinically significant abnormal findings. 
x New York Heart Association functional classification of III or IV (Appendix II)  
 
3.2.12 If cardiac function assessment is clinically indicated or performed:  LVEF less than 
normal per institutional guidelines, or <55%, if threshold for normal not otherwise 
specified by institutional guidelines.   
 
Patients with the following risk factors should have a baseline cardiac function 
assessment: 
x Prior treatment with anthracyclines 
x Prior treatment with trastuzumab or T-DM1 
x Prior central thoracic radiation therapy (RT), including RT to the heart 
x History of myocardial infarction within 6 to 12 months (Patients with history of  
myocardial infarction within 6 months are excluded from the study) 
x Prior history of impaired cardiac function 
 
3.2.13  History of stroke or transient ischemic attack within six months of study registration. 
 
3.2.14 Clinically significant peripheral vascular disease or vascular disease (aortic aneurysm or 
aortic dissection). 
 
3.2.15  Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of study treatment. Patients must have recovered from any effects of any major 
surgery and surgical wound should have healed prior to starting treatment. 
Note: Local surgery of isolated lesions for palliative intent is acceptable. 
 
3.2.16 Evidence of coagulopathy or bleeding diathesis. Therapeutic anticoagulation for prior 
thromboembolic events, including warfarin, is permitted.  Patients receiving warfarin are 
recommended to have careful monitoring of international normalized ratio (INR), as 
detailed in Section 4 and Section 9. 
 
3.2.17  Evidence suggestive of myelodysplastic syndrome (MDS) or acute myelogenous 
leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically 
indicated. 
 
No prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUBCT). 
 
3.2.18 Human Immunodeficiency Virus (HIV) positive patients due to potential drug and drug 

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interactions 
 
3.2.19 Patients may not use any complementary or alternative medicines including natural 
herbal products or folk remedies as they may interfere with the effectiveness of the study 
treatments. 
 
3.2.20  Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
treatment.  
 
Note: Patients, if enrolled, should not receive live vaccine whilst receiving study 
treatment and up to 30 days after the last dose of study treatment. 
 
3.2.21 Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other 
than atrial fibrillation with controlled ventricular rate), or psychiatric illness/social 
situations that would limit compliance with study requirements, substantially increase 
risk of incurring adverse events or compromise the ability of the patient to given written 
informed consent.(27-AUG-2021) 
 
3.2.22 Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A4. Dihydropyridine calcium-channel blockers are permitted for management of 
hypertension. 
  
3.2.23 Current or prior use of immunosuppressive medication within 14 days of study 
registration.  The following are exceptions to this criterion: 
x Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular  
  
 
injection) 
x Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
x Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
 
3.2.24 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to durvalumab, olaparib, or cediranib. 
 
3.2.25 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. 
 
3.2.26 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis 
C.  Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible.  Patients positive for 

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hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA. 
 
3.2.27 Patients who have a history of (non-infectious) pneumonitis that required steroids, or 
current pneumonitis. (27-AUG-2021) 
 
Inclusion of Women and Minorities 
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
Pre-Treatment Assessments (27-AUG-2021) 
 
The following assessments are to be performed and recorded on the appropriate form(s).  
Please note:  Each entry refers to the corresponding footnote at the end of the table.  
Cycle 1 Day 1 treatment should begin within 7 days of registration. 
 
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 (Blood Pressure, Heart Rate,   
Temperature and Pulse Oxygen Saturation) 
≤ 14 days 
X 
Height* 
X 
- 
Weight 
≤ 14 days 
≤ 14 days 
Performance Status (ECOG) 
≤ 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 
Urine protein: creatinine ratio (UPCR) 
≤ 14 days 
≤ 14 days 
TSH 
≤ 28 days 
≤ 28 days 
CA-125 
≤ 28 days 
≤ 28 days 
Pregnancy test (for women of childbearing 
potential) Urine or serum testing is permitted 
≤ 14 days 
< 72 hours 
Electrocardiogram (ECG) 
≤ 28 days 
≤ 28 days 
MUGA or echocardiograma 
≤ 28 days 
≤ 28 days 
Radiographic Tumor Measurementb 
≤ 28 days 
≤ 28 days 
a  MUGA or echocardiogram should be performed at baseline for patients at increased risk for 
compromised LVEF, including patients with (1) prior treatment with anthracyclines, (2) prior treatment 
with trastuzumab or T-DM1, (3) prior central thoracic RT, (4) history of myocardial infarction within the 
12 months prior to registration or (5) prior history of impaired cardiac function. LVEF assessment by 
MUGA or echocardiogram should be performed on every 16-week (+/-1 week) basis for patients with 
these risk factors on cediranib-containing arms. Should the patients discontinue cediranib-containing arm 
therapy due to progression or toxicities within the 16-week (+/- 1 week) time frame before the next LVEF 
assessment, the treating physicians should follow cardiac symptoms and assess LVEF as clinically 
indicated until another therapy is initiated.  
b Radiographic tumor measurements should be obtained via imaging of at least the chest, abdomen, and 
pelvis at baseline. If chest imaging at baseline reveals evidence of measurable disease, then subsequent 
radiographic tumor assessments must also include chest imaging. See RECIST 1.1 for allowable imaging 
modalities used to assess disease at baseline and subsequent assessments. Contrast CT is the preferred 
modality. Tumor reassessment will be time-based at 9 weeks +/- 1 week throughout the study for the 
first year and every 12 weeks (+/- 7 days) after the first year. 
* Height measurement is performed on adult participants during admission or at initial visit to an 

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outpatient facility per clinical practice. As height measurement on adults is not routinely performed 
during follow up visits, the height measurement previously recorded for adult participants may be used 
for calculating drug dosages or body surface area as applicable and can be used for baseline and follow up 
visits data capture. 
 
4.2 
Assessments During Treatment 
 
The following assessments are to be performed and recorded on the appropriate form(s).  
Timing of assessments prior to Cycle 1 Day 1 may be as per pre-treatment assessments 
schedule. Please note: Each entry refers to the corresponding footnote at the end of the 
table.  Please refer to Section 10.4.1 for Specimen Requirements.  
 
ARM I (Non-platinum single agent chemotherapy) (27-AUG-2021): 
 
Assessments 
Prior to day 1 of 
each cycle of 
therapy 
 
Weekly Topotecan 
Days 8 and 15 (if 
applicable) 
Timed (Treatment 
Cycle Independent) 
History and Physical 
≤ 3 days  
 
 
Concomitant Medications 
≤ 3 days 
 
 
Toxicity Assessment 
≤ 3 days 
 
 
Vital Signs, weight 
required 
≤ 3 day 
 
 
Performance Status 
≤ 3 days 
 
 
CBC/Differential/Platelets 
≤ 3 days 
≤ 1 days 
 
Chemistries1  
≤ 3 days 
 
 
CA125 
≤ 3 days 
 
 
Radiographic Tumor 
Measurement 
 
 
See footnote2 
MUGA or echocardiogram 
 
 
See footnote3 
1 Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
albumin, calcium, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
2 Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI 
performed once every 9 weeks (+/- 7 days), for the first 12 months, then every 12 weeks (+/- 7 
days) thereafter, and at any other time if clinically indicated based on symptoms or physical 
signs suggestive of progressive disease. Imaging assessments can be discontinued if disease 
progression is confirmed according to RECIST 1.1. However, if a patient discontinues study 
treatment for any reason other than progression, imaging studies should continue every 9 weeks 
(+/- 7 days) until progression. Utilize same imaging modality of abdomen and pelvis +/- chest 
(for patients with evidence of measurable disease on baseline chest imaging; then subsequent 
radiographic tumor assessments must also include chest imaging. 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.  
3For patients receiving PLD, when the cumulative dose of PLD exceeds 550 mg/m2, it is 
recommended that repeat echocardiogram or MUGA scan be performed every other cycle or 
according to institutional standards. 

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ARMS II, III, IV (27-AUG-2021)(23-AUG-2022): 
 
Assessments 
Prior to 
day 1 of 
each cycle 
of therapy 
 
Every week 
for first 8 
weeks of 
study therapy  
(in person, 
telemedicine, 
or phone) 
Prior to Every 
Odd Cycle 
(i.e., Cycle 3, 
Day 1; Cycle 
5, Day 1; etc.) 
Timed 
(Treatment 
Cycle 
Independent) 
History and Physical 
≤ 1 day 
 
 
 
Concomitant 
Medications1 
≤ 1 day 
 
 
 
Toxicity Assessment 
≤ 1 day 
X 
 
 
Vital Signs2, weight 
required 
≤ 1 day 
 
 
 
Performance Status 
≤ 1 day 
 
 
 
CBC/Differential/Plate
lets 
≤ 3 days  
 
 
 
Chemistries3  
≤ 3 days  
 
 
 
TSH 
 
 
≤ 7 days 
 
Urine 
protein:creatinine ratio 
(UPCR) 
 
 
≤ 7 days 
 
CA125 
≤ 3 days 
 
 
 
MUGA or 
echocardiogram 
See 
footnote4 
 
 
 
Radiographic Tumor 
Measurement 
 
 
 
See  
Footnote5 
Home BP assessment6 
See 
footnote6 
See  
Footnote6 
 
 
1   Because of a potential for interaction of olaparib and cediranib with other drugs through the 
cytochrome P450 system, special attention should be paid to other medications known to affect P450 
isoenzymes, in particular CYP3A4.  Please see Appendix VI for a list of these medications. 
2   Monitoring of vital signs before/during/after the infusion of durvalumab (see Section 6.2.4.1). 
3 Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
albumin, calcium, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
4   MUGA or echocardiogram should be performed at baseline for patients at increased risk for 
compromised LVEF, including patients with (1) prior treatment with anthracyclines, (2) prior 
treatment with trastuzumab or T-DM1, (3) prior central thoracic RT, or (4) history of myocardial 
infarction within the 12 months prior to registration or (5) prior history of impaired cardiac function. 
LVEF assessment by MUGA or echocardiogram should be performed on every 16-week (+/-1 week) 
basis for patients with these risk factors on cediranib-containing arms. Should the patients discontinue 
cediranib-containing arm therapy due to progression or toxicities within the 16-week (+/- 1 week) time 
frame before the next LVEF assessment, the treating physicians should follow cardiac symptoms and 
assess LVEF as clinically indicated until another therapy is initiated.   
5    Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI performed 
once every 9 weeks (+/- 7 days), for the first 12 months, then every 12 weeks (+/- 7 days) thereafter, 

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and at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease. Imaging assessments can be discontinued if disease progression is confirmed 
according to RECIST 1.1. However, if a patient discontinues study treatment for any reason other than 
progression, imaging studies should continue every 9 weeks (+/- 7 days), for the first 12 months, then 
every 12 weeks (+/- 7 days) thereafter until progression (or initiation of subsequent therapy). Utilize 
same imaging modality of abdomen and pelvis +/- chest (for patients with evidence of measurable 
disease on baseline chest imaging; then subsequent radiographic tumor assessments must also include 
chest imaging. 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.  
6    Because of the rapid changes in blood pressure that can occur and the potential for severe life-
threatening complications if hypertension is not appropriately managed, patients on Arms II, III and IV 
should check their blood pressure twice daily for at least the first 8 weeks after starting study drug, or, 
if anti-hypertensive management is required, until a stable anti-hypertensive regimen has been 
established, even if this requires more than 8 weeks.  After 8 weeks or once a stable regimen has been 
achieved, blood pressure monitoring may be reduced to once daily.  Twice daily monitoring should be 
re-implemented after any cediranib hold/dosing delay for two weeks or until the patient is re-
established on a stable anti-hypertensive regimen, whichever takes longer.  Patient blood pressures 
should be reviewed with the study team on a weekly basis for the first 8 weeks of study treatment 
to ensure that blood pressure guidelines are being correctly followed. Blood pressures can be 
reviewed by phone between clinic visits. 
 
4.3 
Assessments in Follow-up  
 
 
The following assessments are to be performed and recorded on the appropriate form(s).  
Vital status and patient-reported outcome assessments should be continued per the 
schedules noted below unless the consent is withdrawn. Removal from study treatment 
and remaining in follow-up is preferred to collect the continued outcome information.   
 
Assessments 
From end of treatment: 
Follow-up forms are collected for the 5- year follow-up period or 
until study termination, whichever occurs first. 
Vital Status 
Every 3 months (+/- 1 week) x 2 years, then every 6 months (+/- 
1 week) x 3 years or until death. 
Toxicity Assessment 
Report all adverse events that occur within 30 days of last 
protocol treatment on the Toxicity form for the last cycle of 
therapy administered.  
For reporting of delayed toxicity, see Section 7 
Radiographic tumor measurement 
Every 9 weeks (+/- 7 days) x 1 year, then every 12 weeks (+/- 7 
days) until progression (or initiation of subsequent therapy).    
(27-AUG-2021) 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION 
  
Patients will be randomized to one of four study arms. 
 
See Appendix III-General Therapy Guidelines 
 

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5.1 
Treatment Plan 
 
Day 1 of the cycle is the first day of the cycle if there is a delay, and the next cycle is to 
be a complete 21 or 28 days. 
 
 
No modification of the regimens is allowed. 
 
Patients randomized to ARM I may be treated with one of the three regimens specified in 
this section per investigator discretion (the planned regimen must be specified prior to 
randomization). The number of cycles of therapy should be administered as clinically 
appropriate.  
 
The patients on cediranib intermittent schedule (5 days on/2 days off) may begin with 2-4 
days on/2 days off during the first week of the cycle to have weekdays (Monday through 
Friday) weekend (Saturday and Sunday) on/off schedule, subsequent administrations are 
then adjusted to maintain a 5 days on/2 days off-interval. 
 
Patients on Arms II, III and IV will need to keep medication and blood pressure diaries. 
A blood pressure cuff will be provided to patients randomized to Arms II, III and IV. 
 
5.1.1 ARM I (Standard of Care/Control Arm) – Physician’s choice Standard of Care 
Chemotherapy 
 
 
Patients randomized to the non-platinum-based chemotherapy arm may be treated with 
one of the three regimens specified in this section per investigator discretion (the planned 
regimen must be specified prior to randomization). The number of cycles of therapy 
should be administered as clinically appropriate. 
 
¾ Regimen 1 (Standard of Care/Control Arm): Paclitaxel 80 mg/m2 intravenously 
(IV) over approximately 60 minutes on days 1, 8, and 15 every 28 days until 
disease progression or adverse events prohibit further therapy. 
 
¾ Regimen 2: Pegylated liposomal doxorubicin 40 mg/m2 IV over approximately 60 
minutes on day 1, every 28 days until disease progression or adverse events 
prohibit further therapy. 
 
¾ Regimen 3: Topotecan 4 mg/m2 IV over approximately 30 minutes on days 1, 8, 
and 15 every 28 days or 1.25 mg/m2 IV over approximately 30 minutes on days 1 
to 5 every 21 days until disease progression or adverse events prohibit further 
therapy. 
 
¾ No modification of the assigned regimens, such as addition of bevacizumab or 
other agents is allowed.  
 
 
 

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5.1.2 Arm II durvalumab (MEDI4736) plus olaparib and cediranib (27-AUG-2021) 
 
Durvalumab (MEDI4736) 1500mg fixed dose IV over approximately 60 minutes, Day 1.  
 
NOTE: Patients must be at least 30 kg in order to be eligible for this study; however, 
should a patient lose weight during treatment and fall at or below 30 kg, patients less than 
or equal to 30 kg actual body weight will be dosed at 20 mg/kg every 4 weeks. When 
patient weight increases to over 30 kg, resume the fixed dosing of durvalumab 
(MEDI4736) at 1500 mg every 4 weeks.  
 
Cediranib 20 mg PO Monday through Friday every week.  Cediranib should be taken on 
an empty stomach in the morning, approximately one hour before taking the morning 
dose of olaparib.  
 
Olaparib 300 mg PO BID. Olaparib should be taken with a light meal or snack twice a 
day approximately 12 hours apart.  
 
One cycle = 28 days. Cycles are continuously numbered regardless of any dose holds or 
interruptions. 
 
Patients will be treated until disease progression or adverse events prohibit further 
treatment. 
 
5.1.3 Arm III durvalumab (MEDI4736) plus cediranib (27-AUG-2021) 
 
Durvalumab (MEDI4736) 1500 mg fixed dose IV over approximately 60 minutes, Day 1, 
every 28 days until disease progression, patient withdrawal or toxicities. 
 
NOTE: Patients must be at least 30 kg in order to be eligible for this study; however, 
should a patient lose weight during treatment and fall at or below 30 kg, patients less than 
or equal to 30 kg actual body weight will be dosed at 20 mg/kg every 4 weeks. When 
patient weight increases to over 30 kg, resume the fixed dosing of durvalumab 
(MEDI4736) at 1500 mg every 4 weeks.  
 
Cediranib 20 mg PO Monday through Friday every week. Cediranib should be taken on 
an empty stomach in the morning.  
One cycle = 28 days. Cycles are continuously numbered regardless of any dose holds or 
interruptions. 
 
Patients will be treated until disease progression or adverse events prohibit further 
treatment. 
 
5.1.4 Arm IV Olaparib and cediranib 
 
Cediranib 20 mg PO daily.  Cediranib should be taken on an empty stomach in the 
morning, approximately one hour before taking the morning dose of olaparib.  

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Olaparib 300 mg PO BID. Olaparib should be taken with a light meal or snack twice a 
day approximately 12 hours apart.  
 
One cycle will be considered 28 days. Cycles are continuously numbered regardless of 
any dose holds or interruptions. 
 
Patients will be treated until disease progression or adverse events prohibit further 
treatment. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. 
 
The concomitant use of herbal therapies is generally not recommended, as their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However the use of calcium with vitamin D and/or minerals, basic 
multivitamins, or melatonin oral supplements will be permitted either at or below the 
recommended dosing by a healthcare provider. Herbal-based multivitamins, medical 
marijuanas or probiotics oral supplements are not allowed.  
 
Concomitant use of know strong cytochrome (CYP) 3A inhibitors or inducers should be 
prohibited while on olaparib monotherapy or olaparib and cediranib combination given 
olaparib is a substrate for CYP3A.  
x Concomitant use of known strong cytochrome (CYP) 3A inhibitors (e.g., 
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with 
ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or 
moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil).   
x Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, 
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, 
efavirenz, modafinil).   
 
5.3 
Duration of Therapy (27-AUG-2021) 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment sections or until one of the following criteria applies: 
x Disease progression  
x Intercurrent illness that prevents further administration of treatment, 
x Unacceptable adverse event(s), as described in Section 6 
x Patient decides to discontinue treatment.  If a patient may decide to discontinue 
study treatment not to withdraw consent, she will be followed up for AEs/disease 
status as per Section 4.3 

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x Patient decides to withdraw consent for participation in the study, or 
x General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
 
Dose delays and modifications will be made using the following recommendations.  
 
x Toxicity assessments will be done using NCI Common Terminology Criteria for 
Adverse Events (CTCAE v.5). CTCAE is identified and located on the CTEP 
website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
x For adverse events (AEs) that are unrelated to the study drugs, study treatment 
may be held for up to 14 days at the discretion of the treating investigator.  Drug 
holds of greater than 14 days for unrelated AEs where the patient is experiencing 
ongoing clinical benefit may be considered after discussion with the Study Chair. 
x All AEs experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. 
Participants continuing to experience toxicity at the off-study visit may be 
contacted for additional assessments until the toxicity has resolved or is deemed 
irreversible. 
x There will be no dose escalations or re-escalations on this study. 
x 
Dose modifications for Arm 1 should follow “institutional and compendium 
guidelines”.  
 
 
Hematologic Issues 
 
Use of hematopoietic agents 
 
x Myeloid growth factors (filgrastim or pegfilgrastim) may be used per institutional 
standards.  It is recommended that National Comprehensive Cancer Network 
(NCCN) and/or ASCO guidelines be consulted.  Filgrastim should be 
administered subcutaneously starting 24 to 72 hours after the last dose of 
chemotherapy and continuing through hematopoietic recovery, but should not be 
administered within the 48 hours preceding the next dose of cytotoxic 
chemotherapy.  Pegfilgrastim should be administered at 6mg subcutaneously 24 
to 72 hours after the last dose of chemotherapy and should not be administered 
within 2 weeks preceding the next dose of cytotoxic chemotherapy.  Pegfilgrastim 
should not be used for patients receiving chemotherapy that is given less than 
every 2 weeks. 
x Use erythropoietin (EPO) per standard of care NCCN and/or institutional 
guidelines, iron supplements, and/or transfusions as clinically indicated for 
management of anemia. Treating physicians should be aware of the recent 
changes in prescribing information for the erythropoiesis stimulating agents 
(including Aranesp, Epogen and Procrit) which note that there is a potential risk 
of shortening the time to tumor progression or disease-free survival, and that these 

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agents are administered only to avoid red blood cell transfusions. They do not 
alleviate fatigue or increase energy. They should not be used in patients with 
uncontrolled hypertension. They can cause an increased incidence of thrombotic 
events in cancer patients on chemotherapy. The updated package inserts should be 
consulted.  
x Transfusions may be administered as clinically indicated for management of 
anemia. 
x Patients will NOT receive prophylactic thrombopoietic agents.  
x Patients may NOT receive amifostine.  
x Initial treatment modifications will consist of cycle delay and/or dose reduction as 
indicated below for each regimen.  
x Management of prolonged hematological toxicities while on olaparib and/or 
cediranib  
 
 
If a patient develops prolonged hematological toxicity such as:  
o ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or 
worse anemia and/or development of blood transfusion dependence 
o ≥2 week interruption/delay in 1 or both investigational drugs due to 
CTCAE Grade ≥3 neutropenia (ANC <1 x 109/L) 
o ≥2 week interruption/delay in 1 or both investigational drugs due to 
CTCAE Grade ≥3 thrombocytopenia and/or development of platelet 
transfusion dependence (Platelets <50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral 
blood smear.  If any blood parameters remain clinically abnormal after 3 weeks of 
dose interruption, the patient should be referred to hematologist for further 
investigations.  Bone marrow analysis and/or blood cytogenetic analysis should be 
considered at this stage according to standard hematological practice.  Both 
investigational drugs should be discontinued if blood counts do not recover to 
CTCAE Grade ≤1 within 3 weeks of dose interruption. 
x All Arms require ANC of 1500 mcl and platelets of 100,000 mcl for treatment 
initiation, the start of each cycle (Day 1), and treatment resumption after 
holding treatment. 
 
6.1 
Arm I (Reference regimen) 
 
6.1.1  Hematologic toxicity 
 
For patients who do not achieve hematological recovery on scheduled day of the cycle, 
complete blood counts should be performed twice weekly until the above defined limits 
are achieved. If hematological recovery is achieved within 14 days after the scheduled 
beginning of the cycle, the full dose of therapy adjusted for the previous nadir should be 
administered immediately. If hematological recovery is not achieved 14 days or more 
after the scheduled day of the course, the patient will discontinue treatment.  
 
6.1.2  Non-hematologic toxicity 

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x Management of non-hematologic toxicities on the reference arm should be per 
institutional practice and guidelines.  Criteria for dose holds and modifications on 
the reference arms for non-hematologic toxicity should follow institutional 
practice and prescribing information.   
x Other Major Organ Toxicity (not evaluated as disease related): If the patient has 
any clinically significant non-hematological drug related toxicity CTCAE grade > 
3, the patient should discontinue protocol therapy unless strong clinical benefit is 
observed and after discussion with the Study Chair. 
x Dose modifications for alopecia, nausea, constipation, or electrolyte abnormalities 
are not recommended.   
x If treatment is delayed for greater than 3 weeks due to a drug-related non-
hematologic toxicity, the patient may be discontinued from protocol-directed 
therapy after consultation with the Study Chair. 
 
6.2 
Arms II [durvalumab (MEDI4736) plus olaparib and cediranib], III durvalumab 
(MEDI4736) plus cediranib alone], and IV [olaparib and cediranib]   
 
For Arms II-IV, at the discretion of the investigator, the study drugs may be held or dose 
modified independently if the observed toxicity is attributed to only one of the drugs, 
while the patient continues to receive the drug not associated with the observed toxicity.  
 
The time cediranib or olaparib is held should not exceed 14 days.   
 
Dose modification/hold of durvalumab) should follow Section 6.2.4.1, below.   
 
Patients experiencing ongoing clinical benefit who experience a related AE where 
continuation of one of the drugs is considered, in the judgment of the treating 
Investigator and the Study Chair, to be potentially life-threatening or with the potential 
for long-term harm to the patient, may be allowed to continue on the unrelated drug(s) 
after discussion with the Study Chair. 
 
Arm II 
The dose levels and the general approach to dose modification of durvalumab, cediranib 
and olaparib combination therapy are shown below.  AEs should be treated with the 
appropriate maximum supportive care, and dose reductions should be clearly documented 
in the case report form. Dose reductions are not permitted for durvalumab 
(MEDI4736).  Dose may be delayed or permanently discontinued as directed in 
Section 6.2.4.1. 
    
Dose Level 
Durvalumab 
1  
A fixed dose of 1500 mg every 4 weeks 
 
Dose level 
Cediranib tablets  
 1 
20 mg Monday through Friday (weekend off) 
-1 
15 mg Monday through Friday (weekend off) 

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Dose Level 
Olaparib tablets 
1  
300 mg twice daily 
-1 
200 mg twice daily 
-2 
150 mg twice daily  
 
 
Arm III 
Dose Level 
Durvalumab 
1  
A fixed dose of 1500 mg every 4 weeks 
 
Dose level 
Cediranib tablets  
1 
20 mg Monday through Friday (weekend off) 
-1 
15 mg Monday through Friday (weekend off) 
 
Arm IV 
Dose level 
Cediranib tablets  
1 
20 mg daily 
-1 
20 mg Monday through Friday (weekend off) 
-2 
15 mg daily 
-3 
15 mg Monday through Friday (weekend off) 
 
Dose Level 
Olaparib tablets 
1  
300 mg twice daily 
-1 
200 mg twice daily 
-2 
150 mg twice daily  
 
6.2.1 Hematologic toxicity 
 
6.2.1.1 Use of hematopoietic agents 
 
Use erythropoietin-stimulating agents per standard of care NCCN and/or institutional 
guidelines, iron supplements, and/or transfusions as clinically indicated for management 
of anemia. Treating physicians should be aware of the recent changes in prescribing 
information for the erythropoiesis stimulating agents (including Aranesp, Epogen and 
Procrit) which note that there is a potential risk of shortening the time to tumor 
progression or disease-free survival, and that these agents are administered only to avoid 
red blood cell transfusions. They do not alleviate fatigue or increase energy. They should 
not be used in patients with uncontrolled hypertension. They can cause an increased 
incidence of thrombotic events in cancer patients on chemotherapy. The updated package 
inserts should be consulted. 
 
Use of granulocyte-colony stimulating factors will not be allowed in Arms II, III and IV. 
 
6.2.2 Dose modifications for hematologic events 

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Table 6.2.2 A:  Management of neutropenia or thrombocytopenia 
 
Olaparib dose 
Cediranib dose 
CTCAE Grade 1-2 
 
ANC >1.0 G/L 
or 
Platelet count >50 
G/L  
Investigator judgement to continue 
treatment or allow dose interruption; 
dose interruptions should be for a 
maximum of 2 weeks; appropriate 
supportive treatment and causality 
investigation 
Investigator judgement to 
continue treatment or allow dose 
interruption; dose interruptions 
should be for a maximum of 2 
weeks; appropriate supportive 
treatment and causality 
investigation 
CTCAE grade 3-4 
 
ANC <1.0 G/L 
or 
Platelet count <50 
G/L 
 
Dose interruption until recovered to 
CTCAE Grade ≤1 for a maximum of 
2 weeks.  
Upon recovery, 
olaparib dose should be reduced by 
one dose level.  If repeat CTCAE 
Grade 3-4 occurrence, further dose 
reduce one or both drugs  
Dose interruption until recovered 
to CTCAE Grade ≤1 for a 
maximum of 2 weeks.  
Upon recovery, cediranib dose 
should be reduced by one dose 
level.  If repeat CTCAE Grade 3-4 
occurrence, further dose reduce 
one or both drugs. 
 
Table 6.2.2 B:  Management of anemia 
 
Olaparib dose 
Cediranib dose 
Hb <10 but ≥8 g/dL 
Give appropriate supportive treatment and 
investigate causality. 
Investigator judgement to continue olaparib or 
interrupt dose for a maximum of 2 weeks. 
If repeat Hb <10 but ≥8 g/dL, dose interrupt 
until Hb ≥10 g/dL for maximum of 2 weeks and 
upon recovery, olaparib dose should be reduced 
by one dose level.  
No change 
Hb < 8 g/dL 
Give appropriate supportive treatment and 
investigate causality. 
Interrupt olaparib until improved to Hb ≥10 
g/dL. Upon recovery, olaparib dose should be 
reduced by one dose level.   
No change 
 
x For AEs that are unrelated to the study drugs, study drug may be held for up to 
14 days at the discretion of the treating investigator.  Drug holds of greater than 
14 days for unrelated AEs where the patient is experiencing ongoing clinical 
benefit may be considered after discussion with the Study Chair. 
 
x Patients experiencing ongoing clinical benefit who experience a related AE where 
continuation of one of the drugs is considered, in the judgment of the treating 
investigator AND the Study Chair, to be potentially life-threatening or with the 
potential for long-term harm to the patient, may be allowed to continue on the 
unrelated drug after discussion with the Study Chair. 
 

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6.2.3 Dose modifications for Non-Hematologic toxicity 
 
 
The management of general AEs not otherwise specified in the following sections should 
be as per Table 6.2.3.A. Management of specific toxicities, including durvalumab-related 
infusion reaction, immune-mediated AEs, hypertension, diarrhea, proteinuria, decrease in 
LVEF, fever and neutropenia, nausea and vomiting, thyroid toxicities, reversible 
posterior leukoencephalopathy syndrome (RPLS) and gastrointestinal perforation should 
Table 6.2.3 A:  General Management of Non-Hematologic Toxicity, Arms II - IV 
Observation 
Action 
AE resolves promptly with supportive care  
Maintain dose level 
Any  t grade 3 non-hematologic (excluding grade 3 
fatigue, or easily correctable asymptomatic grade 3 
laboratory abnormalities) 
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to d grade 1. 
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction 
levels in Section 6.2.3, at the treating 
investigator’s discretion2. The Study 
Chair should be informed regarding all 
dose modifications. 
Any grade 2 non-hematologic AE or grade 3 fatigue, 
that persists despite maximal support.  
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to d grade 1.  
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction 
levels in Section 6.2.3, at the treating 
investigator’s discretion2. The Study 
Chair should be informed regarding all 
dose modifications. Patients whose 
toxicity has not resolved after 14 days 
will be removed from the study 
treatment. 
1. Grade 3 or 4 non-hematologic AE that does not 
resolve to grade 0-2 within 14 days (excluding 
weight loss) despite maximum supportive care after 
treating patient at the lowest reduced dose level.3 
2. Grade 3 or 4 non-hematologic AE lasting > 14 days 
(excluding weight loss) despite maximum 
supportive care and treatment being held. 
Discontinue study drug(s) 
1At the discretion of the investigator, one drug may be held or dose modified or 
discontinued independently if the observed toxicity is attributed to only one of the drugs, 
while the patient continued to receive the second drug not associated with the observed 
toxicity.  The time a given drug is held should not exceed 14 days. 
2Patients who are at the lowest reduced dose level may have their drug resumed at that dose level 
after discussion with the Study Chair if evidence of clinical benefit. 
3For thromboembolic events, treatment may be resumed at the discretion of the investigator once 
patient is asymptomatic. 

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be as further outlined in the below specific subsections and not per Table 6.2.3.A. 
 
 
 
* Management of olaparib-induced nausea and vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. These 
events are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and 
manageable on continued treatment. The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting. For nausea, 
the incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 
months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; 
however, patients should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local treatment practice 
guidelines. Alternatively, olaparib tablets can be taken with a light meal/snack (ie 2 
pieces of toast or a couple of biscuits).  
 
Olaparib dose reduction should be considered for patients requiring consistent anti-emetic 
intervention despite supportive cares per ASCO PARP inhibitor guidelines (Tew et al, J 
Clin Onc, 2020). 
 
6.2.4  Durvalumab-related adverse events 
 
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 Chair. 
 
All toxicities will be graded according to NCI CTCAE, Version 5.0. 
 
6.2.4.1 Monistoring of durvalumab (MEDI4736) administration:  
 
x Patients will be monitored before, during and after the infusion with assessment of vital 
signs at the times specified in the Schedule of Assessments. Patients are monitored (pulse 
rate, blood pressure) every 30 minutes during the infusion period (including times where 
infusion rate is slowed or temporarily stopped). 
 
x Standard infusion time is one hour, however if there are interruptions, the total allowed 
time must not exceed 8 hours at room temperature (otherwise requires new infusion 
preparation).  
 
x For management of patients who experience an infusion reaction, please refer to the 
Section 6.2.4.2. 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. 
 
6.2.4.2 Infusion-related reaction with durvalumab 
x In the event of grade 1 or 2 infusion-related reaction, the infusion rate of study drug 
may be decreased by 50% or interrupted until resolution of the event (up to 4 hours) 
and re-initiated at 50% of the initial rate until completion of the infusion. For patients 
with grade 1 or 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 may be administered at the discretion of 
the investigator.   
x If the infusion-related reaction is grade 3 or higher OR recurrent grade 2 or higher in 
severity, durvalumab (MEDI4736) will be discontinued  
 
Table 6.2.4.2 Management of Infusion-Related Reactions 
Dose Modifications 
Toxicity Management 
Any Grade 
x Management per institutional standard  
x 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, skin rashes etc.) and anaphylaxis (e.g., 
generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of durvalumab 
(MEDI4736) may be decreased by 50% or 
temporarily interrupted until resolution of 
the event 
For Grade 1 or Grade 2: 
x Acetaminophen and/or antihistamines may be 
administered at the discretion of the investigator  
x Consider premedication prior to subsequent doses 
x Steroids should not be used for routine 
premedication of Grade ≤2 infusion reactions. 
Grade 2 
The infusion rate of durvalumab 
(MEDI4736) may be decreased 50% or 
temporarily interrupted until resolution of 
the event (up to 4 hours). Subsequent 
infusions may be given at 50% of the 
initial infusion rate 
Grade 3 or 4 
Permanently discontinue durvalumab 
 
For Grade 3 or 4: 
Manage severe infusion-related reactions (e.g., IM 
epinephrine, followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid) 
 
6.2.4.3 Immune-related adverse events  
x Based on the mechanism of action of durvalumab (MEDI4736) leading to T-cell 
activation and proliferation, there is the possibility of observing immune related 
Adverse Events (irAEs) during the conduct of this study.  Potential irAEs include 
immune mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects 

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should be monitored for signs and symptoms of irAEs.  In the absence of an alternate 
etiology (e.g., infection or progression) signs or symptoms of enterocolitis, dermatitis, 
hepatitis, and endocrinopathy should be considered to be immune-related.   
x Dose modification recommendations and toxicity management guidelines for 
durvalumab, immune-mediated reactions are detailed below. 
 
Table 6.2.4.3 A. General Considerations for immune-related AEs (irAEs) 
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 durvalumab (MEDI4736) is also required for the following conditions: 
x 
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 
x 
Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of dosing 
 
AE Grade: 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen 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 study drug/study regimen 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 are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen may be permanently discontinued. 
Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
 
Note: For asymptomatic amylase or lipase levels of >2× ULN, hold study drug/study regimen, and if complete 
work up shows no evidence of pancreatitis, study drug/study regimen may be continued or resumed. 
 
Note: Durvalumab (MEDI4736) should be permanently discontinued in 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.  Similarly, consider whether study drug/study regimen should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or other similar events even if they 
are not currently noted in the guidelines – when they do not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper. 
 
Note: There are some exceptions to permanent discontinuation of study drug for Grade 4 events (i.e., 
hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).   
 
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.  

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Table 6.2.4.3 A. General Considerations for immune-related AEs (irAEs) 
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 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)a 
− 
Discontinuation of durvalumab (MEDI4736) 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 study drug/study regimen 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; 
imAE Immune-mediated adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth. 
 
 
 
6.2.4.3 B. 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)1 
For Any Grade:  
− 
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 
(asymptomatic, 
clinical or 
diagnostic 
observations 
only; intervention 
not indicated) 
No dose modifications 
required.  However, 
consider holding study 
drug(s) 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 
(symptomatic; 
medical 
intervention 
indicated; 
limiting 
Hold study drug(s) until 
resolution to Grade ≤1. 
x If toxicity worsens, 
treat as Grade 3/4 
x If toxicity improves to 
Grade ≤1, then the 
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. 

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instrumental 
ADL) 
decision to retreat will 
be based upon 
treating physician’s 
discretion and after 
completion of steroid 
taper. 
− 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 
(Grade 3: severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [e.g., 
tracheostomy or 
intubation]) 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening): 
− 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 and consider 
prophylactic antibiotics, antifungals, and in 
particular, anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-
related infections)a 
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). 
− 
When symptoms or evaluation indicate a perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately without any delay. 
− 
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 
No dose modifications. 
For Grade 1: 
− Monitor closely for worsening symptoms. 
− Consider symptomatic treatment, including 

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<4 over baseline 
per day) 
Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations only) 
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 
frequency of 4 to 
6 over baseline 
per day; limiting 
instrumental 
ADL) 
(Colitis: 
abdominal pain; 
mucus or blood 
in stool) 
(Perforation: 
invasive 
intervention not 
indicated) 
Hold 
durvalumab(MEDI473) 
until resolution to Grade 
≤1 
x If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
x If toxicity improves to 
Grade ≤1, then study 
drug(s) can be 
resumed after 
completion of steroid 
taper. 
For Grade 2: 
− Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
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 consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of 
cancer-related infections)a 
Grade 3 or 4 
(Grade 3 
diarrhea: stool 
frequency of ≥7 
over baseline per 
day; limiting 
self-care ADL; 
Grade 4 diarrhea: 
life threatening 
consequences) 
(Grade 3 colitis:  
severe abdominal 
pain, change in 
bowel habits, 
medical 
intervention 
indicated, 
peritoneal signs; 
Grade 4 colitis:  
life-threatening 
consequences, 
Grade 3 
Permanently 
discontinue study 
drug/study regimen for 
Grade 3 if toxicity does 
not improve to Grade 
≤1 within 14 days; 
study drug/study 
regimen can be resumed 
after completion of 
steroid taper. 
 
Grade 4 
Permanently 
discontinue  
study drug/study 
regimen. 
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 and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment 
(refer to current NCCN guidelines for treatment of 
cancer-related infections).a 

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urgent intervention 
indicated) 
 
(Grade 3 
Perforation: 
invasive 
intervention 
indicated; Grade 4 
Perforation: life-
threatening 
consequences; 
urgent intervention 
indicated) 
Hepatitis 
(elevated 
LFTs) 
Infliximab 
should not be 
used for 
management of 
immune-
related 
hepatitis. 
 
 
 
 
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  
(AST or ALT 
>ULN and 
≤3.0×ULN if 
baseline normal, 
1.5-3.0×baseline 
abnormal; and/or 
TB > ULN and 
1.5×ULN if 
baseline 
abnormal) 
x No dose modifications. 
x If it worsens, then treat 
as Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2  
(AST or  
ALT >3.0×ULN 
and ≤5.0×ULN if 
baseline normal, 
>3.-5×baseline if 
baseline abnormal; 
and/or TB > 
1.5×ULN and 
≤3.0×ULN if 
baseline normal, 
>1.5-3.0×baseline 
if baseline 
abnormal) 
x Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
x If toxicity worsens, then 
treat as Grade 3. 
x If toxicity improves to 
Grade ≤1, resume study 
drug/study regimen 
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 and consider 
prophylactic antibiotics, antifungals, and anti-
PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related 

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infections) a 
Grade 3  
(AST or  
ALT >5.0×ULN 
and ≤20×ULN if 
baseline normal, 
>5-20×baseline if 
baseline abnormal; 
and/or TB 
>3.0×ULN and  
≤10.0×ULN if 
baseline normal, 
>3.0-
10.0×baseline if 
baseline 
abnormal) 
 
Grade 4 
(AST or ALT 
>20xULN if 
baseline normal, 
>20xbaseline if 
baseline abnormal; 
an/or TB 
>10xULN if 
baseline normal, 
>10.0×baseline if 
baseline 
abnormal)   
For Grade 3: 
For transaminases 
elevations ≤8 × ULN, or 
bilirubin  elevations 
≤5 × ULN: 
x Hold durvalumab 
(MEDI4736) until 
resolution to Grade ≤1 
or baseline 
x Resume durvalumab 
(MEDI4736) if LFT 
elevations resolve to 
Grade ≤1 or baseline 
within 14 days and 
after completion of 
steroid taper. 
x Permanently 
discontinue 
durvalumab 
(MEDI4736) if no 
resolution  within 
14 days 
 
Permanently discontinue  
durvalumab (MEDI4736) 
for: 
x Transaminases 
elevation >8 × ULN or 
bilirubin >5 × ULN. 
x 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 causeb 
 
 
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).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nephritis or 
renal 
dysfunction 
(elevated 
serum 
creatinine) 
For 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 
> ULN to 1.5 × 
ULN) 
No dose 
modifications. 
For Grade 1: 
− Monitor serum creatinine weekly and any accompanying 
symptoms. 
x If creatinine returns to baseline, resume its regular 

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monitoring per study protocol. 
x If creatinine worsens, depending on the severity, treat as 
Grade 2, 3, or 4. 
− Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− If baseline serum creatinine is elevated above normal, and 
there is a rise to >1 to 1.5 × baseline, consider following 
recommendations in this row. 
Grade 2 
(serum creatinine 
>1.5 to 3.0 × 
baseline; >1.5 to 
3.0 × ULN) 
Hold durvalumab 
(MEDI4736) until 
resolution to Grade 
≤1 or baseline.  
x If toxicity 
worsens, then 
treat as Grade 3 
or 4. 
x If improvement 
to Grade ≤1 or 
baseline, resume 
study drug(s) 
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).a 
− When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; 
>3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × 
ULN) 
Permanently 
discontinue 
durvalumab 
(MEDI4736) 
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 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).a 
Rash or 
Dermatitis 
(including 
Pemphigoid) 
 
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 STUDY DRUG DISCONTINUED IF SUSPECT STEVENS-JOHNSON 
SYNDROME OR TOXIC EPIDERMAL NECROLYSIS. 
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). 

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Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 
events, hold 
durvalumab 
(MEDI4736) until 
resolution to Grade 
≤1 or baseline. 
x If toxicity worsens, 
treat as Grade 3. 
x If toxicity improves 
to Grade ≤1 or 
baseline, resume 
drug(s) 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 durvalumab 
(MEDI4736) until 
resolution to Grade 
≤1 or baseline. 
 
If no improvement 
within 30 days, 
permanently 
discontinue 
durvalumab 
(MEDI4736) 
 
Grade 4 (or life-
threatening): 
Permanently 
discontinue 
durvalumab 
(MEDI4736) 
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) 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).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopath
y 
(e.g., hyperthyr
oidism, 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. 
− For asymptomatic elevations in serum amylase and lipase >ULN and 
<3×ULN, 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 

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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. 
Grade 2 
For Grade 2 
endocrinopathy other 
than hypothyroidism 
and Type 1 diabetes 
mellitus, hold 
durvalumab 
(MEDI4736) until 
patient is clinically 
stable. 
- If toxicity worsens, 
treat as Grade 3/4. 
- Durvalumab 
(MEDI4736) can be 
resumed once event 
stabilizes and after 
completion of 
steroid taper. 
Patients with 
endocrinopathies who 
may require 
prolonged steroid 
replacement can 
resume durvalumab 
(MEDI4736) 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 study drug/study regimen 
interruption, and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, without study 
drug/study regimen 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).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 
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. 

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durvalumab 
(MEDI4736) until 
endocrinopathy 
symptom(s) are 
controlled.  
durvalumab 
(MEDI4736) 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 study 
drug(s) 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 all patients with abnormal endocrine workup, except 
those with isolated hypothyroidism or Type 1 diabetes 
mellitus, 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).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 study drug/study regimen 
interruption, and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen 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).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 study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
durvalumab (MEDI4736) 
until resolution to Grade 
≤1. 
x If toxicity worsens, 
For Grade 2: 
− Consider, as necessary, discussing with the Study Chair. 
− Obtain neurology consult. 
− Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (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). 

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treat as Grade 3 or 4. 
durvalumab (MEDI4736) 
can be resumed after 
improvement to Grade 
≤1 and after completion 
of steroid taper. 
Grade 3 or 4 
For Grade 3: 
Hold durvalumab 
(MEDI4736) until 
resolution to Grade ≤1. 
 
Permanently discontinue 
durvalumab (MEDI4736) 
if Grade 3 imAE does 
not resolve to Grade ≤1 
within 30 days. 
 
For Grade 4: 
Permanently discontinue 
durvalumab (MEDI4736) 
For Grade 3 or 4: 
− Consider, as necessary, discussing with the Study Chair. 
− 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. 
− 
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 
(Guillain-Barre 
[GB]:  mild 
symptoms) 
(Myasthenia 
gravis [MG]: 
asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated)   
No dose modifications. 
For Grade 1: 
− Consider, as necessary, discussing with the Study Chair. 
− Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
− Obtain a neurology consult. 
Grade 2 
(GB: moderate 
Hold durvalumab 
(MEDI4736) until 
For Grade 2: 
− 
Consider, as necessary, discussing with the Study 

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symptoms; 
limiting 
instrumental 
ADL) 
 
(MG: 
moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting age-
appropriate 
instrumental 
ADL) 
resolution to Grade ≤1. 
Permanently discontinue 
durvalumab (MEDI4736) if 
it does not resolve to Grade 
≤1 within 30 days or if there 
are signs of respiratory 
insufficiency or autonomic 
instability. 
Chair. 
− 
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 IG. 
Grade 3 or 4 
(Grade 3 GB: 
severe 
symptoms; 
limiting self-
care ADL;  
Grade 4 GB: 
life-threatening 
consequences; 
urgent 
intervention 
indicated; 
intubation) 
(Grade 3 MG: 
severe or 
medically 
significant but 
not 
immediately 
life-
For Grade 3: 
Hold MEDI4736 
(durvalumab0 until 
resolution to Grade ≤1. 
Permanently discontinue 
durvalumab (MEDI4736) if 
Grade 3 imAE 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 
durvalumab. 
For Grade 3 or 4 (severe or life-threatening events): 
− Consider, as necessary, discussing with Study Chair. 
− 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. 

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threatening; 
hospitalization 
or prolongation 
of existing 
hospitalization 
indicated; 
limiting self-
care ADL;  
Grade 4 MG: 
life-threatening 
consequences; 
urgent 
intervention 
indicated) 
 
Myocarditis  
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 Chair. 
− 
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. 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, 
other medications, or infections) 
− 
Discontinue durvalumab (MEDI4736) permanently if biopsy-proven immune-mediated 
myocarditis regardless of grade 
 
Grade 1 cardiac AE 
(asymptomatic or mild 
symptoms*; clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
*Treat myocarditis 
with mild symptoms 
as Grade 2 
No dose modifications required 
unless clinical suspicion is high 
for myocarditis, in which case 
hold durvalumab (MEDI4736) 
during diagnostic workup.  
- If myocarditis is excluded, 
resume after complete 
resolution to Grade 0. 
- If myocarditis is diagnosed, 
permanently discontinue  
durvalumab MEDI4736) 
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 
For Grade 2:  
- Hold durvalumab 
(MEDI4736) 
- If toxicity rapidly improves 
to Grade 0 and no evidence 
for myocarditis, then the 
decision to reinitiate 
MEDI4736 durvalumab 
(MEDI4736) is based upon 
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). 

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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) 
 
* Consider “new onset 
of symptoms” as 
referring to patients 
with prior episode of 
myocarditis 
treating physician’s clinical 
judgment and after 
completion of steroid taper.  
- If toxicity does not rapidly 
improve, permanently 
discontinue durvalumab 
(MEDI4736) 
- If myocarditis is diagnosed, 
permanently discontinue 
durvalumab (MEDI4736) 
regardless of timeline of 
recovery. 
- If Grade 3-4, permanently 
discontinue durvalumab 
(MEDI4736) 
− 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).a 
Myositis/Polym
yositis 
(“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 Chair. 
− 
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 Chair. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of 
daily living 
Hold durvalumab 
(MEDI4736) until 
resolution to Grade 
≤1. 
Permanently 
discontinue 
durvalumab 
(MEDI4736) if it 
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 

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[ADLs]) 
does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
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 
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 
(Grade 3: pain 
associated with 
severe 
weakness; 
limiting self-
care ADLs 
 
Grade 4: life-
threatening 
consequences; 
urgent 
intervention 
indicated) 
 
For Grade 3: 
Hold durvalumab 
(MEDI4736) until 
resolution to Grade 
≤1. 
Permanently 
discontinue  
durvalumab 
(MEDI4736) if Grade 
3 imAE does not 
resolve to Grade ≤1 
within 30 days or if 
there are signs of 
respiratory 
insufficiency. 
 
For Grade 4: 
Permanently 
discontinue 
MEDI4736 
(durvalumab). 
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 Chair. 
− 
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).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. 
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; imAE 
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. 
 
1 Pneumonitis (ILD) investigation 
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 this table will be applied.  The results of the full diagnostic 
workup (including high-resolution computed tomography (HRCT), blood and sputum culture, hematological parameters, etc.) 

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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.  
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 including  
o 
Physical examination 
 
Signs and symptoms (cough, shortness of breath and pyrexia, etc.), including auscultation for lung field 
will be assessed 
o 
Saturation of peripheral oxygen (SpO2) 
o 
Other items 
 
When pneumonitis (ILD) is suspected during study treatment, the following markers should be 
measured where possible: 
(i) ILD Markers (KL-6, SP-D) and β-D-glucan.  
(ii) Tumor markers: Particular tumor marker swhich are related to disease progression 
(iii) Additional clinical chemistry: CRP, LDH 
 
6.3 
Cediranib-related adverse events 
Cediranib should be discontinued should any of the following AEs occur:  GI 
perforation; arterial thromboembolic events; PRES (radiologically confirmed); severe 
or medically significant hemorrhage and severe persistent hypertension despite 
maximal anti-hypertensive treatment. 
6.3.1 Hypertension  
Only doses of cediranib will be modified for hypertension; olaparib or durvalumab 
(MEDI4736) doses will not be altered unless other toxicities are experienced.  
 
Table 6.3.1 A: Hypertension Monitoring and Management 
x See table for suggested antihypertensive medications by class (Appendix IX). 
x Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
Blockers (ARB), selective beta blockers (BB), Calcium channel blockers (CCB) 
x If patients require a delay of >2 weeks for management of hypertension, discontinuation of 
cediranib may be considered after discussion with the Study Chair. 
x Patients may have up to 4 drugs for management of hypertension prior to any dose reduction 
in cediranib 
x Hypertension should be graded using the NCI CTCAE v5.0. Please note: patients may have 
baseline hypertension meeting CTCAE grading criteria on study entry.  Should patients 
require increase in dosing of BP medication or increased number of medications, they should 
then be noted to have hypertension related to study drug, with grading as per CTCAE 
criteria.  Baseline grade of hypertension should also be recorded in the patient’s record. 
x Note:  Stopping or reducing the dose of cediranib is expected to cause a decrease in BP.  The 
treating physician should monitor the patient for hypotension (also during the weekend when 
the patients do not take cediranib) and adjust the number and dose of antihypertensive 
medications accordingly. Please pressure cuffs with be provided for patients taking cediranib.  
See Section 9.7.4. 
Event 
Definition 
Antihypertensive 
Therapy 
Blood 
Pressure 
Monitoring 
Cediranib Dose 
Modification 
Grade 
Asymptomatic 
transient (<24 
Consider early initiation of 
BP medication for BP > 
Continue 
standard BP 
None 

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1 
hrs) increase by 
>20 mmHg 
diastolic or to 
>140/90 mmHg 
if previously 
WNL 
140/90 mmHg that is 
confirmed on a second 
reading.  Cediranib can cause 
rapid escalation in BP, and 
early initiation of BP 
management can reduce 
likelihood of HTN-related 
complications. 
monitoring 
per treating 
MD and 
confirm 
resolution of 
BP to 
<140/90 
mmHg 
within 36 
hours. 
Grade 
2 
Recurrent or 
persistent (>24 
hrs) or 
symptomatic 
increase by >20 
mmHg 
(diastolic) or to 
> 140/90 
mmHg if 
previously 
WNL 
 
Monotherapy 
may 
be indicated 
Initiate BP medication 
for first line treatment: 
x Suggestion: 
       ACE inhibitor 
 
Escalate dose of medication 
until BP is controlled or at a 
maximum dose 
 
If BP is not controlled 
to < 140/90 mmHg with one 
“maximized” drug regimen, 
then add a second agent: 
Study drug does not need 
to be held unless otherwise 
clinically necessary 
Consider cardiology or renal 
consult 
Increase 
frequency 
of 
monitoring 
(daily) until 
stabilized to 
BP <140/90 
mmHg 
Do not hold 
cediranib unless 
otherwise clinically 
necessary 
Grade 
3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously. 
Maximize 2 drug 
regimen 
x Suggestions: 
ACE inhibitor + BB or 
ACE inhibitor + CCB 
 
Escalate doses of 
existing medication 
until BP is controlled 
or at a maximum dose. 
 
If BP is not controlled to 
< 140/90 mmHg with two 
drug regimen, then add a 
third agent. 
Study Drug will not be held 
Increased 
frequency 
of 
monitoring 
until 
stabilized to 
BP <140/90 
mmHg 
Do not hold 
cediranib or other 
study drug unless BP 
is not decreased to 
less than 150/100 
mmHg 48 hours 
after multi-drug 
therapy is instituted 
or if clinical 
symptoms worsen 
(e.g. headache). 
 
If BP is not 
controlled to less 
than 150/100 
mmHg with 
maximal therapy or if 

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during trial of two drug 
combinations. 
Additional 
antihypertensive drugs, up 
to a total of 4, may be 
maximized for blood 
pressure control. 
Consider consult with a 
blood pressure management 
specialist if greater than 3 
drugs are required for BP 
control. 
clinical symptoms 
worsen, then hold 
drug (up to 14 days) 
until maximum 
effect of the 
antihypertensive 
agents is achieved. 
 
If BP is reduced to 
Grade 1 within 14 
days, cediranib may 
be resumed at prior 
dose. 
Grade 
4 
If threatening 
consequences 
OR 
SBP ≥ 
180mmHg 
OR 
DBP ≥ 
110mmHg 
Initiate treatment 
 
Hospitalize patient for 
ICU management, IV 
therapy as necessary 
 
14 days are allowed to 
maximize the full effect of 
antihypertensive agents. 
 
Intensive 
BP 
monitoring 
(hospitaliza-
tion if 
necessary) 
Hold cediranib. 
 
If BP is reduced to 
Grade 1 within 14 
days, cediranib may 
be resumed at a 
reduced dose after 
discussion with the PI 
Notes: 
x While patients are receiving treatment with cediranib, the early initiation of antihypertensive 
treatment for grade 1 or 2 hypertension to minimize more severe or persistent hypertension is 
not considered a grade 3 adverse event. 
x Decisions to hold or decrease the cediranib dose during treatment must be based on BP 
readings taken in the clinic by a medical professional. 
 
6.3.2 Decreased Left Ventricular Ejection Fraction  
 
Patients who have any of the following should undergo an echocardiogram or MUGA at 
baseline and every four cycles (16 weeks +/-1 week) while on study: 
x Prior treatment with anthracyclines 
x Prior treatment with trastuzumab or T-DM1 
x A New York Heart Association classification of II controlled with treatment  
x Prior central thoracic radiation therapy (RT), including RT to the heart 
x History of myocardial infarction within 6 to 12 months (Patients with history of 
myocardial infarction within 6 months are excluded from the study)  
x Prior history of impaired cardiac function 
 
Only doses of cediranib will be modified for LVEF; olaparib or durvalumab (MEDI4736) 
doses will not be altered unless other toxicities are experienced. The decision to continue 

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or hold cediranib is based on the LVEF as it relates to the institution’s lower limit of 
normal (LLN) and change in ejection fraction from screening (LVEF as measured at 
registration) according to the following table: 
 
Table 6.3.2 A.  Management and Monitoring of Decreased LVEF 
Relationship of 
LVEF to 
Institution’s LLN 
LVEF Decrease 
< 10% 
 
LVEF Decrease 
10-15% 
 
LVEF Decrease 
> 16% 
Normal 
Continue 
Continue 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
1-5% below LLN 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
> 6% below LLN 
 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
 
6.3.3 Diarrhea (27-AUG-2021) 
 
Diarrhea is often observed with cediranib. Diarrhea usually starts early (within the first 
4 weeks of treatment), however, it can occur at any time during treatment. Management 
of diarrhea should start at the first sign of diarrhea. Loperamide and advice on how to 
manage diarrhea should be readily available to patients from the start of cediranib 
treatment so that they can be applied at first episode of diarrhea. Active and early 
management of diarrhea is recommended even with Grade 1 diarrhea.  Management as 
follows: 
 
Table 6.3.3 A:  Management of Diarrhea 
Toxicity 
Management/Modifications 
Initial grade 1 or 2 diarrhea: 
Patients can take loperamide (per standard 
practice) and continue to take loperamide until 
patients are free from diarrhea for at least 12 
hours.  The dose of loperamide should not exceed 
16mg in a 24-hour period. Patients should also be 
counseled to start a BRAT (bananas, rice, 
applesauce, toast) diet.  
 
 
Patients should be instructed to contact their study 
team if mild or moderate (NCI CTCAE Grade 1 or 
2) diarrhea persists for over 48 hours despite 
treatment with loperamide and cediranib dose 
interruption. Cediranib may be restarted at the 

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same dose once patients have been free from 
diarrhea for 12 hours after discussing with the 
study team. 
For either persistent grade 2 diarrhea or grade 3 or 
4 diarrhea *:  
Follow 6.2.3.A  
*Patients with persistent or severe diarrhea (NCI CTCAE Grade 3 or higher) may also require 
dose reduction or discontinuation of therapy with cediranib; follow guidance in Table 6.2.3. 
Patients who are at the lowest reduced dose level may have their drug resumed at that dose level 
after discussion with the Study Chair if evidence of clinical benefit. 
 
6.3.4 Proteinuria 
Although patients with ≥1+ proteinuria at entry are ineligible, increases in proteinuria 
may occur during treatment and should be managed as follows:  
 
Table 6.3.4 A:  Management of Proteinuria 
Proteinuria Value if 
following by U/A 
Dose modification 
Greater than 2+ on urine 
dipstick or U/A  
AND 
Creatinine ≤1.5x ULN 
Continue study drugs at planned dose. 
Greater than 2+ on urine 
dipstick or U/A AND 
Creatinine >1.5x ULN 
Hold cediranib and evaluate possible prerenal causes such as dehydration or 
increased creainine.  
 
6.3.5 Thyroid toxicities 
The use of cediranib has been associated with elevations of the thyroid stimulating 
hormone (TSH) and patients should be managed as per the following table.  
 
In all cases, study treatment should continue unless clinically contraindicated.  Referral to 
an endocrinologist should also be considered if thyroid abnormalities occur.  
 
Table 6.3.5 A:  Monitoring and Management of Thyroid Toxicities 
Result of TSH*, T4, and T3 
Action 
Increases of TSH with normal T4/T3:  
Monitor 
Increases in TSH with normal T4/T3 and adverse 
events suggestive of incipient hypothyroidism: 
Consider replacement thyroxine.   
Increase in TSH with reductions in T4 and T3: 
Consider replacement thyroxine. 

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*Please consider requesting T3/T4 where TSH is elevated. 
 
6.3.6  Reversible Posterior Leukoencephalopathy Syndrome (RPLS)  
 
PRES has been uncommonly reported in clinical studies with cediranib. PRES is a 
neurological disorder which can present with headache, seizure, lethargy, confusion, 
blindness and other visual and neurologic disturbances, and can be fatal. Mild to severe 
hypertension may be present.  In patients developing PRES, treatment of specific 
symptoms including control of BP is recommended. Confirmation of PRES requires brain 
imaging, preferably MRI.  Cediranib should be discontinued following confirmation of 
PRES.  The safety of reinitiating cediranib in patients previously experiencing PRES is 
not known. 
 
Cediranib should be held in patients with symptoms/signs suggestive of RPLS, pending 
work-up and management, including control of blood pressure. Cediranib should be 
discontinued upon diagnosis of RPLS.  
6.3.7  Gastrointestinal perforation 
GI perforation has been uncommonly reported in cediranib treated patients and may be 
fatal. Cediranib should be used with caution in patients at risk and permanently 
discontinued in patients who develop GI perforation. 
6.3.8 Fistula 
In patients treated with cediranib, fistula has been reported and reflected the location of 
the underling malignancy.  In the ovarian cancer population, vaginal fistula has been 
uncommonly reported in cediranib treated patients.  Cediranib should be used with 
caution in patients at risk of fistula and discontinuation of cediranib should be considered 
in patients who develop fistulae. 
6.3.9 Arterial thromboembolism 
Arterial thromboembolic events (including transient ischemic attack and ischemic stroke) 
have been reported in clinical studies with cediranib.  Cediranib should be used with 
caution in patients who are at an increased risk of thrombotic events or who have a 
history of thrombotic events.  Cediranib should be permanently discontinued in patients 
who develop an arterial thromboembolic event. 
6.3.10  Venous thromboembolism 
Venous thromboembolic events including pulmonary embolism and deep vein 
thrombosis have been commonly reported in patients treated with cediranib.  
Anticoagulant treatment should be started in accordance with clinical practice.  
Discontinuation of cediranib may be considered.  Cediranib should be used with caution 
in patients at risk of venous thromboembolism. 
6.3.11 Wound healing 
Treatment with cediranib should be stopped at least 2 weeks prior to scheduled surgery.  
The decision to resume cediranib therapy after surgery should be based on clinical 
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complications during therapy, treatment with cediranib should be interrupted until the 
wound is fully healed.  No formal studies of the effect of cediranib on wound healing 
have been conducted; however in the ICON6 pivotal study there was no evidence of an 
increase in wound healing complications in cediranib treated patients compared with 
placebo. 
6.3.12  Fatigue 
Fatigue is a common adverse drug reaction reported for both cediranib and olaparib.  
Fatigue experienced by patients taking cediranib may be rapid in onset.  During clinic 
visits, patients fatigue levels should be discussed.  Patients should seek medical 
advice early if Grade 2 fatigue develops (moderate fatigue causing difficulty 
performing some activities of daily living). 
Care should be taken to ensure that the nutritional status of the patients is optimized 
and patients should be encouraged to drink plenty of fluids. Patients should be 
encouraged to manage fatigue by alternating periods of rest with light aerobic 
exercise, which may improve the symptoms in some cases. 
Consideration should be given to other possible causes of fatigue (e.g., thyroid 
function, depression/insomnia and other concomitant medicinal products). 
Additionally, short interruption of cediranib dosing (initially 2-3 days-or longer-up 
to a maximum of 21 days) may help relieve fatigue.  When symptoms improve 
cediranib should be restarted with the same dose or, if necessary, a dose reduction 
can be considered. 
6.4 
Olaparib-related AEs 
AEs requiring olaparib to be discontinued: 
x Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) 
x Severe persistent anemia 
x Pneumonitis 
 
6.4.1   AML/MDS 
x Patients who have treatment held for hematologic toxicities should have blood counts 
and differentials checked at least weekly until recovery.  If counts do not improve to 
CTCAE grade 1 or better despite drug cessation for 3 weeks, patients should be 
referred to a hematologist for further assessment.   
x A bone marrow analysis should be considered per hematology assessment given there 
may be potential contributing factors for the development of MDS/AML, such as 
prior exposures to extensive chemotherapy with platinum agents or other DNA 
damaging agents. 
x Patients who develop MDS/AML on treatment should be discontinued from olaparib 
treatment and managed appropriately. 
6.4.2  Management of olparib-related new or worsening pulmonary symptoms 
x If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological 

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abnormalities occur in the absence of a clear diagnosis, an interruption in 1 or both 
investigational drugs dosing is recommended and further diagnostic workup 
(including a HRCT scan) should be performed to exclude pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging 
and symptoms resolve, then investigational drugs can be restarted, if deemed 
appropriate by the investigator.  If significant pulmonary abnormalities are identified, 
these need to be discussed with the Study Chair. 
6.4.3  Management of nausea and vomiting 
x Events of nausea and vomiting are known to be associated with olaparib treatment.  
In study D0810C00019 nausea was reported in 71% of the olaparib treated patients 
and 36% in the placebo treated patients and vomiting was reported in 34% of the 
olaparib treated patients and 14% in the placebo treated patients.  These events are 
generally mild to moderate (CTCAE Grade 1 or 2) severity, intermittent and 
manageable on continued treatment.  The first onset generally occurs in the first 
month of treatment for nausea and within the first 6 months of treatment for vomiting.  
For nausea, the incidence generally plateaus at around 9 months, and for vomiting at 
around 6 to 7 months. 
x No routine prophylactic anti-emetic treatment is required at the start of treatment with 
the olaparib, however, patients should receive appropriate anti-emetic treatment at the 
first onset of nausea or vomiting and as required thereafter, in accordance with local 
treatment practice guidelines. Taking olaparib tablets with food may help alleviate 
symptoms of nausea and vomiting. 
x As per international guidance on anti-emetic use in cancer patients (European Society 
for Medical Oncology [ESMO], NCCN), generally a single agent antiemetic should 
be considered e.g. dopamine receptor antagonist, antihistamines or dexamethasone. 
6.4.4   Management of renal impairment 
x If subsequent to study entry and while still on study treatments, a patient’s estimated 
creatinine clearance (CrCL) falls below the threshold for study inclusion (<50 
mL/min), retesting should be performed promptly.  A dose reduction of olaparib is 
recommended for patients who develop moderate renal impairment (calculated CrCL 
by Cockcroft-Gault equation of ≥31 mL/min and ≤50 mL/min) for any reason during 
the course of the study: the dose of olaparib should be reduced to 150 mg twice daily. 
x Because the CrCL determination is only an estimate of renal function, in instances 
where the CrCL falls to between 31 mL/minutes and 50 mL/minutes, the Investigator 
should use his or her discretion in determining whether a dose change or 
discontinuation of therapy is warranted. 
x Olaparib has not been studied in patients with severe renal impairment 
x (CrCL ≤30 mL/minutes) or end-stage renal disease; if patients develop severe 
impairment or end stage disease is it recommended that olaparib be discontinued. 
6.5 
Management of durvalumab, Olaparib, or Cediranib for Surgery/Procedure  
x At this time there is no recommendation for holding durvalumab (MEDI4736) in the 
event of surgery; decision to defer or hold treatment in the event of surgery is per 
discretion of the PI.  

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x Olaparib should be stopped two weeks prior to planned surgery or at least 1 day prior 
to planned procedures, e.g., colonoscopy. After surgery or procedure, olaparib may be 
restarted when the wound has healed. For planned procedures, olaparib may be 
restarted next day.  
x Because the AEs related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery if these 
symptoms occur. 
x Cediranib has the potential to affect wound healing. Cediranib should be stopped two 
weeks prior to elective surgery and restarted when the wound has healed. In the event 
of emergency surgery, cediranib should be stopped and appropriate precautions 
should be taken to minimize potential risks of bleeding and thrombosis associated 
with this class of agents. 
x Cediranib should be discontinued at least 3 days prior to planned procedures, e.g., 
colonoscopy and cediranib may be restarted 3 days after procedures or when the 
wound has healed.  
x No stoppage of investigational drugs is required for any needle biopsy procedure. 
x Olaparib and/or cediranib should be discontinued for a minimum of 3 days before a 
patient undergoes radiation treatment.  Both drugs should be restarted within 2 weeks 
as long as any bone marrow toxicity has recovered. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
Protocol Agents 
 
 
Investigational Agents 
The investigational agents administered in NRG-GY023 are durvalumab, olaparib, and 
cediranib which are being made available under an IND sponsored by CTEP.  For 
patients receiving durvalumab, olaparib, or cediranib, determination of whether an 
adverse event meets expedited reporting criteria, see the reporting table in Section 7.2.2 
of the protocol. 
 
 
Commercial Agents 
The commercial agents in NRG-GY023 are paclitaxel, topotecan, and pegylated 
liposomal doxorubicin (PLD). For patients receiving paclitaxel, Topotecan, or pegylated 
liposomal doxorubicin determination of whether an adverse event meets expedited 
reporting criteria, see the reporting table in Section 7.2.2.1 of the protocol. 
 
7.2 
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
 

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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. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study Agents 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MEDI4736 (durvalumab, NSC 778709) 
 
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 2833 patients. Below is the CAEPR for MEDI4736 
(durvalumab). 
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 2.4, April 17, 20191 
 
 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (idiopathic 
thrombocytopenic purpura)2 
  
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Myocarditis2 
  

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 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Pericarditis2 
  
ENDOCRINE DISORDERS 
  
 
 
Adrenal insufficiency2 
  
 
 
Endocrine disorders - Other 
(diabetes insipidus) 
  
 
 
Endocrine disorders - Other 
(diabetes mellitus type 1)2 
  
 
Hyperthyroidism2 
 
  
 
 
Hypopituitarism2 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Keratitis2 
  
 
 
Uveitis2 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis2 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastrointestinal disorders -Other - 
(gastrointestinal perforation)2,3 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
 
Pancreatitis2 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Immune system disorders - Other 
(immune related adverse events)2 
  
 
 
Immune system disorders - Other 
(sarcoidosis) 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  Infection4 (Gr 2) 
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) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  

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 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
  
 
Myalgia 
  
 Myalgia (Gr 2) 
 
 
Myositis2 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2,5 
  
 
 
Myasthenia gravis2 
  
 
 
Nervous system disorders - Other 
(aseptic meningitis)2 
  
 
 
Peripheral sensory neuropathy 
  
RENAL AND URINARY DISORDERS 
  
 
Dysuria 
 
 Dysuria (Gr 2) 
 
 
Renal and urinary disorders - Other 
(autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Cough 
 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Pneumonitis2 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(dysphonia) 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash2,6  
 
 Rash2,6 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (scleroderma) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (severe 
dermatitis)2,7 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
NOTE: Cardiomyopathy, and graft versus host disease, while not observed on clinical trials of durvalumab 
(MEDI4736) at this time, are known events with this class of agent (PD-L1 antagonist). 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included 
in the e-mail. 
 
2Immune-mediated adverse reactions (irAEs) have been reported in patients receiving MEDI4736 (durvalumab).  
irAEs can involve any of the organs or systems in the body.  Most irAEs were reversible and managed with 
interruptions of MEDI4736 (durvalumab), administration of corticosteroids and supportive care, however, these 
events can be serious and fatal. 
 
3Gastrointestinal perforations have been observed only in patients receiving durvalumab (MEDI4736) in 
combination with tremelimumab (CP-675,206). 
 

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4Infections includes infection in the lungs, upper respiratory tract, dental and oral soft tissues and other organs under 
the INFECTIONS AND INFESTATIONS SOC.  Infections generally are mild (Gr 1-2) but severe infections 
including sepsis, necrotizing fasciitis, and osteomyelitis have been reported. 
 
5Guillain-Barre Syndrome has been reported in patients receiving durvalumab (MEDI4736) in combination with 
tremelimumab (CP-675,206) but can potentially occur after durvalumab (MEDI4736) monotherapy.  
 
6Rash includes the terms: rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash 
pruritic, rash pustular, erythema, and eczema. 
 
7In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or hemorrhagic manifectations. 
 
Adverse events reported on durvalumab (MEDI4736) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that durvalumab (MEDI4736) caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (coronary artery disease); 
Pericardial effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right ventricular dysfunction; Sinus 
tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental caries; Gastrointestinal disorders - Other 
(gastrointestinal hemorrhage); Mucositis oral; Proctitis; Small intestinal obstruction; Upper gastrointestinal 
hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Non-cardiac chest 
pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver injury); Serum sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound complication 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; Electrocardiogram T wave abnormal; GGT 
increased; Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; 
Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (brain metastasis swelling); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (lung cyst); Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (tumor flare, tumor inflammation); Treatment related secondary malignancy; Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Edema cerebral; Headache; Nervous system disorders - 
Other (axonal neuropathy); Nervous system disorders - Other (hemiparesis); Paresthesia; Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension 
 
Note: Durvalumab (MEDI4736) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 

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7.4 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Olaparib (AZD2281, NSC 747856)(25-JUL-2023) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 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 2.6 June 5, 20231 
 
 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 
  
 
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) 

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Version Date: July 25, 2023 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
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) 
  
VASCULAR DISORDERS 
  
 
 
Vascular disorders - Other 
(venous thromboembolism) 
  
 
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. 
 
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 

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Version Date: July 25, 2023 
(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. 
 
 
7.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for 
Cediranib (AZD2171, NSC 732208) 
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 1608 patients. Below is the CAEPR for Cediranib 
(AZD2171). 
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 

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Version Date: July 25, 2023 
required. 
 
Version 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)   
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal 
fistula2_ENREF_2 
  
 
 
 Gastrointestinal 
perforation3_ENREF_3 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4_ENREF_4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  

NRG-GY023 
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Version Date: July 25, 2023 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar erythrodysesthesia 
syndrome 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
 
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. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 

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GASTROINTESTINAL DISORDERS SOC. 
 
4Infections includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The majority of hemorrhage events 
reported were mild; however, serious events, defined as symptomatic bleeding in a critical area or organ system 
(e.g., eye, gastrointestinal tract, genitourinary [GU] tract, respiratory tract, and nervous system) have been reported. 
 
Adverse events reported on cediranib (AZD2171) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that cediranib (AZD2171) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other 
(polycythemia); Bone marrow hypocellular; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other (premature 
ventricular complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - cardiac; Mobitz (type) II 
atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ears feel full/plugged); Ear and 
labyrinth disorders - Other (viral labyrinthitis); Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (blindness); Eye disorders - Other (visual disturbance); 
Papilledema; Photophobia; Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Bloating; Colitis; Colonic 
obstruction; Duodenal ulcer; Dyspepsia; Enterocolitis; Esophageal necrosis; Esophageal ulcer; Esophagitis; 
Flatulence; Gastric necrosis; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(diverticulitis); Gastrointestinal disorders - Other (hydrops); Gastrointestinal disorders - Other (tongue sensitivity); 
Ileus; Oral pain; Periodontal disease; Peritoneal necrosis; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema limbs; 
Fever; Gait disturbance; Hypothermia; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder obstruction; Hepatic pain; Hepatobiliary disorders - 
Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Immune system disorders - Other (systemic 
inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Fracture; 
Injury, poisoning and procedural complications - Other (tracheostomy malfunction); Intestinal stoma leak; Venous 
injury; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; Cholesterol 
high; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Hemoglobin increased; INR increased; Investigations - Other (elevated ammonia level); Investigations - 
Other (increased blood erythropoietin); Lipase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Avascular necrosis; Back 
pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; Depressed 
level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; Ischemia 
cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - Other (coma); 
Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; Stroke; Syncope; Transient ischemic 
attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 

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REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; Vaginal 
fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; Pharyngolaryngeal 
pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary fistula; Pulmonary hypertension; 
Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pruritus; 
Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other (petechiae); Skin 
and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
Note: Cediranib (AZD2171) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.6 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information. 
 
7.7 
Expedited Reporting of Adverse Events (23-AUG-2022) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site, 
https://ctepcore.nci.nih.gov/ctepaers/security/login  
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP for this study by telephone at 301-897-7497 and to NRG Regulatory 
Affairs by phone at 215-854-0770.  An electronic report must be submitted immediately 
upon re-establishment of the Internet connection. 
 
7.7.1 Expedited Reporting Methods 
x 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.  
 
x 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. 
x A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. 
Sites must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 

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7.7.2 Expedited Reporting Requirements for Adverse Events  
 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a CTEP IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 (FOR ARMS II, III, 
and IV) 
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: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
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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7.7.2.1 Commercial Agent Studies:  Expedited Reporting Requirements for Adverse Events  
that Occur in a Non-IND/IDE trial within 30 Days of the Last Administration of a 
Commercial Agent 1,2 (FOR ARM I ONLY) 
 
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: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events 
2 For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.7.3 Reporting to the Site IRB/REB 
Investigators will report unanticipated problems to NCI CIRB according to the NCI 
CIRB SOPs.  
 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 

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provided. 
 
7.7.4 Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
7.7.5 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 or patient’s 
partner from the time of consent to 90 days after the last dose of study drug must be 
reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES 
 
Investigator and Research Associate Registration with CTEP (25-JUL-2023) 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing 
to NCI-sponsored trials to register with their qualifications and credentials and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 

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https://ctepcore.nci.nih.gov/iam. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository 
(RCR). The RCR is a self-service online person registration application with electronic 
signature and document submission capability. 
 .   
 
RCR utilizes five person registration types. 
x Investigator (IVR) – MD, DO, or international equivalent; 
x Non Physician Investigator (NPIVR) – advanced practice providers (e.g., NP or PA) 
or graduate level researchers (e.g., PhD); 
x Associate Plus (AP) – clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
x Associate (A) – other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
x Associate Basic (AB) – individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
 
 
 
 
 
 
 
 
 
 
 
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: 
x Addition to a site roster; 
x Selection as the treating, credit, or or drug shipment investigator or consenting person 
in OPEN; 
x Ability to be named as the site-protocol Principal Investigator (PI) on the IRB 
approval; and 
x Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log 
(DTL). 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
D 
D 
D 
GCP training 
D 
D 
D 
Agent Shipment Form (if applicable) 
D 
CV (optional) 
D 
D 
D 

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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the 
DTL must be rostered at the enrolling site with a participating organization.  
 
Refer to the NCI RCR page on the CTEP website for additional information. For 
questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1 
Cancer Trials Support Unit Registration Procedures (23-AUG-2022)(25-JUL-2023) 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update 
Management System (RUMS) on the Cancer Trials Support Unit (CTSU) members’ 
website. 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval: 
 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies open to 
the National Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). In addition, U.S.-
based sites must accept the NCI CIRB review to activate new studies at the site after 
March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to 
the CTSU Regulatory Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria for the site to be able to have an 
Approved status following processing of the IRB/REB approval record: 
x Have an active CTEP status; 
x Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating organization’s roster; 
x If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 

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Signatory Institution(s) record; 
x Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; 
x List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
x Have the appropriate CTEP registration type for the protocol. 
 
 
Additional Requirements for Protocol NRG-GY023 Site Registration 
 
Additional site requirements to obtain an approved site registration status include: 
x An active Federal Wide Assurance (FWA) number 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
x An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US Sites only); and  
x Compliance with all applicable protocol-specific requirements (PSRs). 
 
8.1.1 Downloading Site Registration Documents  
 
Download the site registration forms from the NRG-GY023 page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and their associated investigators and staff on a 
participating roster. To view/download site registration forms: 
 
 Log in to the CTSU members’ website (https://www.ctsu.org)  
 Click on Protocols in the upper left of the screen 
o Enter the protocol # NRG-GY023 in the search field at the top of the 
protocol tree; or 
o Click on the By Lead Organization folder to expand, then select NRG, and 
protocol # NRG-GY023. 
 Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided.  
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section of the CTSU members’ website.  The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study. 
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
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describe DTL task assignments, CI signature, and CTEP registration requirements, as 
well as include a Master Task List. 
  
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website go to 
the Regulatory section and select Regulatory Submission. (27-AUG-2021) 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
 
Checking Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
x Click on Regulatory at the top of the screen; 
x Click on Site Registration; and 
x Enter the site’s 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 with in the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
8.2 
Patient Enrollment (23-AUG-2022)(25-JUL-2023) 
 
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 Lead Protocol Organization (LPOs) registration/randomization systems or 
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:   
x Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; 
x To perform enrollments or request slot reservations:  Must be on a LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type; (27-AUG-2021) 
x If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 

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x Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
x Patient has met all eligibility criteria within the protocol stated timeframes; and  
x All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please 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. 
 
9. 
DRUG INFORMATION  
 
9.1 
Investigational Study Agent: Durvalumab (MEDI4736) (NSC# 778709) 
 
9.1.1 Other Names: Imfinzi™ 
 
Classification: Anti-PD-L1 Mab 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Durvalumab (MEDI4736)  inhibits binding of programmed cell death 
ligand 1 (PD-L1) to PD-1 and CD80.  In-vitro studies demonstrate that durvalumab 
(MEDI4736) relieves PD-L1-mediated suppression of human T-cell activation.  
Durvalumab (MEDI4736) does not trigger antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity in cell-based functional assays. 
 
9.1.2 Description: Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody. 
 
9.1.3 How Supplied: Durvalumab (MEDI4736) is supplied by AstraZeneca, and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Durvalumab (MEDI4736) 
injection is a clear to slightly opalescent, colorless to slightly yellow solution for 
intravenous use.  Each vial contains 500 mg of durvalumab (MEDI4736) in 10 mL of 
solution.  Each 1 mL of solution contains 50 mg of durvalumab (MEDI4736) and is 

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formulated in: L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-
trehalose dihydrate (104 mg), polysorbate 80 (0.2 mg), and Water for Injection, USP. 
 
9.1.4 Preparation: Durvalumab (MEDI4736) solution for infusion must be diluted prior to 
administration.To prepare the infusion solution add the dose volume of durvalumab 
(MEDI4736) 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 1 mg/mL to 15 mg/mL. 
 
Infusion bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. 
 
9.1.5 Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return durvalumab (MEDI4736) 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. 
 
9.1.6 Stability: Refer to the package label for expiration. 
 
Total in-use storage time from needle puncture of durvalumab (MEDI4736) vial to start of 
administration should not exceed 8 hours at room temperature or 24 hours at 2-8°C (36-
46°F).  Prior to the start of the infusion, ensure that the bag contents are at room temperature 
(approximately 25°C) to avoid an infusion reaction due to the administration of the solution 
at low temperatures.   
 
9.1.7 Route of Administration: IV infusion 
 
9.1.8 Method of Administration: Infuse over approximately 60 minutes using an infusion set 
containing a 0.22 or 0.2 μm in-line filter.  No incompatibilities between durvalumab 
(MEDI4736) and polyethylene, polypropylene, polyvinylchloride, or polyolefin 
copolymers have been observed.  Flush the IV line with a volume of IV bag diluent 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. 
  
9.1.9 Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
 
9.2 
Olaparib (AZD2281) (NSC# 747856) 
 
9.2.1 Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
9.2.2 Other Names: AZD2281; KU-0059436; CO-CE 42 
 

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9.2.3 
Classification: PARP inhibitor 
 
9.2.4 CAS Registry Number: 763113-22-0 
 
9.2.5 Molecular Formula:  C24H23FN4O3  
M.W.: 434.46 
 
9.2.6 Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
9.2.7 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.  
 
9.2.8 Description: crystalline solid 
 
9.2.9 How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, 
film-coated tablets in 100 mg and 150 mg strengths.  
 
x 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
x 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.  
 
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. 
 
9.2.10 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.   
 
9.2.11 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. 
 
9.2.12 Route and Method of Administration:  Oral. Take tablets without regard to meals. 
 
9.2.13 Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 

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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 
caution when given concomitantly with olaparib. 
 
Patients who are taking warfarin may participate in this trial; however, it is recommended 
that international normalised ratio (INR) be monitored carefully at least once per week for 
the first month, then monthly if the INR is stable. Non-vitamin K antagonist oral 
anticoagulants (NOACs), subcutaneous heparin and low molecular weight heparin may be 
given concomitantly with olaparib and INR monitoring is not required. If NOACs are used, 
it is preferable to avoid CYP3A substrates (e.g apixaban and rivaroxaban) if possible. 
 
9.2.14 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 one (1) month after the last dose of olaparib.  It is not 
known whether olaparib is found in seminal fluid, so as a precaution, male study participants 
must use a condom during treatment and for three (3) months after the last dose and should 
avoid fathering a child or donating sperm during this same time period. 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. 
 

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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. 
 
9.3 
 Cediranib (NSC# 732208) 
 
9.3.1 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1- yl)propoxy] 
quinazoline maleate 
 
9.3.2 Other Names: cediranib maleate, AZD2171 maleate  
 
9.3.3 
Molecular Formula: C25H27FN4O3 · C4H4O4        M W: 566.59 (maleate salt), 450.52 (free 
base) 
 
9.3.4 
Approximate Solubility: The aqueous solubility of cediranib (AZD2171) is 0.0006 mg/mL 
for the free base (distilled water, pH 8.1 at 25°C) and 1.76 mg/mL for the maleate salt 
(distilled water, at 25°C).  
 
9.3.5 
Mode of Action: Cediranib (AZD2171) is a highly potent tyrosine kinase inhibitor of all 
three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3). Inhibition of 
VEGF signaling leads to inhibition of angiogenesis, neovascular survival and vascular 
permeability. Pre-clinical tumor models show that cediranib (AZD2171) reduces micro-
vessel density and metastasis, indicating that it limits tumor growth. 
 
9.3.6 
How Supplied:  Astra-Zeneca supplies and CTEP, NCI, DCTD distributes cediranib 
(AZD2171). The agent is available as beige, round, biconvex, film-coated tablets containing 
15 mg, and 20 mg of cediranib (AZD2171) free base.  The 15 mg and 20 mg tablets are 7 
mm and 8 mm in diameter, respectively.  Each high-density polyethylene bottle contains 35 
tablets. 
 
In addition to the active pharmaceutical ingredient, tablet excipients include mannitol, 
dibasic calcium phosphate anhydrous, sodium starch glycolate, microcrystalline cellulose, 
and magnesium stearate with a film coat containing hypromellose 2910, polyethylene glycol 
400, red iron oxide, yellow iron oxide, black iron oxide, and titanium dioxide.  
 
9.3.7 
Storage: Store intact bottles at controlled room temperature 20°C to 25°C (68 to 77°F).  
 
If a storage temperature excursion is identified, promptly return cediranib (AZD2171) 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.   

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9.3.8 
Stability: Stability studies are ongoing. Dispense cediranib (AZD2171) tablets in their 
original containers. Alternatively, if exact quantity is dispensed in a pharmacy bottle, the 
supply should be assigned a 30-day expiration. 
 
9.3.9 
Route and Method of Administration:  Oral.   Cediranib (AZD2171) tablets should be 
taken either one hour before or two hours after meals.  
 
 
If the study sponsor determines appropriate, cediranib tablets may be administered as a 
dispersion in plain water. Liquids other than non-carbonated water should not be used and 
the tablets should not be crushed or ground. The following procedure is recommended by 
the manufacturer for patients who can swallow liquids: 
 
Drop the appropriate dose of cediranib tablet/s into a glass containing 50-60 mL non-
carbonated water. Stir the tablet/s until dispersed in the water, about 10 minutes (no 
crushing). Swallow the liquid immediately after dispersion is completed. Any residue in the 
glass is mixed with a half glass of water and swallowed. 
 
9.3.10 Potential Drug Interactions: Cediranib (AZD2171) clearance is primarily mediated by 
flavin-containing monooxygenase enzymes (FMO1 and FMO3) and UPDGT1A4. It is not a 
substrate of CYP450 enzymes. In vitro studies suggest that cediranib (AZD2171) is a 
substrate for P-glycoprotein (P-gp), but not breast cancer resistance protein (BCRP). 
Since clinically relevant induction or inhibition of FMO enzymes is uncommon, use caution 
in patients taking concomitant medications that are strong inhibitors (e.g. ketoconazole) 
or strong inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin and St. 
John’s Wort) of UPDGT1A4 or P-gp in particular. If chronic concomitant administration 
of strong inducers or inhibitors is unavoidable, consult the protocol document and/or the 
principal investigator before making any dose adjustments. 
 
 
In vitro studies using hepatic cultures show that cediranib (AZD2171) did not inhibit 
CYP 1A2, 2A6, 2C8, 2C9, 2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 
and 3A4/5. It did weakly inhibit CYP 2D6 and 3A4/5, but this inhibition not expected to 
cause any clinically relevant drug interactions.  The possibility that cediranib (AZD2171) 
may induce gastrointestinal CYP3A and UPDGT enzymes cannot be excluded; therefore 
the efficacy of hormonal contraceptives may be reduced. Advise women study 
participants to use an additional non-hormonal contraceptive method. 
 
In vitro studies show that cediranib (AZD2171) is a weak inhibitor of BCRP, P-gp, 
OATP1B1, OATP1B3, OCT2,MATE1, UGT isoforms 1A1, 1A4 and 2B7. Use caution 
in patients who are taking concomitant medications that are sensitive substrates although 
clinically relevant inhibition of any of these is considered unlikely. In vivo studies show 
that cediranib (AZD2171) could increase exposure of drugs like metformin by inhibiting 
renal tubular transporter MATE2-K, but this is thought to be infrequent and mild in 
severity. Cediranib is not an inhibitor of OAT1 or OAT3.  
 
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human serum albumin and α1-acid glycoprotein accounting for most of this binding. Use 
caution in patients taking concomitant medications with narrow therapeutic ranges that 
are also highly protein-bound. 
 
 
Oral anticoagulants are not absolutely contraindicated during treatment with AZD2171 
(cediranib); however, use cediranib (AZD2171) with caution and increase monitoring in 
patients while on study. Patients who receive VEGF inhibitors are at increased risk of 
bleeding and hemorrhage. 
 
9.3.11 Patient Care Implications: Agents that inhibit VEGF signaling have the potential to 
affect wound healing. For patients already enrolled onto the protocol, the manufacturer 
recommends holding cediranib (AZD2171) for 2 weeks prior to surgery and restarting 
when the surgical wound is healed. Protocol exclusion criteria should include patients 
who have had major thoracic or abdominal surgery within 2 weeks prior to start of study 
or patients with any surgical incision that is not fully healed.  
 
Advise women study participants of reproductive potential to use effective contraception 
while receiving study treatment and for at least 6 weeks after the last dose of cediranib 
(AZD2171). The efficacy of hormonal contraceptives may be reduced while receiving 
cediranib and an additional non-hormonal method should be considered. Men study 
participants should use a condom while receiving cediranib and for at least one week 
after the last dose. Refer to the protocol document for specific guidance. 
 
 
 
 
9.4 
Commercial Agent—Paclitaxel (NSC# 673089) 
 
 
 
  
9.4.1  Formulation:  
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi-dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition to 6mg of 
paclitaxel, each mL of sterile non-pyrogenic solution contains 527mg of purified 
Cremophor® EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
9.4.2   Storage/Stability  
Storage: Unopened vials of paclitaxel are stable to the date indicated on the package 
when stored between 20 to 25°C (68 to 77°F). Protect from light. 
 
Stability: Commercially available paclitaxel will be labeled with an expiration date. All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration 
of drug and the time elapsed after preparation, although when prepared as described 
below, solutions of paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 
hours. 
 
9.4.3 Preparation: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 
0.9% Sodium Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose 
and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a 
final concentration of 0.3 to 1.2mg/mL.  The solutions are physically and chemically 
stable for up to 27 hours at ambient temperature (approximately 25°C / 77°F) and room 

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lighting conditions.   
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be 
leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in 
bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags and 
administered through polyethylene-lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a microporous membrane 
not greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, 
which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant 
leaching of DEHP.   
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 
antagonists prior to paclitaxel administration in order to prevent severe hypersensitivity 
reactions. Patients who experience severe hypersensitivity reactions to paclitaxel may be 
re-challenged with the drug.  
 
9.4.4 Adverse Effects: Consult the package insert for the most current and complete 
information.  
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 
9.5 
Commercial Agent: Topotecan (NSC# 609699) 
 
9.5.1 Formulation:   
Topotecan is a cell cycle specific inhibitor of the nuclear enzyme topoisomerase I. It has 
a mean half-life of approximately three hours. Topotecan’s metabolism and clearance 
are complex but it is estimated that approximately 40% of the drug undergoes renal 
clearance.  
 
9.5.2 Supplier/How Supplied:   
Topotecan is commercially available and is supplied in a sterile form for intravenous use 
only.  
x Topotecan for Injection (lyophilized powder) is available generically as a sterile, 
lyophilized, buffered, light yellow to greenish powder available in single use vials 
containing topotecan hydrochloride equivalent to 4 mg of topotecan as the free base, with 
mannitol 48 mg and tartaric acid 20 mg. Hydrochloric acid and sodium hydroxide may be 
used to adjust the product pH.  Available products do not contain an antimicrobial 
preservative; thus any unused product should be discarded within 24 hours of initial vial 
entry. 
x Topotecan Injection (solution) is available generically in individually-packaged single-
use vials containing a sterile, non-pyrogenic, clear, yellow to yellow-green solution of 
topotecan HCl equivalent to 4 mg of topotecan as the free-base at a concentration of 1 
mg/mL.   

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9.5.3 Solution Preparation:   
 
Topotecan for Injection (lyophilized powder) reconstitution: 
x Reconstitute lyophilized topotecan HCl with 4 mL sterile Water for Injection, USP 
(SWFI), to produce a yellow to yellow-green solution with concentration equal to 1 
mg/mL and a pH within the range, 2.5 – 3.5. 
x Dilute an amount of drug appropriate for a patient’s dose in 50 – 250 mL of either 0.9% 
Sodium Chloride Injection (0.9%NS) or 5% Dextrose Injection (D5W), USP. 
 
 
  
Topotecan Injection (solution) reconstitution: 
x Each milliliter of solution contains topotecan hydrochloride equivalent to 1 mg of 
topotecan (free base), with 5 mg tartaric acid, NF, and SWFI. Hydrochloric acid and/or 
sodium hydroxide may be added to adjust product pH within the range 2.6 – 3.2. 
x Dilute an amount of Topotecan Injection (1 mg/mL) appropriate for a patient’s dose in a 
minimum volume of 50 mL of either 0.9% Sodium Chloride Injection (0.9%NS) or 5% 
Dextrose Injection (D5W), USP. 
 
9.5.4  Storage/Stability:   
Topotecan for Injection (lyophilized powder) storage and stability: 
x Store intact vials protected from light in the original cartons at controlled room 
temperature between 20° – 25°C (68° – 77°F). 
x After reconstitution with SWFI, vials should be used immediately.  
x After dilution with 0.9% NS or D5W, solutions prepared with Topotecan 
Injection are stable for at least 24 hours when stored at 20° – 25°C under ambient 
lighting conditions. 
 
 
Topotecan Injection (solution) storage and stability: 
x Store intact vials under refrigeration at 2° – 8°C (35.6° – 46.4°F) and protected  
from light in the original packaging carton. 
x After dilution with 0.9% NS or D5W, solutions prepared with Topotecan 
Injection are stable for 24 hours when stored at 20° – 25°C (68° – 77°F) under 
ambient lighting. 
 
9.5.5   Adverse effects:  
¾ Hematologic:  thrombocytopenia, leukopenia, anemia, neutropenia 
¾ Gastrointestinal:  nausea and vomiting, mucositis, diarrhea 
¾ Skin: rash 
¾ Other:  alopecia, fever, flu-like symptoms 
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 
9.6 
Commercial Agent: Pegylated Lipomosal Doxorubicin (PLD) 
 
Pegylated liposomal doxorubicin (PLD) is commercially available.  All commercially 
available sources are allowed including: 

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x Generic PLD (http://www.caraco.com/outserts/Doxorubicin%20HClLip.pdf) 
x Lipodox ® 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203263lbl.pdf) 
x Doxil ® (http://www.doxil.com/assets/DOXIL_PI_Booklet.pdf) 
 
Refer to the PLD package insert (Doxil, Lipodox™) for the most complete and current 
information on the following: 
 
9.6.1 Formulation:   
PLD (doxorubicin HCl liposome injection) is supplied as a sterile, translucent, red 
liposomal dispersion in 5 mL (Lipodox only), 10 mL, or 30 mL glass, single-use vials. 
Each vial contains doxorubicin HCl at a concentration of 2 mg/mL.  
 
9.6.2 Storage:  
Refrigerate unopened vials of PLD at 2°–8°C (36°–46°F). Avoid freezing. Prolonged 
freezing may adversely affect liposomal drug products; however, short-term freezing 
(less than 1 month) does not appear to have a deleterious effect on PLD. 
 
9.6.3 Preparation:  
PLD doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior 
to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose 
Injection, USP prior to administration. Aseptic technique must be strictly observed since 
no preservative or bacteriostatic agent is present in PLD. Diluted PLD should be 
refrigerated at 2°C–8°C (36°F–46°F) and administered within 24 hours. 
x Do not mix with other drugs. 
x Do not use with any diluent other than 5% Dextrose Injection.  
x Do not use any bacteriostatic agent, such as benzyl alcohol.  
x PLD is not a clear solution but a translucent, red liposomal dispersion.  
x Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Do 
not use if a precipitate or foreign matter is present.  
x Do not use in-line filter. 
 
9.6.4 Procedure for Proper Handling and Disposal:   
Caution should be exercised in the handling and preparation of PLD.  
 
The use of gloves is required.  
If PLD comes into contact with skin or mucosa, immediately wash thoroughly with soap 
and water.  
PLD should be considered an irritant and precautions should be taken to avoid 
extravasation. With intravenous administration of PLD, extravasation may occur with or 
without an accompanying stinging or burning sensation, even if blood returns well on 
aspiration of the infusion needle. If any signs or symptoms of extravasation have 
occurred, the infusion should be immediately terminated and restarted in another vein. 
PLD must not be given by the intramuscular or subcutaneous route.  
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drugs.  
 
 
9.6.5 Adverse Effects:  Consult the PLD package insert for the most current and complete 
information. 
 
9.6.6 Supplier: Commercially available from Ortho Biotech Products, LP Raritan, NJ  
(DOXIL) and Caraco Pharmaceutical Laboratories Ltd, Detroit, MI (Lipodox).  
 
Consult the American Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 
9.7 
Agent Ordering and Agent Accountability 
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.   
 
9.7.1 Investigator Brochure Availability 
The current versions of the durvalumab, olaparib, and cediranib IB(s) will be accessible 
to site investigators and research staff through the PMB OAOP application. Access to 
OAOP requires the establishment of a CTEP IAM account and the maintenance of an 
“active” account status, a “current” password and active person registration status.  
Questions about IB access may be directed to the PMB IB Coordinator via email. 
 
9.7.2 Agent Accountability 

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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. 
 
9.7.3 PMB Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov   
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP   
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator: IBCoordinator@mail.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
 
9.7.4 Blood Pressure Cuffs 
A patient who is randomized to Arm II, II or IV will be given a blood pressure cuff.  
Blood pressure cuffs that are supplied for this study, are only to be used for this study.   
 
9.7.4.1 Supply and Distribution: Blood pressure cuffs will be supplied and distributed by 
VWR. Each kit contains a blood pressure monitor (which includes standard size cuff), an 
adaptor and a large size cuff. Kits will be shipped in the original manufacturer’s 
packaging.  
 
9.7.4.2 Ordering Instructions: No starter supplies are available. Sites are permitted to order a 
maximum of 10 Blood Pressure kits at a time for enrolled patients in cediranib-containing 
arms (Arms II, III, and IV). To obtain the kits, please complete the “Shipment 
Authorization Form” and email to Lisa Rutter at lisa.rutter@vwr.com and also include 
Lucy Andrews (lucy.andrews@vwr.com) and Stacey Brackley 
(stacey.brackley@vwr.com). The form is available on the CTSU website. Please allow 72 
hours to process and ship orders.  If request is received at 4:30pm UK time, processing 
time will be 3 days beginning the following day. 
 
10. 
PATHOLOGY/BIOSPECIMEN 
 
10.1 
Central Pathology Review Guidelines 
Not applicable 
 

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10.2 
Biospecimen Selection for Integral Biomarker Testing 
Not applicable 
 
10.3 
Biospecimen Selection for Integrated Biomarker testing 
Not applicable 
 
 
10.4 
Biospecimen Submission Tables 
Biospecimens listed below should not be submitted until after patient registration and 
Bank ID assignment. A detailed description of biospecimen procedures can be found in 
Appendix VI. 
 
10.4.1 Mandatory Biospecimen Submissions  
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s specimens as outlined below. 
 
Required Biospecimen (Biospecimen Code) 
Collection Time Point 
Sites Ship To 
FFPE TUMOR TISSUE (Submit one of the following – Listed in order of preference) 
FFPE Recurrent Primary or Recurrent 
Metastatic Tumor (FRP01 or FRM01)1 
Block must be submitted2 
Prior to study treatment 
NRG Oncology BB-
Columbus within 8 
weeks of registration3 
FFPE Persistent Primary or Persistent 
Metastatic Tumor (FPP01 or FPM01)1 
Block must be submitted2 
FFPE Primary or Metastatic Tumor (FP01 or 
FM01)1 
Block must be submitted2 
Prior to all treatment 
BLOOD BIOSPECIMENS 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) tube(s) 
Prior to study treatment 
NRG Oncology BB-
Columbus the day 
collected3 
1 
A copy of the corresponding pathology report must be shipped with all tissue biospecimens sent to the 
NRG BB-Columbus. 
2 
Only blocks will be accepted. Please provide Appendix XII to your pathologist. 
3 
NRG Oncology BB-Columbus / Protocol NRG-GY023, 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 
Biospecimen Selection for Exploratory Biomarker Testing 
Biomarker testing of banked biospecimens will not occur until an amendment to this 
treatment protocol or separate correlative science protocol is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
 
10.5.1 PD-L1 and Tumor Infiltrating Lymphocyte Immunohistochemistry 
Upon approval, the NRG Biospecimen Bank-Columbus will fresh-cut unstained sections 
of FFPE tumor for distribution to TBD for PD-L1 and tumor infiltrating lymphocyte 
(TIL) immunohistochemistry (IHC). 
 

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10.5.2 Homologous Recombination Deficiency 
Upon approval, DNA extracted from whole blood and formalin-fixed, paraffin-embedded 
(FFPE) tumor will be batch shipped by the NRG BB-Columbus to Dr. Elizabeth Swisher 
for BROCA-HR testing. 
 
Special Note Regarding Genetic Testing: Given the potential clinical implications 
conferred by detecting a germline mutation in one of these proven cancer genes, the 
following disclosure procedure articulated by the American College of Medical 
Genetics and Genomics will be followed. 
 
1. For each subject with a clinically actionable result from BROCA sequencing, the 
testing laboratory will contact the NRG study PI at the enrolling institution to notify 
them that a research test result of potential clinical importance has been identified in 
one of their study participants. Please include the mutation in the genetic counselor’s 
report and place a copy of the report in the research record. 
2. The PI at the enrolling institution will be responsible for contacting the study 
participant to inform them that study-related research has uncovered genetic 
information that might affect their clinical care. Each participant can then: 
a. Elect not to receive the information, which will be retained by the enrolling 
physician in the event that the participant changes their mind at a later date.  
b. Elect to receive the information, in which case pre-test counseling should be 
provided prior to clinical testing of a freshly drawn blood sample. After being 
counseled, the patient may (i) decide not to undergo clinical testing for the 
mutation identified under research, or (ii) decide to undergo clinical testing, in 
which case a new blood sample will be collected at the enrolling site and shipped 
directly to the CLIA-approved laboratory for mutation confirmation at no cost to 
the patient. The clinical genetic test result will be returned to the clinicians 
involved in counseling and managing this aspect of the patient's care and it will be 
their responsibility to disclose the results to the patient. 
 
10.6 
Banking Biospecimens for Future Research 
Biomarker testing of banked biospecimens will not occur until an amendment to this 
treatment protocol or separate correlative science protocol is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
 
Details regarding the banking and use of biospecimens for future research can be found in 
Appendix X. 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
Not Applicable 
 
12. 
ASSESSMENT OF EFFECT 
  
12.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 

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guideline (version 1.1). [Eur J Ca 45:228-247, 2009] Changes in the largest diameter 
(uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria.  
  
12.1.1 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured 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 

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measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
  
 
12.1.2 Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
  
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans), but NOT lung. 
  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline, and the lesions should be 

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measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible. If possible, body 
scans should be performed with breath-hold scanning techniques. 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases, e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when measurable disease has met criteria for 
response or stable disease. This confirmation is necessary to differentiate response or 
stable disease versus progressive disease, as an effusion may be a side effect of the 
treatment. 
 
12.2 
Response Criteria 
Determination of response should take into consideration all target (See 12.2.1) and non-
target lesions (See 12.2.2). 
 
12.2.1 Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 

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more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters (i.e. the nadir) while on 
study.  
 
12.2.2 Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) Progressive Disease 
(PD): Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion 
increase. 
  
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular 
time point. 
  
Although a clear progression of only “non-target” lesions is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
12.2.3 Evaluation of Best Overall Response  
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest sum recorded since baseline). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria in some 
circumstances. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion 
 
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

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accepted as disease progression. 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline 
(i.e., Non-Target Disease) 
 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion 
 
** ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.2.4 Best Overall Confirmed Response  
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error.  
This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required confirmation in such trials. 
 
However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies 
where stable disease or progression are the primary endpoints, confirmation of response 
is not required since it will not add value to the interpretation of results.  Therefore, for 
GY023, confirmation of response is not required. 
 
Time Point Response 
First time point 
Time Point Response 
Subsequent time 
point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD 
duration met, otherwise, PD 
Non-Target Lesions 
New Lesions* 
Time Point 
Response 
CR 
No 
CR 
CR 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

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

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Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since date of study entry, including the baseline measurements. 
 
12.4 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression or death, whichever occurs first.  Patients who are alive without 
documentation at the time of analysis will censored on the date of last tumor assessment. 
Disease progression will be defined using RECIST v1.1 criteria (Section 12.2), as 
determined by the treating physician. 
 
12.5 
Overall Survival 
Overall Survival (OS) is defined as the duration of time from study entry to date of death 
from any cause.  A subject who has not died will be censored on the date that they were 
last known to be alive.   
 
13. 
DATA AND RECORDS 
 
13.1 
Data Submission/Data Reporting (23-AUG-2022)(25-JUL-2023) 
Medidata Rave is the clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
Requirements to access Rave via iMedidata: 
x Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
x 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; 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only or RAVE SLA role must have at a minimum an 
Associate (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory Application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in 

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the email or log in to iMedidata via the CTSU members’ website under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right-corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under under the study name. 
  
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in the Regulatory application will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Data Management section under the 
Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU members’ website 
in the Data Management > Rave section or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.   
 
Rave-CTEP-AERS integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting. Sites must initiate all AEs for this study in 
Medidata Rave. 
 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period is used to collect AEs that start during the period or 
persist from the previous reporting period. AEs that occur 30 days after the last 
administration of the investigational agent/intervention are collected using the Late 
Adverse event form.  
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct; and 
x 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 (i.e., checking the 

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box Send All AEs for Evaluation and save the form). Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting. A report is initiated in 
CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements. The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form. Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited reports in CTEP-AERS. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
x Study specific documents: Protocols > Documents> Protocol Related 
Documents>Adverse Event Reporting; and   
x Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
Data Quality Portal  
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports. Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website. Staff who have Rave study access can access the Rave study data vis 
direct links available in the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 

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a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
13.2 
NRG Data Management Forms 
Refer to the CTSU member website for the table of Required Forms and Materials 
 
13.3 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.   
 
DMU Light Monitoring 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via 
the DMU.  DMU Light reporting consists of Patient Demographics, On/Off Treatment 
Status, Abbreviated Treatment and Course information, and Adverse Events as 
applicable.  Instructions for setting up and submitting data via DMU are available on the 
CTEP Website:  (https://ctep.cancer.gov/protocolDevelopment/dmu.htm).   
 
Note:  All adverse events (both routine and serious) that meet the protocol mandatory 
reporting requirements must be reported via DMU in addition to expedited reporting of 
serious adverse events via CTEP-AERS.   
 
14. 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This is as a 4-arm randomized phase II study to assess whether the experimental arms 
provide superior efficacy relative to the standard of care (SOC).  The design includes an 
interim futility when about 60% information is available in any pair of the SOC arm and 
one of the experimental arms.  The four treatment arms are defined in Section 5.1.  (23-
AUG-2022) 
 
The randomization procedure will assign each experimental arm to 2 patients, for every 1 
patient randomized to the SOC arm.  The randomization procedure tends to balance the 

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treatment allocation within patient-level stratification factors. The randomization will be 
stratified by:  
 
1) Any prior immune checkpoint inhibitor (Yes/No) 
2) Any prior PARP inhibitor (Yes/No) 
 
A web-based enrollment procedure will be used to register patients onto the study. 
Immediately after a subject 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 treatments will be sequentially drawn from pre-allocated 
blocks of randomly permuted treatments, which are created for each stratum. The 
treatment assignments will be revealed to institutions and patients after registration is 
complete. 
   
14.2 
Study Endpoints 
 
Primary Endpoint: Progression Free Survival (PFS), as defined in Section 12.4.  The 
following censoring rules will also be applied: 
1) Patients who are alive without documentation of disease progression at the time of 
analysis will censored on the date of last tumor assessment. 
2) Patients who initiate a non-protocol anticancer therapy will be censored on the date of 
her last assessment prior to beginning that therapy 
3) Patients who have no post-enrollment assessments will be censored 1 day after 
enrollment 
 
Secondary Endpoints 
1) Objective Response Rate (ORR), quantified as the binomial proportion of patients 
with measurable disease at enrollment who have a Best Overall Response of CR or 
PR, as defined in Section 12.2 
2) Duration of Response is defined in Section 12.3 
3) Overall Survival, as defined in Section 12.5 
4) 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.  
 
14.3 
Primary Objectives Study Design 
 
The primary objective is to assess whether of the experimental regimens provide superior 
efficacy (PFS) relative to the standard of care.  The specific hypotheses are described 
below. 
 
14.3.1 Primary Hypothesis and Endpoints 
 
The null and alternative hypotheses for comparing the PFS hazards of treatment arms (i,j) 
are: 
 

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ܪ0௜/௝: Δ୧,୨=
ఒ೔
ఒೕ≥1.0  vs  ܪܣ௜/௝: Δ୧,୨< 1.0
where (λi, λj) are the PFS hazards in arms (i,j) respectively, and Δi/j is the corresponding 
hazard ratio.  All hypotheses are assessed with one-sided log-rank tests.
14.3.2 How Primary Endpoints Will Be Analyzed
The null hypotheses are rejected for the superiority of arm(i) over arm(j).  The following 
diagram shows the hypothesis testing strategy.
The first gatekeeping hypothesis compares the triplet arm(2) to the SOC arm(1), rejecting 
at α level =0.10.  If this test fails to reject, formal testing of the other hypotheses will 
stop.  If this test rejects, the doublet arms (3) and (4) are separately compared to the SOC 
arm(1), each test rejecting at α level =0.10.  The triplet arm (2) will then be compared to 
the doublet arms(3,4) that demonstrate superiority over the SOC arm(1), with each test 
rejecting at α level =0.15.  If found to be superior to either doublet, the triplet arm will be 
considered interesting for future research. If one test fails to reject, arms demonstrating 
superiority on previous tests in the hierarchy will be considered interesting for future 
research.
The primary analyses will be based on a stratified logrank test, including all patients 
enrolled onto the study regardless of compliance to their assigned study regimen. Patients 
will be grouped by their randomized treatment for intention-to-treat analyses (ITT).  
Treatment hazard ratios and 90% confidence intervals will be estimated using a 
proportional hazards model specified with a main-effect for the randomized treatment 
assignment (experimental ref: SOC) and stratified by the randomization stratification 
factors. 
The final analysis will be done when at least 18 PFS events are observed in the SOC Arm 
(which is the expected number to occur with 47 events total for each Hi/1 comparison 
when the hazard ratio is Δi/1 = 0.50.  If warranted, the triplet arm(2) comparisons to 
doublet arms(3,4) that are superior to the SOC will be done at this time.

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A proportional hazards model will be used to estimate the treatment hazard ratios and 
corresponding confidence interval, after adjusting for the patients’ stratification values. 
Time to event endpoints will be presented by Kaplan Meier methods.  Product-limit 
methods will be used to estimate the cumulative distribution of PFS duration for each of 
the study treatments. 
 
14.3.3 Sample Size and Power Calculations:  
 
Total accrual of at least 164 patients is expected.  When accrual matures, 23 patients are 
expected in the SOC arm, and 47 in each experimental arm.  
 
For experimental arm comparisons to the SOC arm (Δi/1 i ϵ {2,3,4}) with one-sided 
α=0.10, a total of 47 PFS events has power=0.80 to detect a hazard ratio of Δi/1 = 0.50.   
 
The design parameters are based on the following piecewise-hazard assumptions for the 
SOC arm, obtained from control arm of the AURELIA trial48.  
 
Months from 
Enrollment 
Proportion 
Alive and 
Progression 
Free 
0 
100 
1.5 
90 
3.4 
50 
6.0 
20 
15 and beyond 
1.0 
 
If the PFS times are exponentially distributed, and the median PFS is 3.4 months in the 
SOC arm, a hazard ratio of Δi/1 =0.50 corresponds to a median PFS of 6.8 months in the 
experimental arm. The relationship between power and the minimum detectable hazard 
ratio (HR) is shown in the table below.  If the true Δi/1 is 0.60, the power decreases to 
0.61. 
 
HR 
Power 
0.50 
0.80 
0.55 
0.71 
0.60 
0.61 
 
 
14.4 
Study Monitoring of Primary Objectives 
 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 

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on an “as needed” basis.  
 
Consent withdrawals are individually reviewed and approved by the study data manager 
as part of routine data curation processes.  Withdrawas and other reasons for 
discontinuation are summarized and monitored in all routine DMC reporting.  If 
discontinations are frequent enough to potentially jeoprodize the primary objectives, an 
appropriate course of action will be determined by a blinded, ad hoc committee with 
representation from the study chair, NRG clinical and statistical leadership, and the 
sponsor.  If deemed necessary by this group, a drafted protocol amendment will be 
developed and presented to the DMC for input on patient safety. 
 
The design includes an interim futility analysis to occur when a total of 28 PFS events 
(60% information) are observed in any pair of arm(1) and one of the experimental arms. 
This is expected to occur approximately 11 months after starting accrual. If the HR (Δi/1 i 
ϵ {2,3,4}) estimate is >0.87, consideration will be given to dropping arm (i) for futility. 
The SOC arm(1) will not be dropped unless all experimental arms demonstrate futility.  
The probability of futility for an experimental arm is 0.66 under the null hypothesis, and 
0.09 under the alternative hypothesis (i.e., 0.09 of the 0.20 beta is spent at the interim 
analysis).  The interim analysis results will be examined by the NRG Oncology Data 
Monitoring Committee. The decision to terminate accrual to an arm may include 
consideration of toxicities, treatment compliance, and progression-free survival and other 
endpoints, and results from external studies. 
 
If the study is still accruing patients, accrual will not be suspended for the interim 
analysis. 
 
14.5 
Accrual/Study Duration Considerations 
 
With an accrual rate of 10 eligible patients per month (1.3 patients per month for the SOC 
arm, 2.9 for each experimental arm), a sample size of 164 patients will accrue over 16.4 
months.  At this time, 23 patients are expected in the SOC arm, and 47 in each 
experimental arm.  A follow-up period of 1.0 month should provide the needed number 
of events. Total study duration is estimated to be 17.4 months.  
 
 
 
 
 
14.6 
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 
2 
0 
0 
0 
2 
Asian 
10 
0 
0 
0 
10 
Native Hawaiian or Other 
Pacific Islander 
1 
0 
0 
0 
1 

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Black or African American 
10 
0 
0 
0 
10 
White  
132 
0 
6 
0 
138 
More Than One Race 
0 
0 
3 
0 
3 
Total 
155 
0 
9 
0 
164 
 
 
 
 
 
 
 
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 
 
 
 
 
 
Asian 
 
 
 
 
 
Native Hawaiian or Other 
Pacific Islander 
 
 
 
 
 
Black or African American 
 
 
 
 
 
White  
 
 
 
 
 
More Than One Race 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

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

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APPENDIX III-GENERAL THERAPY GUIDELINES 
 
x For cycle lengths greater than or equal to 21 days, a patient will be permitted to 
have a new cycle of chemotherapy delayed up to 7 days (without 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. 
x 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 cycle lengths greater than or equal to 21 days.  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). 
x 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. 
x 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). 
x 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

NRG-GY023 
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Version Date: July 25, 2023 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), 
if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected. Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
E-mail: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
 
 
 
 

NRG-GY023
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Version Date: July 25, 2023
APPENDIX V-DURVALUMAB (MEDI4736) CLINCAL TRIAL WALLET CARD
CLINICAL TRIAL WALLET CARD
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room.
Patient Name:  
Diagnosis:  
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #:  NRG-GY023
Study Drug(S): MEDI4736 (durvalumab)
For more information: 
1-800-4-CANCER
cancer.gov 
clinicaltrials.gov

NRG-GY023 
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Version Date: July 25, 2023 
 
APPENDIX VI- CEDIRANIB PATIENT DRUG INTERACTIONS HANDOUT AND 
WALLET CARD  
 
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): 
Cediranib 
(AZD2171) 
 
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.  
 
These are the things that your healthcare providers need to know: 
Cediranib (AZD2171) interacts with certain enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
 
Explanation 
CYP 
isoenzymes  
 
 
 
 
 
The enzymes in question are CYP 3A4, 2D6, flavin-containing 
monooxygenase (FMO) and UGT1A4. Cediranib (AZD2171) is metabolized 
by FMO1, FMO3 and UGT1A4 and may be affected by other drugs that 
strongly inhibit or induce these enzymes.  Cediranib (AZD2171) weakly 
inhibits CYP 2D6 and 3A4 and may increase levels of affected substrates.  
Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, 
therefore potentially reducing the effectiveness of hormonal contraceptives.  
 
Cediranib (AZD2171) is 95% protein bound (human serum albumin and 
alpha-1-acid glycoprotein) and may displace other highly protein-bound drugs. 
Use caution in patients taking concomitant medications with narrow 
therapeutic ranges.   
 
 
Protein 
transporters 
 
The transport proteins in question are P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). Cediranib (AZD2171) requires P-gp to move in 
and out of cells. Cediranib (AZD2171) inhibits P-gp, BCRP and MATE2-K 
which may affect the clearance of other drugs that are dependent on these 
transport proteins.  
 
 
 
These are the things that you need to know: 
The study drug cediranib, may interact with other drugs which can cause side effects.  For this 

NRG-GY023 
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Version Date: July 25, 2023 
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 FMO1, FMO3, UGT1A4 and P-gp.” Cediranib (AZD2171) inhibits 
enzymes “CYP 2D6 and 3A4, transport proteins P-gp, BCRP and MATE2-K and is highly 
protein-bound.” These characteristics may change how other medicine works in your body.  
 
x 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. 
x Cediranib (AZD2171) may potentially reduce the effectiveness of hormonal 
contraceptives. Please check with your study provider about using contraception while on 
study treatment. 
x Patients receiving Cediranib (AZD2171) are at increased risk of bleeding. If you are 
receiving anticoagulation therapy, you will be monitored more frequently.  
x Make sure your doctor knows to avoid certain prescription medications.  
x 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.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version DEC 2019 
 
 
 
 
 

NRG-GY023
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Version Date: July 25, 2023
EMERGENCY 
INFORMATIO
N
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  
Cediranib interacts with: CYP 3A4, 2D6, FMO and UGT1A4 which are needed 
to clear cediranib from the body; transport proteins P-gp, needed to move 
cediranib in and out of cells; and P-gp, BCRP and MATE2-K needed to clear 
other drugs from the body. Cediranib must be used very carefully with other 
medicines.
Patient Name: 
Use caution and avoid the 
following drugs if possible:
Hormonal contraceptives
Your healthcare providers should be aware of any medicines that are “strong 
inducers/inhibitors of FMO1, FMO3, UGT1A4 and P-gp.” Cediranib (AZD2171) 
inhibits enzymes “CYP 2D6 and 3A4, transport protein, P-gp. BCRP and
MATE2-K and is highly protein-bound.”
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): 
Cediranib 
(AZD2171)
             Version DEC/2019
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
Fold at dotted lines:
     
  
  
            

NRG-GY023
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Version Date: July 25, 2023
APPENDIX VII- OLAPARIB PATIENT CLINICAL TRIAL WALLET CARD 
CLINICAL TRIAL WALLET CARD
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room.
Patient Name:  
Diagnosis:  
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #:  NRG-GY023
Study Drug(S):  olaparib
For more information: 
1-800-4-CANCER
cancer.gov 
clinicaltrials.gov

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Version Date: July 25, 2023 
APPENDIX VIII-ARM 2 CEDIRANIB AND OLAPARIB PATIENT DRUG DIARY (23-
AUG-2022) 
 
Today’s Date ______________________________ Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
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. 
CEDIRANIB 
Take ____ (number) _____ mg tablets once a day. 
Take on an empty stomach 1 hour before taking 
the morning dose of olaparib. 
OLAPARIB 
Take _____ (number) ______ mg and _____ (number) _____ mg 
tablets twice a day 12 hours apart. 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/2021 
2 
0 
7:00 
1 
1/1/2021 
2 
0 
8:00 
8:00 
1 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature ____________________________                    Date______________ 

NRG-GY023 
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Version Date: July 25, 2023 
APPENDIX IX-ARM 3 CEDIRANIB PATIENT DRUG DIARY (23-AUG-2022) 
 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle (28 days).  
3. Record the date, the number of pills you took, and when you took them.  
4. Bring your pill bottles (including empty bottles) and this form to every appointment. 
5. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
6. 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. 
7. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
 
 
 
 
 
 
 
 
 
 
CEDIRANIB 
Take __(number) ____mg and __(number) ____ mg tablets once daily. Take on an empty stomach. 
Day 
Date 
15mg 
20mg 
AM 
1 
1/1/2021 
2 
0 
7:00 
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’s Signature ____________________________                    Date______________ 
 
 

NRG-GY023 
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Version Date: July 25, 2023 
APPENDIX X-ARM 4 CEDIRANIB AND OLAPARIB PATIENT DRUG DIARY (23-
AUG-2022) 
 
Today’s Date ______________________________ Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
7. Complete one form for each cycle (28 days). 
8. Record the date, the number of tablets you took, and when you took them. 
9. Bring your pill bottles (including empty bottles) and this form to every appointment. 
10. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
11. 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. 
12. 
The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
CEDIRANIB 
Take ____ (number) _____ mg tablets once a day. 
Take on an empty stomach 1 hour before taking 
the morning dose of olaparib. 
OLAPARIB 
Take _____ (number) ______ mg and _____ (number) _____ mg 
tablets twice a day 12 hours apart. 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/2021 
2 
0 
7:00 
1 
1/1/2021 
2 
0 
8:00 
8:00 
1 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature ____________________________                    Date______________ 

NRG-GY023 
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Version Date: July 25, 2023 
APPENDIX XI- PATIENT BLOOD PRESSURE DIARY 
 
Today’s Date ___________________________ 
Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
Instructions to the Patient: 
1. Your blood pressure readings have two numbers. The first number is the pressure in your blood vessels during a heart 
beat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic). 
These numbers are usually written with a slash in between them (for example, normal blood pressure is 120/80). 
2. Record the date, then record your blood pressure twice each day using a home blood pressure monitor. 
x Each morning while you are resting (not while you are active: dressing, making breakfast, etc.) 
x Each evening at bedtime or while you are relaxing during the evening 
3. If you take your blood pressure at other times, record the numbers and time under “Other Readings.” 
4. If your systolic pressure is greater than 140 OR your diastolic blood pressure is greater than 90, please contact your 
local doctor’s office at __________________________ for instructions. 
5. Please bring this form to every clinic visit or appointment. 
Day 
Date 
AM 
Readings 
PM 
Readings 
Other 
Readings 
(include 
time) 
Day 
Date 
AM 
Readings 
PM 
Readings 
Other 
Readings 
(include 
time) 
1 
 
/ 
/ 
 
15 
 
/ 
/ 
 
2 
 
/ 
/ 
 
16 
 
/ 
/ 
 
3 
 
/ 
/ 
 
17 
 
/ 
/ 
 
4 
 
/ 
/ 
 
18 
 
/ 
/ 
 
5 
 
/ 
/ 
 
19 
 
/ 
/ 
 
6 
 
/ 
/ 
 
20 
 
/ 
/ 
 
7 
 
/ 
/ 
 
21 
 
/ 
/ 
 
8 
 
/ 
/ 
 
22 
 
/ 
/ 
 
9 
 
/ 
/ 
 
23 
 
/ 
/ 
 
10 
 
/ 
/ 
 
24 
 
/ 
/ 
 
11 
 
/ 
/ 
 
25 
 
/ 
/ 
 
12 
 
/ 
/ 
 
26 
 
/ 
/ 
 
13 
 
/ 
/ 
 
27 
 
/ 
/ 
 
14 
 
/ 
/ 
 
28 
 
/ 
/ 
 
Patient’s Signature: ___________________________________________        Date: ___________________ 
Physician’s office will complete this section: 
Date of this clinic visit ___________________ 
Physician/Nurse’s Signature __________________________________             Date _______________ 
 
 

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Version Date: July 25, 2023 
APPENDIX XII- ORAL ANTIHYPERTENSIVE MEDICATIONS.  
 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential 
drug-interactions with cediranib through CYP450. Agent classes are listed in order of 
preference in the absence of any other compelling indication, such as impaired renal 
function, proteinuria, etc. Note that each agent’s dosing should be maximized before being 
replaced or adding another agent class. 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediat
e dose 
Maximum 
dose 
Hepatic 
metabolism 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x 
daily 
50 mg 3x 
daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg 
daily 
40 mg daily Yes (CYP450 
unknown) 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 40 mg daily 
Yes, but not 
CYP450 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg 
daily 
CYP 3A4 and 
2C9 substrate 
candesartan 
4 mg daily 
8-16 mg 
daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg 
daily 
CYP 2C9 
substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg 
daily 
Yes, but not 
CYP450 
Selective 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 

NRG-GY023 
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Version Date: July 25, 2023 
E Blockers 
(BB) 
atenolol 
25 mg daily 
50 mg daily 
100 mg 
daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg 
daily 
20 mg daily 
CYP 3A4 
substrate 
D and E 
Blocker 
labetalol 
100 mg twice 
daily 
200 mg 
twice daily 
400 mg 
twice daily 
Yes, but not 
CYP450 
Diuretics 
Hydralazine 
10 mg four 
times daily 
25 mg four 
times daily 
50 mg four 
times daily 
no 
Hydrochlorot
hiazide 
12.5 mg AM 
daily 
25 mg AM 
daily 
50 mg AM 
daily 
no 
Furosemide  
20 mg daily 
20 mg twice 
daily 
40 mg twice 
daily 
no 
Ni 
trates 
Isosorbide 
dinitrate ER 
40 mg daily 
40 mg twice 
daily 
80 mg twice 
daily 
CYP 3A4 
substrate 
Isosorbide 
mononitrate 
ER 
30 mg AM 
daily 
60 mg AM 
daily 
90 mg AM 
daily 
CYP 3A4 
substrate 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 
60 mg daily 90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate  
 
 
 
 
 
 

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Version Date: July 25, 2023 
APPENDIX XIII– TRANSLATIONAL SCIENCE BIOSPECIMEN PROCEDURES  
(23-AUG-2022) 
 
1. Obtaining a Bank ID for Translational Science Biospecimens 
 
An NRG Bank ID is automatically assigned once the biospecimen consent questions are 
completed in Rave. the biospecimen consent questions ae located on the Specimen Consent. The 
NRG Bank ID will appear at the top of the biospecimen transmittal forms located in the 
Translational Research Folder in Rave. 
 
All biospecimens and accompanying paperwork must be labeled with this coded patient number. 
 
Please contact Support if you need assistance (Email: support@nrgoncology.org). Do not contact 
the NRG Biospecimen Bank, as the bank is not responsible for NRG Bank ID assignment. 
 
2. Requesting Translational Science Biospecimen Kits 
 
Biospecimen kits are not provided for this study. 
 
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. Redact personally 
identifiable information, including name, medical record/account numbers, etc. Do not redact the 
surgical pathology ID number, block number, or collection date. A completed copy of the 
Pathology Materials Verification Form (Appendix XI) 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: 
x 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. 
x Primary (FP01) or metastatic (FM01) tumor should be collected prior to all treatment. 
 
3.1.2 FFPE Type 
Only blocks will be accepted. Please provide Appendix XII 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: 

NRG-GY023 
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Version Date: July 25, 2023 
 
 *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 (23-AUG-2022) 
The type of biospecimen (block) should be specified on Form TR. 
 
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 
Whole Blood 
 
4.1.1 Collection Time Points 
Whole blood should be collected prior to study treatment as per Section 10.4.1. 
 
4.1.2 Collecting Whole Blood 
1.  Label the lavender/purple top (EDTA) collection tube as described above. Do not use glass 
blood collection tubes. 
2. Draw 10mL 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 

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Version Date: July 25, 2023 
collected. If the specimen absolutely cannot be shipped the day it is collected, please contact 
the NRG BB-Columbus. 
 
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. 
 
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 
 
x Translational science biospecimens should not be shipped until after patient registration and 
Bank ID assignment. 
x An electronically completed copy of the biospecimen transmittal form must be included for 
each translational science biospecimen. 
x All translational science biospecimens should be shipped to: 
 
NRG BB-Columbus / Protocol NRG-GY023 
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 
Pathology Materials Verification Form (Appendix XI) should be shipped using your own 
container at your own expense to the NRG BB-Columbus at the address above.  

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Do not ship FFPE tissue for Saturday delivery. 
 
6.2 
Whole Blood Shipped to the NRG BB-Columbus 
x 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. 
x 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.  
 
6.2.1 
Whole Blood Collected in EDTA Tubes 
 
To ship whole blood collected in 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 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 EDTA Tubes 
 
1. Ship whole blood collected in EDTA tube(s) 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://ricapps.nationwidechildrens.org/KitManagement/). Attach the air bill. 
9. 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: Testing of banked biospecimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in accordance with 
National Clinical Trials Network (NCTN) policies. 

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The patient’s biospecimen consent choices will be recorded on the signed informed consent 
document and electronically via the Specimen Consent form. At the time of biospecimen 
selection for project distribution, the most recent consent information will be used. 
 
Sites can amend a patient’s choices regarding the future use of her biospecimens at any 
time if the patient changes her mind. 
 
If the patient revokes permission to use her biospecimens, the NRG BB-Columbus will destroy 
or return any remaining biospecimens. The patient’s biospecimens will not be used for any 
further research; however, any biospecimens distributed for research prior to revoking consent 
cannot be returned or destroyed. In addition, the patient cannot be removed from any research 
that has been done with her biospecimens distributed prior to revoking consent. 
 
Note: If return of biospecimens is requested, shipping will be at the site’s expense. 
 
 

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APPENDIX XIV-BIOSPECIMEN BANK-COLUMBUS PATHOLOGY MATERIALS  
VERIFICATION FORM 
 
This form should be completed by the person in the pathology department who provides the 
FFPE materials to the requestor. Please return this form, along with the FFPE materials, to 
the requestor. The requestor must include this completed form with the shipment of FFPE 
materials. 
 
REQUIRED FFPE MATERIALS 
One of the following archival tumor types must be submitted (listed in order or preference): 
x recurrent (FRP01) or metastatic (FRM01) – i.e., collected prior to study treatment; 
x persistent primary (FPP01) or metastatic (FPM01) – i.e., collected prior to study 
treatment; or 
x primary (FP01) or metastatic (FM01) tumor – i.e., collected prior to any treatment. 
  
Only blocks will be accepted. Please provide Appendix XII 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) 
 
 
□ 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 XV– LETTER TO PATHOLOGISTS 
 
Dear Pathologist, 
 
Your site is a participant in NRG GY023, “A randomized phase II trial of triplet therapy (PD-L1 
inhibitor, durvalumab, in combination with olaparib and cediranib) compared to olaparib and 
cediranib or durvalumab (MEDI4736) and cediranib or standard of care chemotherapy in woman 
with platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal or fallopian cancer 
who have received prior bevacizumab.” 
 
This study includes exploratory biomarker testing, including PD-L1 and tumor infiltrating 
lymphocyte immunohistochemistry that requires all slides used must be fresh cut. 
 
Given the biospecimen requirements for this biomarker testing, NRG GY023 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 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. Jung-Min Lee (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, 
 
Jung-Min Lee, MD 
Heather A Lankes, PhD, MPH